Association of tumor necrosis factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: A meta-analysis of 14 case-control studies

Zhenlian Zhang; Dilihumaier Duolikun; Tingting Dang; Yuanyuan Wang; Lijuan Ma; Xueyun Ma; Qiaoling Yao

doi:10.1371/journal.pone.0290239

. 2023 Aug 18;18(8):e0290239. doi: 10.1371/journal.pone.0290239

Association of tumor necrosis factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: A meta-analysis of 14 case-control studies

Zhenlian Zhang ^1,^2,^#, Dilihumaier Duolikun ^1,^#, Tingting Dang ³, Yuanyuan Wang ³, Lijuan Ma ^1,², Xueyun Ma ^1,², Qiaoling Yao ^1,^2,^*

Editor: Cho Naing⁴

PMCID: PMC10437904 PMID: 37595008

Abstract

Although numerous studies have suggested the association between TNF-α-308G/A polymorphism and susceptibility to obstructive sleep apnea (OSA), the results remained controversial and ambiguous. We performed the present meta-analysis to derive a more precise estimation.The PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang databases, and Weipu databases (until January 8, 2022) were accessed to retrieve relevant articles. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were calculated using the STATA statistical software.Totally, fourteen studies involving 2595 cases and 2579 controls were enrolled in this meta-analysis. Pooled results demonstrated significant association between TNF-α-308G/A polymorphism and OSA risk for the overall population(allele model:OR = 1.87 [1.47, 2.38] (n = 14), dominant model: OR = 1.88[1.48, 2.39] (n = 14), recessive model:OR = 2.83 [2.00, 4.00] (n = 11), homozygous model:OR = 3.30 [2.32, 4.68] (n = 11), and heterozygous model:OR = 1.67 [1.36, 2.06] (n = 14); P<0.001, respectively).Subgroup analysis showed that in both Caucasians and Asians, the A allele conferred increased risk to OSA compared to the G allele (Caucasians: OR = 1.40[1.03, 1.90] (n = 5), P = 0.033, Asians: OR = 2.30 [1.62, 3.26] (n = 9), P< 0.001). In subgroup analysis restricted to hospital-based individuals, significant association between TNF-α-308G/A polymorphism and OSA risk was identified under each genetic model. Whereas, in population-based individuals, increased risk of OSA were only found in homozygous model (OR = 2.19[1.23, 3.90] (n = 3), P = 0.008) and recessive model (OR = 1.77 [1.00, 3.13] (n = 3), P = 0.048). There was a substantial between-study heterogeneity (I² = 69.10%) across studies which was explained by source of control participants (P = 0.036) by meta-regression. The results of leave-one-out meta-analysis and publication bias suggested the reliability and stability of our results.This meta-analysis suggested that TNF-α-308A allele may be a risk factor for the development of OSA. However, large scale,multi-center and well-designed case-control studies are needed in the future.

Introduction

Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder resulting from the repetitive obstruction of the upper airway during sleep with prevalence ranging from 9% to 38% in the general population. The prevalence rises with advancing age, male sex, and high body mass index [1]. Published studies reported the associations between OSA and increased risk of cardiovascular disease, cognitive impairment, cancer, and metabolic syndrome [2–5]. Although continuous positive airway pressure (CPAP) is the first-line therapy for OSA, improving its compliance and identifying novel therapy strategies are still actively studied. Thus, OSA remains a public health challenge around the world, up till now, its etiology and pathogenesis are not fully understood.

Recently, the heritability of OSA and the indices of OSA severity, such as apnea hypopnea index (AHI), respiratory disturbance index (RDI), and oxygen desaturation index (ODI) were reported by Szily and coworkers [6]. Moreover, published studies have shown that OSA is more prevalent in Asia than in Europe. Ethnic differences in severity and treatment were also illustrated, indicating the potential role of genetic factors in imparting the variance of OSA [7–9]. Genetic associations with OSA, including the tumor necrosis factor (TNF)-α-308G/A polymorphism, have been studied extensively [10]. This polymorphism is characterized by adenine (A) substituted for guanine (G), which induces the expression of TNF-α [11, 12]. Remarkably, compared with control subjects, patients with OSA have higher systemic TNF-α levels, which showed a positive correlation with OSA severity [13]. Taken together, these findings suggest that TNF-α-308G/A polymorphism may be involved in the pathogenesis of OSA.

Although numerous studies have investigated the association between TNF-α-308G/A polymorphism and susceptibility to OSA, the results remained controversial and ambiguous [14, 15], which may be related to ethnicity, source of control, genotyping method, sample size, and so on. TNF-α-308G/A polymorphism in the promoter region of TNF gene is reported to be closely associated with OSA risk [14, 16], whereas others are not [15, 17]. Despite previous meta-analyses have been conducted [18–21], a number of relevant studies are not enrolled in their meta-analyses [14–16, 22, 23]. Hence, we performed a meta-analysis to derive a more accurate evaluation of the association between TNF-α-308G/A polymorphism and OSA susceptibility in all available studies. Moreover, source of the control participants was firstly used for subgroup analyses and confirmed to be the potential source of between-study heterogeneity by meta-regression.

Materials and methods

Search strategy

The PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang databases, and Weipu databases (until January 8, 2022) were used to perform a systematic search for the identification of studies addressing the association of TNF-α-308 G/A polymorphism and OSA. The adopted appropriate combinations of search terms were as follows: “obstructive sleep apnea syndrome”, “OSAS”, “obstructive sleep apnea”, “OSA” and “tumor necrosis factor”, “TNF”, “tumor necrosis factor-a”, “TNF-α” and “polymorphism”, “gene”, “variant”, and “mutation”. A manual search was also performed by reviewing the references of relevant studies and review articles.

