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. 2022 Oct 10;13:1008184. doi: 10.3389/fimmu.2022.1008184

Cumulative evidence for associations between genetic variants in interleukin 17 family gene and risk of human diseases

Tianyu Liu 1,†, Lei Yang 1,†, Xiaolong Lv 1,†, Chunjian Zuo 2, Chenhao Jia 1, Zelin Yang 1, Chongqi Fan 1, Huanwen Chen 1,*
PMCID: PMC9589504  PMID: 36300118

Abstract

Background

Genetic association studies have elucidated the link of variants in the interleukin 17 (IL-17) family genes with susceptibility to human diseases, yet have obtained controversial outcomes. Therefore, we sought to update comprehensive synopsis of variants in the IL-17 family genes with susceptibility to human diseases.

Methods

Our study screened the Pubmed and Web of Science to enroll eligible articles and performed a meta-analysis, then graded the cumulative evidence of significant association using Venice criteria and false-positive report probability test, and finally assessed the function of variants with strong evidence.

Results

Seven variants in IL-17 family genes had significant relationships with susceptibility to 18 human diseases identified by meta-analyses. Strong evidence was assigned to 4 variants (IL-17A rs2275913, IL-17A rs8193037, IL-17F rs1889570, IL-17F rs763780) with susceptibility to 6 human diseases (lung and cervical cancer, spondyloarthritis, asthma, multiple sclerosis, rheumatoid arthritis), moderate to 2 variants with risk of 5 diseases, weak to 5 variants with risk of 10 diseases. Bioinformatics analysis suggested that the variants with strong evidence might fall in putative functional regions. Additionally, positive relationships for 5 variants with risk of 4 diseases (based on two datasets) and 14 variants with risk of 21 diseases (based on one dataset) were considered noteworthy.

Conclusions

This study offers updated and comprehensive clues that variants in the IL-17 family genes are significantly linked with susceptibility to cervical, lung cancer, asthma, multiple sclerosis, rheumatoid arthritis and spondyloarthritis, and elucidates the crucial role of the IL-17 regions in the genetic predisposition to cancer or noncancerous diseases.

Keywords: interleukin 17 family gene, variant, cancer, noncancerous diseases, susceptibility

Introduction

Interleukin (IL) 17 (IL-17), a homodimeric glycoprotein composed of 155 amino acids, remains a pro-inflammatory and its family genes contain six groups (IL-17A to F) (1). The IL-17 signaling system has a crucial impact on different tissues such as lung, skin, kidney, brain, bone, articular cartilage, meniscus and hematopoietic tissue (1); this system mediated by the binding to IL-17 receptors can active multiple cell types (such as fibroblasts, endothelial cells, epithelial cells, keratinocytes and macrophages) (2). It could be activated which produces cell subsets of IL-17 that play a crucial role in multiple essential biological activities and accelerating occurrences of human diseases, involving novel coronavirus disease 2019 (COVID-19) (3).

As early as 2006, Hizawa et al. found five single nucleotide polymorphisms (SNPs) in IL-17F and found that rs763780 {His-to-Arg substitution at amino acid 161 (H161R)} in the third exon of the IL-17F gene influenced the susceptibility to asthma and chronic obstructive pulmonary disease (COPD) in the Japanese population (4, 5). Since then, a range of genetic association studies found that SNPs in IL-17 family genes have been shown to be linked with the risk of multiple diseases. In 2007, Arisawa et al. identified that IL-17F rs763780 and IL-17A rs2275913 in Japanese population had been shown to be linked with the risk of ulcerative colitis (UC) (6). Subsequently, studies also found that IL-17 family genes are linked with multiple cancers risk, including ovarian (7), breast (8), hepatocellular (9), esophageal (10), gastric (11) and lung cancer (12). In 2014, two researchers independently performed a meta-analysis and attempted to elucidate the relationship between IL-17A rs2275913 and IL-17F rs763780 and cancer risk in Asians (13, 14). Interestingly, the outcomes of the two studies were inconsistent. Recently, in an updated meta-analysis conducted in multiple countries from the Asian ancestry, SNP rs2275913 and SNP rs763780 associated with 31,234 subjects were tested. Then it was discovered that IL-17A rs2275913 acted as risk factors for gastric, cervical, colorectal and oral cancer, and IL-17F rs763780 for cervical and oral cancer (15).