Inclusion and exclusion criteria

Studies that met the following criteria were included in the meta-analysis: (1) studies addressing the association of TNF-α-308 G/A polymorphism with OSA, (2) case–control design, (3) adequate genotype distributions in cases and controls, and (4) full-text studies published in English and Chinese. The exclusion criteria we adopted were as follows: (1) enrolled patients without OSA; (2) enrolled patients without available genotype distribution; (3) letter, editorial, review or meta-analysis, abstract, conference papers, case report, studies on animals or cell-lines; and (4) duplicate studies. The definition of OSA was as described in the primary studies.

Data extraction

The following data were extracted independently from each eligible study by two investigators (Zhang ZL and DD): first author’s surname, year of publication, country, ethnicity, age, body mass index, gender (male/female), AHI of cases and controls, source of control, controls matched for, genotype method, Hardy–Weinberg equilibrium (HWE) in controls, sample size, and genotype frequencies in cases and controls. Discrepancies were settled through consultation. We contacted the authors by email if detailed data were missing.

Quality assessment

The Newcastle–Ottawa Scale (NOS) captured the quality of eligible studies in terms of three parts, including “Selection”, “Comparability”, “Exposure”, stratified into by low- (0–3), moderate- (4–6), and high-quality (7–9) levels in accordance with scores.

Statistical analysis

The STATA statistical software (version 16.0) was used to carry out the meta-analyses. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the Z test to evaluate the association of TNF-α-308 G/A polymorphism with OSA risk under the following genetic models: dominant (AA + AG vs. GG), recessive (AA vs. AG + GG), homozygous (AA vs. GG), heterozygote (AG vs. GG) and allele (A allele vs. G allele) models. The Pearson’s χ2 test was performed to evaluate the HWE in control groups. The heterogeneity across studies was evaluated using the Cochran’s Q and the I² statistics. Significant heterogeneity was considered when P < 0.1 for the Q-test or I² > 50%. Thus, the random-effects model was applied to calculate the pooled ORs. Otherwise, the fixed-effects model was implemented. Subgroup analyses and meta-regression were conducted to explore potential sources of heterogeneity in total models according to ethnicity and source of control. The sensitivity analysis which was carried out with leave-one-out meta-analysis were performed for all genetic models to further confirm the reliability and stability of the results. Harbord funnel plot and Peters test were performed to access the publication bias for all models. P-value < 0.05 was considered to indicate statistical significance.

Results

Selection of studies

The process of study selection was presented in Fig 1. A total of 437 studies were initially identified through the database described above. 196 studies were screened after removing duplicates. By screening titles and abstracts, 148 studies were excluded because they were 1) meta-analyses or reviews (n = 29), 2) letters, editorials, abstracts, and case reports (n = 10), 3) studies on animals or cell lines (n = 61), 4) studies not on TNF-α (n = 34), studies not for case-control study(n = 1), and 5) studies not on OSA (n = 13). A total of 48 full-text articles were further assessed for eligibility, and 34 articles were excluded because they were not for TNF-α rs1800629 (n = 33) or had insufficient data (n = 1) [24]. Finally, 14 studies were eligible for the inclusion criteria and enrolled in this meta-analysis with a total number of 5174 subjects consisting of 2595 cases and 2579 controls [14–17, 22, 23, 25–32].

Characteristics of the included studies

As summarized in Table 1, all eligible studies were published from 2005 to 2021. In terms of study populations, nine studies were conducted in Asian and five in Caucasian. The sources of the control participants were hospital-based (HB) in nine studies and population-based (PB) in five studies. The polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), TaqMan assay, DNA sequencing, KASP and Mass Array technology were used to identify the genotype in eligible studies. The HWE test was conducted for the control group in each eligible study. Only one study did not conform to the HWE law (P < 0.05) [26]. All eligible studies were of moderate or high quality according to the NOS quality assessment.

Table 1. Basic characteristics of included studies.

author	year	case	control	case			control			HWE	source of control participants	genotype method	country	ethnicity	Quality score
author	year	case	control	GG	AG	AA	GG	AG	AA	HWE	source of control participants	genotype method	country	ethnicity	Quality score
Riha [32]	2005	103	190	52	44	7	130	52	8	0.344	PB	TaqMan	UK	Caucasian	8
Li [30]	2006	24	48	11	10	3	35	12	1	0.981	HB	TaqMan	China	Asian	8
Liu [31]	2006	76	42	45	23	8	35	6	1	0.268	HB	PCR-RFLP	China	Asian	8
Popko [28]	2008	102	77	73	29	0	59	18	0	0.246	PB	PCR-RFLP	Poland	Caucasian	9
Bhushan [26]	2009	104	103	74	22	8	90	10	3	0.001	HB	PCR-RFLP	Indians	Asian	8
Karkucak [27]	2012	69	42	51	18	0	33	9	0	0.437	HB	PCR-RFLP	Turkish	Caucasian	8
Almpanidou [25]	2012	220	319	118	83	19	221	84	14	0.107	PB	PCR-RFLP	Greek	Caucasian	9
Guan [29]	2013	531	162	430	95	6	143	18	1	0.604	HB	PCR-RFLP	China	Asian	8
Li [17]	2013	155	100	137	18	0	88	12	0	0.523	PB	DNA sequencing	China	Asian	8
Wang [22]	2014	78	78	54	16	8	66	10	2	0.057	HB	PCR-RFLP	China	Asian	8
Petrek [15]	2015	116	351	85	30	1	248	98	5	0.175	PB	Mass Array technology	Czech	Caucasian	5
Zhu [16]	2015	200	200	124	46	30	166	31	3	0.278	HB	DNA sequencing	China	Asian	8
Zhang [14]	2019	750	800	576	153	21	656	132	12	0.077	HB	TaqMan	China	Asian	8
Abulikemu [23]	2021	67	67	42	20	5	60	6	1	0.098	HB	KASP	China	Asian	7

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Abbreviation

HWE, Hardy-Weinberg equilibrium

PB,population-based

HB,hospital-based

PCR-RFLP:polymerase chain reaction-restriction fragment length polymorphism

KASP,kompetitive allele specific PCR.

Quantitative synthesis

Pooled results demonstrated significant association between TNF-α-308G/A polymorphism and OSA risk for overall population under specific genetic models (Fig 2A and Table 2) (allele model:OR = 1.87 [1.47, 2.38] (n = 14), dominant model: OR = 1.88[1.48, 2.39] (n = 14), recessive model:OR = 2.83 [2.00, 4.00] (n = 11), homozygous model:OR = 3.30 [2.32, 4.68] (n = 11), and heterozygous model:OR = 1.67[1.36, 2.06] (n = 14); P<0.001, respectively).Subgroup analysis according to ethnicity showed that in both Caucasians and Asians, the A allele conferred increased risk to OSA compared to the G allele(Fig 2B and Table 2) (Caucasians: OR = 1.40[1.03, 1.90] (n = 5), P = 0.033, Asians: OR = 2.30 [1.62, 3.26] (n = 9), P< 0.001). In subgroup analysis restricted to HB individuals, significant association between TNF-α-308G/A polymorphism and OSA risk was identified under each genetic model (Fig 2C and Table 2). Whereas, in PB individuals, increased risk of OSA were only found in homozygous model (OR = 2.19[1.23, 3.90] (n = 3), P = 0.008) and recessive model (OR = 1.77 [1.00, 3.13] (n = 3), P = 0.048) (Table 2).

Fig 2 — A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

Table 2. Meta-analysis results of association between TNF-α-308G/A polymorphism and OSA.

Contrast model		Subjects (cases/controls)	Studies,n	OR (95%CI)	P ^*	I²(%)
Total studies
allele model	A vs. G	5190/5158	14	1.87 (1.47, 2.38)	0	69.10
dominant model	AA/AG vs. GG	2595/2579	14	1.88(1.48, 2.39)	0	59.50
recessive model	AA vs. AG/GG	2269/2360	11	2.83 (2.00, 4.00)	0	15.00
homozygous model	AA vs. GG	2269/2360	11	3.30 (2.32, 4.68)	0	20.80
heterozygous model	AG vs. GG	2595/2579	14	1.67 (1.36, 2.06)	0	38.80
Subgroup analysis
Caucasians
allele model	A vs. G	1220/1958	5	1.40(1.03, 1.90)	0.033	53.50
dominant model	AA/AG vs. GG	610/979	5	1.48 (1.03, 2.13)	0.035	56.30
recessive model	AA vs. AG/GG	439/860	3	1.77 (1.00, 3.13)	0.048	0.00
homozygous model	AA vs. GG	439/860	3	2.19 (1.23, 3.90)	0.008	0.00
heterozygous model	AG vs. GG	610/979	5	1.46 (1.04, 2.06)	0.029	48.10
Asians
allele model	A vs. G	3970/3200	9	2.30 (1.62, 3.26)	0	72.60
dominant model	AA/AG vs. GG	1985/1600	9	2.23 (1.59, 3.14)	0	62.80
recessive model	AA vs. AG/GG	1830/1500	8	3.51 (2.06, 5.98)	0	11.00
homozygous model	AA vs. GG	1830/1500	8	4.22 (2.32, 7.67)	0	23.10
heterozygous model	AG vs. GG	1985/1600	9	1.86 (1.40, 2.47)	0	39.60
Subgroup analysis
HB
allele model	A vs. G	3798/3084	9	2.37 (1.68, 3.32)	0	70.40
dominant model	AA/AG vs. GG	1899/1542	9	2.30 (1.66, 3.20)	0	58.70
recessive model	AA vs. AG/GG	1830/1500	8	3.51 (2.06, 5.98)	0	11.00
homozygous model	AA vs. GG	1830/1500	8	4.22 (2.32, 7.67)	0	23.10
heterozygous model	AG vs. GG	1899/1542	9	1.89 (1.45, 2.47)	0	31.40
PB
allele model	A vs. G	1392/2074	5	1.35 (0.98, 1.85)	0.068	58.40
dominant model	AA/AG vs. GG	696/1037	5	1.41 (0.97, 2.06)	0.074	61.40
recessive model	AA vs. AG/GG	439/860	3	1.77 (1.00, 3.13)	0.048	0.00
homozygous model	AA vs. GG	439/860	3	2.19 (1.23, 3.90)	0.008	0.00
heterozygous model	AG vs. GG	696/1037	5	1.40 (0.98, 2.00)	0.066	54.50

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Abbreviation

HB: hospital-based

PB: population-based

Note:P^*:P value for pooled OR.

Heterogeneity and sensitivity analysis

Significant between-study heterogeneity was considered in overall pooled analysis under allele, dominant and heterozygous models. Thus, random-effects model was applied to calculate the pooled ORs. Meta-regression was conducted to explore potential source of between-study heterogeneity, showing that the source of control participants caused the heterogeneity between studies in allele model (P = 0.036) (Fig 3A). However, we did not find the potential source of heterogeneity in dominant(P = 0.216 for ethnicity, P = 0.124 for source of control participants) and heterozygous models(P = 0.303 for ethnicity, P = 0.181 for source of control participants). Additionally, as presented in Fig 3B, results of leave-one-out meta-analysis showed no significant effect on the pooled ORs by any single study. Moreover, while omitting one study without confirmation of HWE [26], pooled ORs were not noticeably changed (OR = 1.83[1.42, 2.35]), further confirming the reliability and stability of present meta-analysis.

Fig 3 — A: meta-regression(P = 0.036); B: sensitivity analysis; C: Harbord funnel plot (Harbord test *P =* 0.368, Peters test *P =* 0.120).

Publication bias

Harbord funnel plot and Peters test were performed to estimate publication bias under all genetic models, and no evidence of publication bias was found in this meta-analysis (A vs. G: Harbord test P = 0.368, Peters test P = 0.120; AA/AG vs. GG: Harbord test P = 0.212, Peters test P = 0.097; AA vs. AG/GG: Harbord test P = 0.810, Peters test P = 0.300; AA vs. GG: Harbord test P = 0.921, Peters test P = 0.266; AG vs. GG: Harbord test P = 0.131, Peters test P = 0.084) (Fig 3C).