Even though previous studies evaluate the relationship between SNPs in IL-17 family genes and the risk of diseases, the outcomes are controversial. In addition, an updated research synopsis with comprehensive functional annotation had not been conducted to assess the epidemiological evidence of associations with IL-17 family genes and risk of all human diseases thus far. Therefore, we carried out meta-analysis to elucidate the relationships of SNPs in the IL-17 genes with susceptibility to disease, offered the epidemiological evidence for variants with significant relationships, and evaluated the functions of significant variants using public sources.

Materials and methods

Our research followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) and the Human Genome Epidemiology Network for systematic review of genetic association studies (16, 17).

We screened genetic association studies from Pubmed and Web of science up to 30 Apr 2022 using “{interleukin-17} OR {IL-17} OR {IL-17}” AND “{variant} OR {variation} OR {polymorphism} OR {genotype} OR {single nucleotide polymorphism} OR {SNP}”. We also collected additional articles by retrieving published reviews, meta-analyses studies, etc.

The inclusion criteria are as follows: (i) they were concentrated on the relationships between SNPs in IL-17 family genes and susceptibility to human cancers or non-neoplastic diseases performed in case-control, cohort or cross-sectional studies (ii) they could provide the genotype data to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) under additive genetic model, (iii) they were published in English by form of full-text. The exclusion criteria are presented, (i) they lacked sufficient information (especially the quantity of genotype and/or allelic distributions), (ii) the study was not focused on SNP in IL-17 family genes, (iii) they were not published as full reports, such as conference abstracts and letters to editors, (iv) they concentrated on cancer mortality.

Data extraction

Two authors extracted the data independently using a predesigned collection sheet and any disagreement could be solved with the corresponding author by discussion together. The extracted data were as follows: first author, publishing year, study design, country or region, ethnicity, gene name, variant, cases and controls, genotype counts, minor allelic frequency (MAF). When previous articles studied on the same or overlapping data, we only extracted data from papers with largest sample size and most detailed information.

Statistical analysis

In our study, statistical tests of meta-analysis in the additive genetic association were two-tailed, and a P < 0.05 was significant level unless otherwise stated, which were conducted using Stata, version 15 (Stata, College Station, TX, USA). Meta-analyses were performed for variants with at least three datasets. We used the Cochran’s Q test to evaluate the heterogeneity between studies (18), while I2 statistic was applied to quantify and evaluate the heterogeneity (19). Sensitive analyses were performed to evaluate whether the significant association was lost when excluding a single study (dataset), or the first published study, or studies deviated from the Hardy-Weinberg equilibrium (HWE) in the controls. We investigated the probability of an excess of significant findings for single meta-analysis (20). Begg’s test and Egger’s test were conducted to assess potential publication bias and small-study bias, respectively (21, 22). Moreover, P<0.1 as the significant level in the assessment of heterogeneity, an excess of significant findings, Begg’s test and Egger’s test.

Assessment of epidemiological credibility

Our study graded the epidemiological credibility of significant associations identified by main meta analyses using the Venice guideline (23) and false positive report probability (FPRP) test (24) (see Supplementary Method ).

Functional annotation

Our study assessed the potential functional effect of variants on 6p12.2 using data from the Encyclopedia of DNA Elements (ENCODE) tool HaploReg (v4.1) (25) and the UCSC Genome browser (http://genome.ucsc.edu/). We analyzed the regions of promoter or enhancer activity, local histone modification, DNase I hypersensitivity, transcription factor binding motifs and proteins bound to these regulatory sites. In addition, we examined genome-wide cis-eQTL data in multiple tissues from two major eQTL databases: the Genotype-Tissue Expression Project (26) and the Multiple Tissue Human Expression Resource Project (27) to determine whether these genes might explain the observed associations in these loci. We used the data from the Phase 3 of the 1000 Genomes Project to perform linkage disequilibrium (LD) analysis for variants positively associated with susceptibility to cancer and noncancerous diseases in current study (28).

Result

Characteristics of the included studies

As presented in Figure 1 , a total of 227 eligible papers including 73,509 cases and 93,253 controls were enrolled ( Supplementary Table 1 ); 135 papers focused on relationships between 10 variants in IL-17 family genes and 25 diseases (5 cancers as well as 20 noncancerous diseases). The distributions of SNPs (n) with human diseases were presented: asthma (n=5), autoimmune thyroid diseases (AITD) (n=1), cervical cancer (n=3), COPD (n=2), colorectal cancer (n=2), coronary artery disease (CAD) (n=2), functional dyspepsia (FD) (n=3), gastric cancer (n=4), hepatitis B Virus (HBV) infection (n=4), hepatocellular carcinoma (n=1), immune thrombocytopenia (ITP) (n=3), inflammatory bowel disease (IBD) (n=3), leprosy (n=2), lung cancer (n=4), multiple sclerosis (MS) (n=1), osteoarthritis (OA) (n=2), periodontitis (n=2), pre-eclampsia (PE) (n=2), psoriasis (n=1), recurrent miscarriage (RM) (n=1), rheumatoid arthritis (RA) (n=5), spondyloarthritis (SpA) (n=2), systemic lupus erythematosus (SLE) (n=1), tuberculosis (TB) (n=3), Type 1 diabetes mellitus (T1DM) (n=1).

Figure 1.

Figure 1

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Flow diagram of search strategy and study selection.

Associations between IL-17 variants and risk of human diseases

we carried out meta-analyses to investigate correlations of 10 SNPs in IL-17 family genes with 5 cancers as well as 20 non-cancer diseases based on at least 3 datasets, under an additive genetic model. As presented in Table 1 and Supplementary Table 2 , 7 polymorphisms (rs1889570, rs2275913, rs2397084, rs3748067, rs763780, rs8193036, rs8193037) were associated with susceptibility to 4 types of carcinoma (colorectal, cervical, lung and gastric cancer) and 14 non-cancer diseases (AITP, asthma, CAD, HBV infection, ITP, IBD, leprosy, MS, OA, psoriasis, RA, SpA, SLE, TB) (28 associations, P<0.05). The cervical cancer susceptibility had positive association with minor allele of rs2275913 in Asians (OR=1.391), rs3748067 (OR=1.493) and rs763780 (OR=1.184). Apart from that, rs2275913 had an elevated susceptibility to colorectal cancer (OR=1.452); the positive association could be found in Asians and mixed populations (OR=1.524, OR=2.038, respectively), rather than in Caucasians. Apart from colorectal cancer, rs2275913 had an increased predisposition to gastric cancer (OR=1.281); the positive association could be found both in Asians and Caucasians (OR=1.264, OR=1.723, respectively); this SNP could increase risk of lung cancer (OR=1.213). Moreover, rs8193037 could elevate lung carcinoma susceptibility (OR=2.129).

Table 1.

Associations between variants in the IL-17 family genes associated with risk of human disease in meta-analysis under additive model (at least 3 datasets).