Discussion

On the basis of 14 studies involving 2595 cases and 2579 controls, the present meta-analysis aimed to clarify the association between TNF-α-308G/A polymorphism and susceptibility of OSA. Pooled results demonstrated a significant association of TNF-α-308A allele and increased risk of OSA (OR = 1.87 [1.47, 2.38], P < 0.001), indicating that TNF-α-308A allele may be a risk factor for the development of OSA.

Furthermore, results of subgroup analysis remarkably showed a 1.40-fold increased risk of OSA for Caucasians and a 2.30-fold increased risk of OSA for Asians with allele A, suggesting the significant influence of ethnicity on OSA risk. This finding is consistent under different genetic models and may explain the higher prevalence of OSA in Asians than in Europeans [9]. Moreover, under allele model, stratified analysis by source of control showed increased risk of OSA in HB studies (OR = 2.37 [1.68, 3.32], P < 0.001) but not in PB studies (P = 0.068), indicating that certain aspects of the study design may affect the results of a case–control study. Besides, results of the codominant model proved that carrying either genotype AA or genotype AG would put people at higher risk for OSA, which is consistent with the findings that level of TNF-α for individuals with genotypes AG and AA is higher than that of individuals with genotype GG [33].

Evidence showed that TNF inhibition was associated with decreased risk of OSA [34]. Interestingly, evidence demonstrated a high level of circulating TNF-α in patients with OSA, indicating that TNF-α may be a promising circulating biomarker to assess the degree of OSA [13, 35–37]. We have comprehensively analyzed the results of 14 studies through present meta-analysis and found increased risk of OSA in those with TNF-α-308A allele, which may be explained by elevated TNF-α expression via regulating the promoter transcriptional activity [12].Moreover,TNF-α gene lies in the highly polymorphic major histocompatibility complex (MHC) region. Apart from TNF-α-308 G/A polymorphism, TNF-α-238 G/A (rs361525), TNF-α-857G/A (rs1799724), and TNF-α-1031 T/C (rs1799964) are identified. Therefore, the linkage disequilibrium between alleles across the MHC may be involved in regulating the expression of TNF-α. In addition to gene-gene interactions, gene-environment interactions may also play a role in regulating TNF-α expression and thus participating in the pathogenesis of OSA.Thus, although our results showed that TNF-α-308G/A polymorphism was an important gene locus affecting risk of OSA, the mechanism is complex and should be further studied.

Previous meta-analyses were conducted by Varvarigou et al. in 2011 (three studies) [20], Huang et al. in 2012 (four studies) [21], Zhong et al. in 2014 (seven studies) [19], and Wu et al. in 2014 (ten studies) [18]. Similar to the above meta-analyses, our results demonstrated a significant association of TNF-α-308A allele and increased risk of OSA. However, our meta-analysis was on the basis of 14 case–control studies involving 2595 cases,while the largest sample size in previous meta-analyses was 10 studies with 1522 patients [18], providing more convincing and precise evidence that TNF-α-308G/A polymorphism increased the susceptibility to OSA. Statistical similar OSA risk were observed both in European (1.68-fold) and Asian population (2.02-fold) carrying A allele by Wu et al. [18], whereas higher risk of OSA for Asians with allele A(2.30-fold) than Caucasians(1.40-fold) was found in the present meta-analysis. Moreover, source of control participants was firstly used for subgroup analyses, showing that TNF-α-308A allele increases the risk of OSA in HB case–control studies but not in PB studies, suggesting the influence of study design on results. Additionally, we further performed meta-regression and found that source of control participants may be the potential source of heterogeneity

Study limitations

Although the results of sensitivity analysis and publication bias suggested the stability of our results, some limitations should be considered. First, language bias resulted from limitation to publication in English and Chinese. Second, the confounding bias created by unavailable factors in most eligible studies like sex, age, body mass index, life style, AHI, comorbidities, other gene polymorphisms that may play important roles in the pathophysiology of OSA. Third, sampling bias resulted from enrolling a study unconforming to HWE law [26]. Fourth, there could be additional factors that have not been included in this review.

In summary, the present meta-analysis indicated significant association between allele A and increased susceptibility of OSA. However, large scale,multi-center and well-designed case-control studies are also needed in the future. Meanwhile, it is also of great significance to explore the mechanism of TNF-α-308 G/A polymorphism involved in OSA pathogenesis.

Supporting information

S1 Table. PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.^{(30.9KB, docx)}

S2 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(15.1KB, docx)}

S1 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the dominant model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(1,017.9KB, tif)}

S2 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the recessive model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(975.7KB, tif)}

S3 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the homozygous model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(982.5KB, tif)}

S4 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the heterozygous model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(1,019.1KB, tif)}

Acknowledgments

We appreciate the contribution of participants and researchers in the studies included in this review.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was supported by Natural Science Foundation of Xinjiang Uygur Autonomous Region (No.2021D01C278) received by ZZL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0290239.r001

Decision Letter 0

Maria Elisabeth Johanna Zalm

9 Aug 2022

PONE-D-22-04764Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: An updated meta-analysis of 14 case-control studiesPLOS ONE

Dear Dr. Yao,

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

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Reviewer #1: Yes

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Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript is a meta-analysis of the association between Tumor Necrosis Factor-α-308G/A polymorphism and obstructive sleep apnea. The statistical analysis of 14 case-control studies selected for this review was conducted rigorously and this meta-analysis is appropriately based on the Prisma checklist. The introduction of this manuscript reported previous meta-analyses in this area and explained that they included additional case-control studies.

The conclusions are based on the findings obtained through adequate statistical analysis. However, the discussion should include some limitations related to the genetic association studies and the fact that the studies included in this meta-analysis did not report the effect of AIH (apnea, hypoapnea index), oxygen saturation levels, arousals, comorbidities, sex, age, and other factors that could play an important role in the pathophysiology of the obstructive sleep apnea.