Gene Variant Allelesa Ethnicity MAFb Number Evaluation Disease Risk Heterogeneity Venice Criteriac FPRP valuesd Credibility of Evidencee
Studies Cases Controls OR (95%CI) P value I 2 (%) P Q
Asthma
IL17F rs1889570 C/T Overall 0.3826 3 1275 1376 1.109 (0.888-1.384) 0.361 73.5 0.023
IL17F rs1889570 C/T Asian 0.3235 2 856 983 1.230 (1.075-1.401) 0.003 32.9 0.222 ABA 0.032 Strong
IL17F rs1889570 C/T Other 0.5305 1 419 393 0.915 (0.753-1.112) 0.371 NA NA
IL17A rs2275913 G/A Overall 0.3527 6 1051 1741 0.946 (0.690-1.296) 0.728 78.8 < 0.001
IL17A rs2275913 G/A Asian 0.4277 3 774 883 0.976 (0.681-1.400) 0.896 78.7 0.009
IL17A rs2275913 G/A Caucasian 0.2331 3 277 534 0.891 (0.419-1.896) 0.765 85.9 0.001
IL17F rs2397084 T/C Overall 0.0230 3 415 565 3.220 (1.895-5.473) < 0.001 0.0 0.965 CAA 0.110 Weak
IL17F rs2397084 T/C Asian 0.0045 1 221 223 3.572 (0.738-17.292) 0.114 NA NA
IL17F rs2397084 T/C Caucasian 0.0351 2 194 342 3.167 (1.805-5.556) < 0.001 0.0 0.826
IL17F rs763780 T/C Overall 0.1060 7 1714 2032 0.925 (0.670-1.277) 0.635 71.6 0.002
IL17F rs763780 T/C Asian 0.1050 5 1520 1690 1.039 (0.743-1.452) 0.824 74.5 0.003
IL17F rs763780 T/C Caucasian 0.0848 2 194 342 0.536 (0.294-0.979) 0.042 0.0 0.363 CAA 0.771 Weak
IL17A rs8193036 C/T Asian 0.2856 3 1087 1224 0.833 (0.721-0.962) 0.013 83.1 0.003 ACC 0.197 Weak
Autoimmune thyroid diseases
IL17F rs763780 T/C Asian 0.1161 3 1265 1189 1.623 (1.101-2.393) 0.014 73.8 0.022 BCC 0.444 Weak
Cervical cancer
IL17A rs2275913 G/A Asian 0.3086 6 1634 2235 1.391 (1.263-1.532) < 0.001 0.0 0.617 AAA <0.001 Strong
IL17A rs3748067 C/T Asian 0.1721 4 1017 1418 1.493 (1.112-2.015) 0.008 69.0 0.022 BCC 0.264 Weak
IL17F rs763780 T/C Asian 0.2329 5 1449 1865 1.184 (1.045-1.342) 0.008 7.7 0.363 AAA 0.135 Strong
Chronic obstructive pulmonary disease
IL17A rs2275913 G/A Overall 0.2026 5 1404 1729 1.023 (0.778-1.344) 0.871 76.0 0.002
IL17A rs2275913 G/A Asian 0.4527 1 152 201 0.624 (0.455-0.875) 0.004 NA NA
IL17A rs2275913 G/A Mixed 0.1695 4 1252 1528 1.163 (0.976-1.385) 0.091 30.1 0.231
IL17A rs8193036 C/T Overall 0.7273 5 1404 1729 1.070 (0.868-1.320) 0.525 65.1 0.022
IL17A rs8193036 C/T Asian 0.2985 1 152 201 1.448 (1.049-2.000) 0.025 NA NA
IL17A rs8193036 C/T Mixed 0.7833 4 1252 1528 0.995 (0.820-1.208) 0.960 52.5 0.097
Colorectal cancer
IL17A rs2275913 G/A Overall 0.2714 7 1345 1535 1.452 (1.178-1.790) < 0.001 65.1 0.009 ACC 0.014 Moderate
IL17A rs2275913 G/A Asian 0.3250 3 630 825 1.524 (1.155-2.011) 0.003 63.0 0.067
IL17A rs2275913 G/A Caucasian 0.2120 3 598 610 1.254 (0.871-1.805) 0.223 69.8 0.036
IL17A rs2275913 G/A Mixed 0.1850 1 117 100 2.038 (1.298-3.198) 0.002 NA NA
IL17F rs763780 T/C Overall 0.1880 6 1841 1307 1.267 (0.933-1.720) 0.130 58.9 0.033
IL17F rs763780 T/C Asian 0.1417 3 1422 867 1.270 (0.825-1.956) 0.278 77.1 0.011
IL17F rs763780 T/C Caucasian 0.0754 2 302 340 1.403 (0.655-3.004) 0.384 65.8 0.087
IL17F rs763780 T/C Mixed 0.9700 1 117 100 1.003 (0.331-3.035) 0.996 NA NA
Coronary artery disease
IL17A rs2275913 G/A Overall 0.3293 8 3654 3298 1.179 (1.026-1.354) 0.020 69.4 0.002 ACA 0.272 Weak