The methodology is appropriate and rigorous. The inclusion and exclusion criteria are well formulated. The statistical analysis used in this meta-analysis included: Pearson’s χ2 test performed to evaluate the Hardy–Weinberg equilibrium (HWE), Cochran’s Q and the I2 statistics to evaluate heterogeneity, Z and OR test to evaluate genetic models, Harbord funnel plot and Peters test to identify publication bias. The results of these analyses are shown in tables and figures (forest plots, Harbord funnel plot) and show complete information about the association between Tumor Necrosis Factor-α-308G/A polymorphism and obstructive sleep apnea reported in case-control studies.

Data from each case-control study is described in the manuscript. Prisma checklist is supporting information. Complete and broad statistic results are shown. The references included the articles selected for this meta-analysis and previous meta-analyses among others.

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Reviewer #1: Yes: Liliana Otero

**********

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Attachment

Submitted filename: PLOS ONE Reviewer TNFa.pdf

Click here for additional data file.^{(53.7KB, pdf)}

PLoS One. 2023 Aug 18;18(8):e0290239. doi: 10.1371/journal.pone.0290239.r002

Author response to Decision Letter 0

18 Sep 2022

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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Response: Thank you for this comment. We have carefully revised the manuscript according to the PLOS ONE style templates.All the revised portions of the manuscript are now marked in red (except in the clean version of the revised manuscript, also submitted).

Response: Thank you for this comment. Participant consent is not applicable since the present meta-analysis was based on published data.

3. Thank you for stating in your Funding Statement:

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

Response: Thank you for this comment. The amended Funding Statement marked in red has been within our cover letter accordingly.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

Response: Thank you for this comment. Since the present meta-analysis was based on published data, all relevant data are within the manuscript and its Supporting information files.The updated Data Availability statement marked in red has been within our cover letter accordingly.

Response: Thank you for this comment. We have listed Supporting Information captions at the end of the manuscript in a section titled “Supporting information”.

Reviewer #1:

This manuscript is a meta-analysis of the association between Tumor Necrosis Factor-α-308G/A polymorphism and obstructive sleep apnea. The statistical analysis of 14 case-control studies selected for this review was conducted rigorously and this meta-analysis is appropriately based on the Prisma checklist. The introduction of this manuscript reported previous meta-analyses in this area and explained that they included additional case-control studies.

Response: Thank you for your comment.According to your suggestion, we have revised the second limitation in discussion:The etiology of OSA is likely multifactorial, however, sex, age, body mass index, life style, AHI, comorbidities, other gene polymorphisms and other factors that may play important roles in the pathophysiology of OSA were not available in most eligible studies. Therefore gene–gene or gene–environment interactions were not evaluated in the present meta-analysis.Thus, the second limitation may be unadjusted pooled estimates by potential confounding factors.

Thank you and best regards.

Yours sincerely,

Qiao ling Yao

Corresponding author:Qiao-ling Yao,PhD

Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China.

Email: 49165627@ qq.com

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(17.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0290239.r003

Decision Letter 1

Cho Naing

20 Feb 2023

PONE-D-22-04764R1Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: An updated meta-analysis of 14 case-control studiesPLOS ONE

Dear Dr. Yao,

Please submit your revised manuscript by Apr 06 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Cho Naing, MBBS, PhD, FRCP

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: An updated meta-analysis of 14 case-control studies

Abstract

Line # 31

OSA was used for the first time in this section; kindly spell it out.

Line # 35

Please replace the term ‘used” with “accessed”

As the authors describe how to estimate association in the current metanalysis, it should be "pooled odds ratio or summary odds ratio."

Line # 40-42; Line # 44-45; Line # 48-49

Please provide number of studies for the respective effect estimates.

Line # 49-50

“Substantial between-study heterogeneity” is preferable.

“ p value” of the I2 test should be deleted.

Line # 51

Better to describe as “Source of control participants”.

What sensitivity analysis is it for? Please provide specifically.

Sensitivity analysis for "source of control participants" was reported in the text.

In the abstract, I feel a lack of recommendation in the conclusions. Based on the study limitations that the authors identified during the current research, please suggest future well-designed case control studies, etc.

TEXT

Line # 87

Please omit the word "an updated". Publications from the past were not done by this team.

Search Strategy

Please provide “search strategy for PubMed and Embase in supplementary so that the audiences can replicate.

Line #101

Criteria # 1 is a doubtful. Did you select studies that showed only susceptible to OSA, but not protective. In earlier part, the authors claimed that “the results (from single studies) remained controversial and ambiguous”.

The authors should have selected studies that assessed association between TNF-α-308G/A polymorphisms and OSA (regardless of direction of association)

Line # 111

“The definition of OSA was as described in the primary studies” is preferable.

Line # 117

HWE should have been spelled out as the authors didn't use an abbreviation.

Line # 120

"Missing" is preferable than "ambiguous" as a description.

Line # 124

To the best of my understanding, the NOS checklist is a 9-star tool, with 9 being the highest possible star/score. It is impossible to score more than 9.

Line # 117

The abbreviation HWE may be used at this juncture (please refer to my comments on line #117).

Line # 155; 172-175; 178 Please provide number of studies for the respective effect estimates.

Line #188

This should come at the top of this paragraph.

Line # 198

For the dominant model and heterozygous models, please provide p values. What about the remaining models?

Please remove p value for I2 test.

Table #2

Please remove the last column with I2 test p value.

Discussion

This section requires more efforts.

As this is a meta-analysis, citations to individual studies should be reduced/shortened.

Please briefly describe how the current study and previous reviews in this field are compared and contrasted.

Please use a subheading of the “study limitations” for clarity

To add a recommendation as a concluding remark. Please note my recommendation for this section of the abstract.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: The manuscript was well written. Introduction clearly and adequately stated the background of the current issue of the obstructive sleep apnea. Nevertheless, there are some suggestions as follow.

Results:

Table 1- Basic Characteristics of included studies

In this table, suggest to provide reference number in addition to author names.

In figures, it would be great if authors could provide the forest plots of effect estimates for each genetic models as a supplemenatary file.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

**********

PLoS One. 2023 Aug 18;18(8):e0290239. doi: 10.1371/journal.pone.0290239.r004

Author response to Decision Letter 1

5 Apr 2023

Dear Editor and Reviewers,

Thank you very much for all your insightful comments and suggestions. They have been very helpful. We carefully modified the manuscript accordingly. All the revised portions of the manuscript are now marked in red (except in the clean version of the revised manuscript, also submitted). Please, see below for our responses (in blue) to all the comments/suggestions.

Journal Requirements:

1.Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: Thank you for this comment. We have carefully reviewed reference list and ensureed that it is complete and correct.

Additional Editor Comments:

Abstract

Line # 31

OSA was used for the first time in this section; kindly spell it out.

Response: Thank you for this comment. We have spelled it out.

Line # 35

Please replace the term ‘used” with “accessed”

As the authors describe how to estimate association in the current metanalysis, it should be "pooled odds ratio or summary odds ratio."

Response: Thank you for this comment. We have replaced the term “used” , “pooled odds ratio” with “accessed”and “pooled odds ratio”,respectively.

Line # 40-42; Line # 44-45; Line # 48-49

Please provide number of studies for the respective effect estimates.

Response: Thank you for this comment. We have provided number of studies for the respective effect estimates.

Line # 49-50

“Substantial between-study heterogeneity” is preferable.

“ p value” of the I2 test should be deleted.

Response: Thank you for this comment. We have replaced the term “statistically significant heterogeneity” with “Substantial between-study heterogeneity”. “ p value” of the I2 test has be deleted.

Line # 51

Better to describe as “Source of control participants”.

Response: Thank you for this comment. We have replaced the term “source of control” with “Source of control participants”.

What sensitivity analysis is it for? Please provide specifically. Sensitivity analysis for "source of control participants" was reported in the text.

Response: Thank you for this comment. Sensitivity analysis refers to the method of testing the robustness of the results obtained under certain assumptions, and observing whether the pooled results have changed before and after changing some important factors, so as to judge the robustness of the results of meta-analysis. In this study,we conducted a sensitivity analysis by removing individual studies one by one to observe the difference between the combined and total effects of the remaining studies, and examined the impact of individual studies. As described in line199-200: as presented in Fig 3B, results of sensitivity analysis showed no significant effect on the pooled ORs by any single study, further confirming the reliability and stability of the results.

Response: Thank you for this comment. Recommendation has been added in the conclusions:However, large scale,multi-center and well-designed case-control studies are also needed in the future.

TEXT

Line # 87

Please omit the word "an updated". Publications from the past were not done by this team.

Response: Thank you for this comment. The word "an updated" has been omitted.

Search Strategy

Please provide “search strategy for PubMed and Embase in supplementary so that the audiences can replicate.

Response: Thank you for this comment. Search strategy has been provided in S2 table.

Line #101

The authors should have selected studies that assessed association between TNF-α-308G/A polymorphisms and OSA (regardless of direction of association)

Response: Thank you for this comment.The word " the susceptibility of " has been omitted.

Line # 111

“The definition of OSA was as described in the primary studies” is preferable.

Response: Thank you for this comment. We have replaced the term “the definition of OSA used in each eligible study was accepted” with “The definition of OSA was as described in the primary studies”.

Line # 117

HWE should have been spelled out as the authors didn't use an abbreviation.

Response: Thank you for this comment. We have spelled it out.

Line # 120

"Missing" is preferable than "ambiguous" as a description.

Response: Thank you for this comment. We have replaced the term “ambiguous” with “Missing”.

Line # 124

To the best of my understanding, the NOS checklist is a 9-star tool, with 9 being the highest possible star/score. It is impossible to score more than 9.

Response: Thank you for this comment. We have changed it to 9.

Line # 117

The abbreviation HWE may be used at this juncture (please refer to my comments on line #117).

Response: Thank you for this comment. The abbreviation HWE has been used.

Line # 155; 172-175; 178 Please provide number of studies for the respective effect estimates.

Response: Thank you for this comment. We have provided number of studies for the respective effect estimates.

Line #188

This should come at the top of this paragraph.

Response: Thank you for this comment. It has been at the top of this paragraph

Line # 198

For the dominant model and heterozygous models, please provide p values.

Response: Thank you for this comment. P values for the dominant model and heterozygous models have been provided.

What about the remaining models?

Response: Thank you for this comment. Meta-regression was conducted to explore potential source of between-study heterogeneity, therefore, we only conducted meta-regression analysis on allele,dominant and heterozygous models.

Please remove p value for I2 test.

Response: Thank you for this comment. We did not remove the P value(P=0.036) because it is the P value of meta regression.

Table #2

Please remove the last column with I2 test p value.

Response: Thank you for this comment. We have removed the last column with I2 test p value.

Discussion

This section requires more efforts.

As this is a meta-analysis, citations to individual studies should be reduced/shortened.

Please briefly describe how the current study and previous reviews in this field are compared and contrasted.

Response: Thank you for this comment. We have carefully modified the discussion.

Please use a subheading of the “study limitations” for clarity

Response: Thank you for this comment. Subheading of the “study limitations” has been added.

To add a recommendation as a concluding remark. Please note my recommendation for this section of the abstract.

Response: Thank you for this comment.Recommendation has been added: however, large scale,multi-center and well-designed case-control studies are also needed in the future. Meanwhile, it is also of great significance to explore the mechanism of TNF-α-308 G/A polymorphism involved in OSA pathogenesis.

Reviewers' comments:

Review Comments to the Author

Results:

Table 1- Basic Characteristics of included studies

In this table, suggest to provide reference number in addition to author names.

Response: Thank you for this comment. Reference number has been added in table1.

In figures, it would be great if authors could provide the forest plots of effect estimates for each genetic models as a supplemenatary file.

Response: Thank you for this comment. The forest plots of effect estimates for each genetic models have been provided as supplemenatary figures.

Thank you and best regards.