IL17A rs2275913 G/A Asian 0.3178 6 2534 2411 1.197 (1.053-1.360) 0.006 52.1 0.064
IL17A rs2275913 G/A Caucasian 0.2841 1 220 220 1.527 (1.150-2.026) 0.003 NA NA
IL17A rs2275913 G/A Mixed 0.1904 1 900 667 0.870 (0.724-1.045) 0.137 NA NA
IL17A rs3748067 C/T Asian 0.6603 4 1197 1170 0.723 (0.572-0.913) 0.006 55.3 0.082 ACA 0.140 Weak
Functional dyspepsia
IL17A rs2275913 G/A Asian 0.3936 3 175 564 0.815 (0.632-1.052) 0.116 0.0 0.943
IL17F rs2397084 T/C Other 0.0860 3 237 695 0.885 (0.290-2.702) 0.831 79.1 0.008
IL17F rs763780 T/C Overall 0.1178 6 412 1314 0.891 (0.688-1.154) 0.383 0.0 0.667
IL17F rs763780 T/C Asian 0.1257 3 175 564 0.676 (0.447-1.022) 0.063 0.0 0.998
IL17F rs763780 T/C Other 0.1120 3 237 750 1.089 (0.779-1.522) 0.617 0.0 0.952
Gastric cancer
IL17A rs2275913 G/A Overall 0.3845 18 6207 8902 1.281 (1.179-1.392) < 0.001 60.5 < 0.001 ACA <0.001 Moderate
IL17A rs2275913 G/A Asian 0.3855 17 6046 8731 1.264 (1.165-1.372) < 0.001 58.4 0.001
IL17A rs2275913 G/A Caucasian 0.3333 1 161 171 1.723 (1.258-2.358) 0.001 NA NA
IL17A rs3748067 C/T Asian 0.3385 11 3022 5284 0.981 (0.750-1.283) 0.889 83.6 < 0.001
IL17A rs4711998 A/G Asian 0.3316 3 1750 2066 1.001 (0.906-1.105) 0.989 41.7 0.180
IL17F rs763780 T/C Asian 0.6781 10 3944 4566 1.042 (0.805-1.348) 0.756 87.4 < 0.001
Hepatitis B Virus infection
IL17A rs2275913 G/A Overall 0.4986 13 2633 2479 0.968 (0.834-1.124) 0.671 68.4 < 0.001
IL17A rs2275913 G/A Asian 0.5085 12 2434 2307 0.964 (0.821-1.133) 0.660 70.7 < 0.001
IL17A rs2275913 G/A Caucasian 0.3663 1 199 172 1.024 (0.760-1.381) 0.875 NA NA
IL17A rs4711998 A/G Asian 0.2324 4 533 617 1.068 (0.678-1.683) 0.776 81.9 0.001
IL17F rs763780 T/C Overall 0.1727 7 1445 1546 0.852 (0.739-0.982) 0.027 82.0 < 0.001 BBC 0.082 Weak
IL17F rs763780 T/C Asian 0.1727 6 1246 1374 0.826 (0.713-0.957) 0.011 83.8 < 0.001
IL17F rs763780 T/C Caucasian 0.0610 1 199 172 1.345 (0.760-2.379) 0.309 NA NA
IL17A rs8193036 C/T Asian 0.2656 6 1260 945 0.947 (0.707-1.269) 0.717 74.7 0.001
Hepatocellular carcinoma
IL17A rs2275913 G/A Asian 0.5100 4 462 450 1.108 (0.755-1.626) 0.600 72.9 0.011
Immune thrombocytopenia
IL17F rs763780 T/C Overall 0.2721 6 568 748 0.683 (0.290-1.608) 0.382 89.5 < 0.001
IL17F rs763780 T/C Asian 0.3186 3 413 473 0.486 (0.362-0.653) < 0.001 0.0 0.966 CAC 0.002 Moderate
IL17F rs763780 T/C African 0.1916 3 155 274 0.975 (0.110-8.619) 0.382 94.0 < 0.001
Inflammatory Bowel Disease
IL17A rs2275913 G/A Asian 0.4202 3 580 764 1.051 (0.783-1.412) 0.740 71.1 0.031
IL17F rs763780 T/C Overall 0.0840 5 1108 2928 0.877 (0.728-1.055) 0.164 51.9 0.081
IL17F rs763780 T/C Asian 0.1531 3 393 994 0.750 (0.585-0.962) 0.024 51.9 0,125 CCC 0.352 Weak
IL17F rs763780 T/C Caucasian 0.0486 2 715 1934 1.081 (0.817-1.429) 0.587 0.0 0.417
IL17A rs8193036 C/T Asian 0.2854 3 597 1016 1.012 (0.764-1.340) 0.936 65.1 0.057
Leprosy
IL17A rs2275913 G/A Mixed 0.2304 3 132 369 0.971 (0.726-1.299) 0.841 6.9 0.342
IL17F rs763780 T/C Overall 0.1791 5 444 537 0.364 (0.268-0.496) < 0.001 80.8 < 0.001 CCC <0.001 Moderate
IL17F rs763780 T/C Mixed 0.0707 3 304 369 0.870 (0.537-1.409) 0.571 0.0 0.884
IL17F rs763780 T/C Other 0.4167 2 140 168 0.200 (0.131-0.303) < 0.001 0.0 0.936
Lung cancer
IL17F rs12203582 G/A Asian 0.5968 4 320 1432 1.103 (0.918-1.325) 0.293 0.0 0.790
IL17A rs2275913 G/A Overall 0.3778 5 559 1690 1.213 (1.039-1.375) 0.014 0.0 0.918 AAA 0.046 Strong
IL17A rs2275913 G/A Asian 0.4092 4 320 1432 1.260 (1.053-1.509) 0.012 0.0 0.963
IL17A rs2275913 G/A Caucasian 0.2035 1 239 258 1.088 (0.802-1.477) 0.586 NA NA
IL17A rs3819024 A/G Asian 0.4426 3 322 1098 0.940 (0.784-1.127) 0.503 0.0 0.832
IL17A rs8193037 G/A Asian 0.1120 3 322 1098 2.129 (1.677-2.702) < 0.001 49.5 0.138 BBA <0.001 Strong
Multiple sclerosis
IL17F rs763780 T/C Overall 0.1414 4 774 1064 1.154 (0.608-2.193) 0.661 85.1 < 0.001
IL17F rs763780 T/C Asian 0.1386 2 691 874 0.687 (0.548-0.862) 0.001 0.0 0.884 BAA 0.036 Strong
IL17F rs763780 T/C African 0.1737 2 83 190 2.064 (1.348-3.161) 0.001 0.0 0.682
Osteoarthritis
IL17A rs2275913 G/A Overall 0.3448 6 1791 2324 1.232 (1.024-1.483) 0.027 71.7 0.003 ACA 0.347 Weak
IL17A rs2275913 G/A Asian 0.3665 3 1306 1383 1.411 (1.105-1.804) 0.006 77.8 0.011
IL17A rs2275913 G/A Caucasian 0.3130 3 485 941 1.048 (0.839-1.310) 0.680 38.8 0.195
IL17F rs763780 T/C Overall 0.1088 7 2671 4420 1.344 (1.111-1.626) 0.002 57.1 0.030 ACA 0.049 Moderate
IL17F rs763780 T/C Asian 0.1348 4 2102 3237 1.239 (1.026-1.497) 0.026 57.3 0.071
IL17F rs763780 T/C Caucasian 0.0376 3 569 1138 1.754 (1.157-2.661) 0.008 39.3 0.193
Periodontitis
IL17A rs2275913 G/A Overall 0.3253 11 935 971 1.304 (0.892-1.908) 0.171 83.0 < 0.001
IL17A rs2275913 G/A Caucasian 0.3547 3 535 524 0.942 (0.782-1.134) 0.526 0.0 0.744
IL17A rs2275913 G/A Mixed 0.2920 4 300 347 1.040 (0.514-2.103) 0.914 84.0 < 0.001
IL17A rs2275913 G/A Other 0.2800 4 100 100 2.498 (0.993-6.235) 0.052 74.3 0.009
IL17F rs763780 T/C Overall 0.0563 5 500 507 1.251 (0.840-1.860) 0.270 0.0 0.520
IL17F rs763780 T/C Mixed 0.0656 4 300 347 1.506 (0.955-2.373) 0.078 0.0 0.935
IL17F rs763780 T/C Caucasian 0.0375 1 200 160 0.658 (0.281-1.543) 0.336 NA NA
Pre-eclampsia
IL17A rs2275913 G/A Overall 0.4129 3 1923 2296 1.009 (0.919-1.108) 0.848 0.0 0.860
IL17A rs2275913 G/A Asian 0.4111 2 1662 2018 1.020 (0.922-1.129) 0.702 0.0 0.896
IL17A rs2275913 G/A Caucasian 0.4245 1 261 278 0.950 (0.745-1.210) 0.676 NA NA
IL17F rs763780 T/C Overall 0.0979 3 1923 2296 0.995 (0.852-1.162) 0.947 54.4 0.111
IL17F rs763780 T/C Asian 0.1017 2 1662 2018 0.938 (0.793-1.109) 0.451 0.0 0.342
IL17F rs763780 T/C Caucasian 0.0737 1 261 278 1.449 (0.948-2.217) 0.087 NA NA
Psoriasis
IL17F rs763780 T/C Overall 0.1219 6 1151 975 1.499 (0.899-2.499) 0.121 80.2 < 0.001
IL17F rs763780 T/C Asian 0.0955 2 324 363 1.571 (1.118-2.207) 0.009 0.0 0.371 BAA 0.307 Weak
IL17F rs763780 T/C Caucasian 0.0274 2 601 462 1.378 (0.811-2.343) 0.236 0.0 0.371
IL17F rs763780 T/C African 0.0750 1 60 60 4.111 (1.856-9.105) < 0.001 NA NA
IL17F rs763780 T/C Other 0.4567 1 166 150 0.676 (0.492-0.929) 0.016 NA NA
Recurrent Miscarriage
IL17A rs2275913 G/A Overall 0.4725 3 290 309 1.148 (0.753-1.752) 0.520 65.6 0.055
IL17A rs2275913 G/A Caucasian 0.5265 2 170 189 0.924 (0.666-1.282) 0.634 0.0 0.451