Yours sincerely,

Qiao ling Yao

Corresponding author:Qiao-ling Yao,PhD

Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China.

Email: 49165627@ qq.com

Mobile Number:15022917911

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(22.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0290239.r005

Decision Letter 2

Cho Naing

2 May 2023

PONE-D-22-04764R2Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: An updated meta-analysis of 14 case-control studiesPLOS ONE

Dear Dr. Yao,

Please submit your revised manuscript by Jun 16 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Cho Naing, MBBS, PhD, FRCP

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments:

Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: An updated meta-analysis of 14 case-control studies"

The authors still need to revise an array of points. I also recommend reviewing the manuscript for language proficiency.

Title

Regarding my background comments, the phrase "an updated" has to be removed from the title.

Previous publications were not done by this team.

Abstract

Line #32………. “Obstructive” should not be capitalized

Line #41……… Please include the names of genetic models that were created for overall population. I believe that overall population was assessed using five different genetic models such as allele. "Dominant, recessive, homozygous, and heterozygous models"

Line # 47, 49……….. To spell out HB and PB

Line # 50…………. Name the genetic models for AA in comparison to GG, AG/GG

Line # 53…………. The statement "a leave-one-out meta-analysis" should be applied.

Line # 56……… Take out the word “also”

TEXT

Line # 63……….. replacing "published studies reported" for "increasing evidence has demonstrated" Line # 68/ 69………. Please rephrase this sentence. The word "thus" was used twice

Line # 72………. The wording "by Szily and coworkers or By Szily and associates" should have been used.

Line # 72………. Replace the word "strong evidence" with lighter tone, like "published studies."

Line # 78, 79, 80…… The authors could combine these two sentences into one and then cite [13] afterward.

Line # 90………. “Hence” is a preferrable term.

Line # 92………. “Source of the control participants”

Line # 114……… Please, remove “additionally”.

Line # 133……… Please keep "homozygous" and "heterozygous" while removing "codominant."

Line # 138……The word .”Otherwise” is preferrable to “By contrast”..

Line # 141……. So as to differentiate it from statistical models (Random. Fixed models), it needs to be mentioned as "for all genetic models".

Line # 141-142………… Are you referring to "a leave-one-out metanalysis" for the stability of the results.

Line # 146……… Literature search and characteristics of included studies.

Please separate the subheadings into two sections, such as "Selection of Studies" and "Characteristics of the Included Studies."

Line # 157……… This sentence should be placed at the beginning of paragraph, “Selection of studies”.

Line # 160, 165 and 166……… It is better to use "eligible". (Please follow this suggestion wherever it is applicable.)

Line # 162……… Source of the control participants?

Line # 167-168……… Please rephrase this sentence.

Table 1…….. Footnotes are incomplete. HB? PB?

Last column…….. Quality score?

Line # 175……… Please add the names of the genetic models for the audiences' convenience. Apply this recommendation to Table 2 as well by including a new column for the genetic model's name.

Line # 204-205………Please clearly indicate that the results are "results of a leave-one-out metanalysis" (also see my comments on Lines 53 and 141–142).

Study limitations

Line # 273…………….. Stability is an appropriate term. What about the reliability? Which analysis/results captured the reliability?

Line # 273…………….. Language bias or information bias?

Line # 275-283……………..Please rephrase the sentences and shorten it.

First, language bias/informational bias? Second, the confounding bias created by……. Third, not all studies conform to the HWE. So, what type of bias? Fourth, there could be additional factors that have not been included in this review.

Acknowledgements

Are you thanking your research team members or the participants and researchers in the studies included in your review? Please clarify.

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2023 Aug 18;18(8):e0290239. doi: 10.1371/journal.pone.0290239.r006

Author response to Decision Letter 2

15 Jun 2023

Dear Editor and Reviewers,

Journal Requirements:

1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: Thank you for this comment. We have carefully reviewed reference list and ensureed that it is complete and correct.

Additional Editor Comments:

Title

Regarding my background comments, the phrase "an updated" has to be removed from the title.

Previous publications were not done by this team.

Response: Thank you for this comment. The phrase "an updated" has been removed from the title.

Abstract

Line #32………. “Obstructive” should not be capitalized

Response: Thank you for this comment. “Obstructive” has been capitalized.

Response: Thank you for this comment. The names of genetic models that were created for overall population has been included.

Line # 47, 49……….. To spell out HB and PB

Response: Thank you for this comment. HB and PB have been spelled out.

Line # 50…………. Name the genetic models for AA in comparison to GG, AG/GG

Response: Thank you for this comment. We have named the genetic models for AA in comparison to GG, AG/GG.

Line # 53…………. The statement "a leave-one-out meta-analysis" should be applied.

Response: Thank you for this comment. The statement "a leave-one-out meta-analysis" has been applied.

Line # 56……… Take out the word “also”

Response: Thank you for this comment. The word “also” has been taken out.

TEXT

Line # 63……….. replacing "published studies reported" for "increasing evidence has demonstrated"

Response: Thank you for this comment. We have replaced "published studies reported" for "increasing evidence has demonstrated".

Line # 68/ 69………. Please rephrase this sentence. The word "thus" was used twice

Response: Thank you for this comment. We have.rephrased this sentence.

Line # 72………. The wording "by Szily and coworkers or By Szily and associates" should have been used.

Response: Thank you for this comment. The wording "by Szily and coworkers" has been used.

Line # 72………. Replace the word "strong evidence" with lighter tone, like "published studies."

Response: Thank you for this comment. We have replaced "strong evidence" for "published studies".

Line # 78, 79, 80…… The authors could combine these two sentences into one and then cite [13] afterward.

Response: Thank you for this comment. We have combined these two sentences into one and then cited [13] afterward.

Line # 90………. “Hence” is a preferrable term.

Response: Thank you for this comment. We have replaced "Herein" for " Hence ".

Line # 92………. “Source of the control participants”

Response: Thank you for this comment. We have replaced "control source " for " source of the control participants".