IL17A rs2275913 G/A African 0.3875 1 120 120 1.634 (1.137-2.348) 0.008 NA NA
Rheumatoid arthritis
IL17A rs2275913 G/A Overall 0.3661 13 3826 4011 0.862 (0.833-0.955) 0.001 6.8 0.378 AAA 0.001 Strong
IL17A rs2275913 G/A Asian 0.4633 1 615 839 0.875 (0.754-1.016) 0.080 NA NA
IL17A rs2275913 G/A Caucasian 0.3908 8 2452 2389 0.896 (0.824-0.974) 0.010 27.4 0.209
IL17A rs2275913 G/A Mixed 0.2687 4 759 783 0.897 (0.744-1.082) 0.255 5.0 0.368
IL17F rs2397084 T/C Caucasian 0.1056 4 800 695 1.575 (0.499-4.968) 0.439 94.9 < 0.001
IL17A rs3819024 A/G Overall 0.3712 3 2053 2266 0.914 (0.834-1.002) 0.056 0.0 0.603
IL17A rs3819024 A/G Asian 0.4816 1 615 839 0.880 (0.758-1.021) 0.092 NA NA
IL17A rs3819024 A/G Caucasian 0.3842 1 937 928 0.913 (0.800-1.043) 0.179 NA NA
IL17A rs3819024 A/G Mixed 0.1513 1 501 499 1.019 (0.798-1.300) 0.882 NA NA
IL17F rs763780 T/C Overall 0.0713 9 1297 1264 1.650 (0.792-3.437) 0.181 89.9 < 0.001
IL17F rs763780 T/C Caucasian 0.0751 6 1039 980 2.070 (0.794-5.395) 0.137 92.9 < 0.001
IL17F rs763780 T/C Mixed 0.0581 3 258 284 0.977 (0.527-1.812) 0.941 23.4 0.271
IL17A rs8193036 C/T Overall 0.3941 3 2052 2261 1.074 (0.905-1.276) 0.414 65.8 0.054
IL17A rs8193036 C/T Asian 0.2555 1 615 839 1.250 (1.056-1.479) 0.010 NA NA
IL17A rs8193036 C/T Caucasian 0.2974 1 936 923 0.953 (0.827-1.097) 0.502 NA NA
IL17A rs8193036 C/T Mixed 0.7986 1 501 499 1.050 (0.843-1.309) 0.662 NA NA
Spondyloarthritis
IL17A rs2275913 G/A Mixed 0.2500 4 439 784 1.401 (1.156-1.698) 0.001 25.2 0.260 BBA 0.015 Strong
IL17F rs763780 T/C Mixed 0.0522 4 439 788 3.684 (2.737-4.960) < 0.001 0.0 0.431 BAA <0.001 Strong
Systemic lupus erythematosus
IL17A rs2275913 G/A Overall 0.2338 5 941 1289 1.160 (1.007-1.336) 0.040 53.5 0.072 ACA 0.429 Weak
IL17A rs2275913 G/A African 0.2807 3 515 695 1.281 (1.071-1.533) 0.007 63.2 0.066
IL17A rs2275913 G/A Caucasian 0.3105 1 59 95 0.975 (0.592-1.604) 0.920 NA NA
IL17A rs2275913 G/A Mixed 0.1573 1 367 499 0.985 (0.758-1.281) 0.910 NA NA
Tuberculosis
IL17A rs2275913 G/A Overall 0.4066 12 4240 4983 0.998 (0.854-1.165) 0.975 79.5 < 0.001
IL17A rs2275913 G/A Asian 0.4283 5 3137 3549 1.066 (0.894-1.270) 0.478 80.4 < 0.001
IL17A rs2275913 G/A Caucasian 0.4039 5 727 1052 1.120 (0.799-1.572) 0.511 79.4 0.001
IL17A rs2275913 G/A Mixed 0.2287 2 376 382 0.594 (0.399-0.884) 0.010 48.6 0.163 BBA 0.406 Weak
IL17A rs3748067 C/T Asian 0.1429 3 2365 2305 1.244 (0.939-1.649) 0.129 71.4 0.030
IL17F rs763780 T/C Overall 0.0990 8 3574 4238 1.380 (1.084-1.758) 0.009 72.0 0.001 ACA 0.188 Weak
IL17F rs763780 T/C Asian 0.1139 5 3137 3549 1.426 (1.082-1.879) 0.012 0.0 0.665
IL17F rs763780 T/C Caucasian 0.0225 3 437 689 1.088 (0.607-1.951) 0.776 83.3 < 0.001
Type 1 diabetes mellitus
IL17A rs2275913 G/A Overall 0.3288 3 155 184 1.223 (0.887-1.685) 0.219 31.4 0.233
IL17A rs2275913 G/A Other 0.2333 2 30 30 0.580 (0.229-1.466) 0.249 0.0 0.782
IL17A rs2275913 G/A Caucasian 0.3474 1 125 154 1.360 (0.965-1.918) 0.079 NA NA
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OR, odds ratio; A, adenine; T, thymine; G, guanine; C, cytosine; NA, not applicable.