Line # 114……… Please, remove “additionally”.

Response: Thank you for this comment. We have removed “additionally”.

Line # 133……… Please keep "homozygous" and "heterozygous" while removing "codominant."

Response: Thank you for this comment. We have removed “codominant”.

Line # 138……The word .”Otherwise” is preferrable to “By contrast”..

Response: Thank you for this comment. We have replaced "By contrast" for "Otherwise ".

Line # 141……. So as to differentiate it from statistical models (Random. Fixed models), it needs to be mentioned as "for all genetic models".

Response: Thank you for this comment. We have replaced "for all models " for " for all genetic models ".

Line # 141-142………… Are you referring to "a leave-one-out metanalysis" for the stability of the results.

Response: Thank you for this comment.Yes.

Line # 146……… Literature search and characteristics of included studies.

Please separate the subheadings into two sections, such as "Selection of Studies" and "Characteristics of the Included Studies."

Response: Thank you for this comment. We have separated the subheadings into "Selection of Studies" and "Characteristics of the Included Studies."

Line # 157……… This sentence should be placed at the beginning of paragraph, “Selection of studies”.

Response: Thank you for this comment. This sentence “The process of study selection was presented in Fig 1.” has been placed at the beginning of paragraph “Selection of studies”.

Line # 160, 165 and 166……… It is better to use "eligible". (Please follow this suggestion wherever it is applicable.)

Response: Thank you for this comment. We have replaced "enrolled " for " eligible ".

Line # 162……… Source of the control participants?

Response: Thank you for this comment. "Source of the control participants " has been used.

Line # 167-168……… Please rephrase this sentence.

Response: Thank you for this comment.We have rephrased this sentence.

Table 1…….. Footnotes are incomplete. HB? PB?

Last column…….. Quality score?

Response: Thank you for this comment.” PB,population-based; HB,hospital-based ” have been existed in footnotes. We have replaced " score " for " Quality score " in last column.

Line # 175……… Please add the names of the genetic models for the audiences' convenience. Apply this recommendation to Table 2 as well by including a new column for the genetic model's name.

Response: Thank you for this comment. We have added the names of the genetic models and included a new column for the genetic model's name in Table 2.

Line # 204-205………Please clearly indicate that the results are "results of a leave-one-out metanalysis" (also see my comments on Lines 53 and 141–142).

Response: Thank you for this comment. We have replaced "sensitivity analysis " for " eligible " leave-one-out meta-analysis".

Study limitations

Line # 273…………….. Stability is an appropriate term. What about the reliability? Which analysis/results captured the reliability?

Response: Thank you for this comment. “Reliability” has been removed.

Line # 273…………….. Language bias or information bias?

Line # 275-283……………..Please rephrase the sentences and shorten it.

Response: Thank you for this comment. We have modified it as follows: First, language bias resulted from limition to publication in English and Chinese. Second, the confounding bias created by unavailable factors in most eligible studies like sex, age, body mass index, life style, AHI, comorbidities, other gene polymorphisms that may play important roles in the pathophysiology of OSA. Third, sampling bias resulted from enrolling a study unconforming to HWE law. Fourth, there could be additional factors that have not been included in this review.

Acknowledgements

Are you thanking your research team members or the participants and researchers in the studies included in your review? Please clarify.

Response: Thank you for this comment. We have modified it as follows: We appreciate the contribution of participants and researchers in the studies included in this review.

Thank you and best regards.

Yours sincerely,

Qiao ling Yao

Corresponding author:Qiao-ling Yao,PhD

Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China.

Email: 49165627@ qq.com

Mobile Number:15022917911

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(22KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0290239.r007

Decision Letter 3

Cho Naing

7 Aug 2023

Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: A meta-analysis of 14 case-control studies

PONE-D-22-04764R3

Dear Dr. Yao,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Cho Naing, MBBS, PhD, FRCP

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have improved the manuscript, accordingly.

Thank you.

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0290239.r008

Acceptance letter

Cho Naing

11 Aug 2023

PONE-D-22-04764R3

Association of Tumor Necrosis Factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: A meta-analysis of 14 case-control studies

Dear Dr. Yao:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Cho Naing

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.^{(30.9KB, docx)}

S2 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(15.1KB, docx)}

S1 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the dominant model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(1,017.9KB, tif)}

S2 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the recessive model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(975.7KB, tif)}

S3 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the homozygous model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(982.5KB, tif)}

S4 Fig. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the heterozygous model.

A: overall results; B: subgroup analysis by ethnicity; C: subgroup analysis by source of control.

(TIF)

Click here for additional data file.^{(1,019.1KB, tif)}

Attachment

Submitted filename: PLOS ONE Reviewer TNFa.pdf

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Association of tumor necrosis factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: A meta-analysis of 14 case-control studies

Zhenlian Zhang

Dilihumaier Duolikun

Tingting Dang

Yuanyuan Wang

Lijuan Ma

Xueyun Ma

Qiaoling Yao

Roles

Abstract

Introduction

Materials and methods

Search strategy

Inclusion and exclusion criteria

Data extraction

Quality assessment

Statistical analysis

Results

Selection of studies

Fig 1. Flow diagram of study selection (PRISMA format).

Characteristics of the included studies

Table 1. Basic characteristics of included studies.

Quantitative synthesis

Fig 2. Forest plots of the association between TNF-α-308G/A polymorphism and OSA under the allele model.

Table 2. Meta-analysis results of association between TNF-α-308G/A polymorphism and OSA.

Heterogeneity and sensitivity analysis

Fig 3. Meta-regression, sensitivity analysis and publication bias in overall population under the allele model.

Publication bias

Discussion

Study limitations

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Maria Elisabeth Johanna Zalm

Roles

Author response to Decision Letter 0

Decision Letter 1

Cho Naing

Roles

Author response to Decision Letter 1

Decision Letter 2

Cho Naing

Roles

Author response to Decision Letter 2

Decision Letter 3

Cho Naing

Roles

Acceptance letter

Cho Naing

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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