a Major alleles (reference)/minor alleles.

b Frequency of minor allele in controls.

c Strength of epidemiological evidence based on the Venice criteria.

d FPRP values at prior probability of 0.05 at power OR of 1.5, and the FPRP level of noteworthiness is 0.20.

e Degree of epidemiological credibility based on the combination of results from Venice guidelines and FPRP tests.

For non-cancer disease, current results showed that significant relationships with asthma risk were found for rs1889570 in Asians (OR=1.230), rs2397084 (OR=3.220), rs763780 (OR=0.536) and rs8193036 (OR=0.833). In addition, rs763780 had an elevated susceptibility to AITD (OR=1.623) in Asians. For CAD, significant relationships were found for rs2275913 (OR=1.179). Additionally, rs3748067 could reduce risk of CAD in Asians (OR=0.723). For HBV infection, rs763780 had a decreased susceptibility to HBV infection (OR=0.852), especially among Asians (OR=0.826). Apart from that, rs763780 could decrease susceptibility to ITP (OR=0.486) and risk of IBD (OR=0.750) in Asians. Apart from that, rs763780 had a reduced susceptibility to leprosy (OR=0.364) and risk of MS (OR=0.687), respectively. Interestingly, current results showed that rs2275913 could increase risk of OA (OR=1.232), SpA (OR=1.401) and SLE (OR=1.160), whereas decrease susceptibility to RA (OR=0.862) and TB (OR=0.594); rs763780 could increase risk of OA (OR=1.344), psoriasis (OR=1.571), SpA (OR=3.684) and TB (OR=1.380), respectively.

Additionally, 8 SNPs (rs12203582, rs2275913, rs2397084, rs3748067, rs3819024, rs8193036, rs763780 and rs4711998) had no association with susceptibility to 14 human diseases (asthma, COPD, colorectal cancer, FD, gastric cancer, HBV infection, hepatocellular carcinoma, IBD, lung cancer, PE, RM, RA, TB and T1DM) in additive model. Of these, 3 SNPs had no association with 3 diseases (rs3748067 and rs763780 for gastric cancer; rs2275913 for HBV infection; rs3748067 for TB) with at least 2,300 case and 2,300 controls. Also, we calculated the statistical power to confirm whether the bigger sample size confirming these relationships is required in next study ( Table 2 and Supplementary Table 3 ).

Table 2.

Variants in IL-17 family genes showing no relation to risk of disease in meta-analyses in additive model.

Gene Variant Allelesa Disease Ethnicity MAFb Number Evaluation Meta-analysis risk Heterogeneity
Studies Sample size (case/control) OR (95%CI) P value I2(%) P (Q)
IL17A rs2275913 G/A Asthma Overall 0.3527 6 2792 (1051/1741) 1.108 (0.755-1.626) 0.600 72.9 0.011
IL17A rs2275913 G/A COPD Overall 0.2026 5 3133 (1404/1729) 1.051 (0.783-1.412) 0.740 71.1 0.031
IL17A rs8193036 C/T COPD Overall 0.7273 5 3133 (1404/1729) 1.012 (0.764-1.340) 0.936 65.1 0.057
IL17F rs763780 T/C Colorectal cancer Overall 0.1880 6 3148 (1841/1307) 1.103 (0.918-1.325) 0.293 0.0 0.790
IL17A rs2275913 G/A Functional dyspepsia Asian 0.3936 3 739 (175/564) 0.940 (0.784-1.127) 0.503 0.0 0.832
IL17F rs763780 T/C Functional dyspepsia Overall 0.1178 6 1726 (412/1314) 1.304 (0.892-1.908) 0.171 83.0 < 0.001
IL17A rs3748067 C/T Gastric Cancer Asian 0.3385 11 8306 (3022/5284) 1.251 (0.840-1.860) 0.270 0.0 0.520
IL17A rs4711998 A/G Gastric Cancer Asian 0.3316 3 3816 (1750/2066) 1.009 (0.919-1.108) 0.848 0.0 0.860
IL17F rs763780 T/C Gastric Cancer Asian 0.6781 10 8510 (3944/4566) 0.995 (0.852-1.162) 0.947 54.4 0.111
IL17A rs2275913 G/A Hepatitis B Virus infection Overall 0.4986 13 5112 (2633/2479) 1.148 (0.753-1.752) 0.520 65.6 0.055
IL17A rs4711998 A/G Hepatitis B Virus infection Asian 0.2324 4 1150 (533/617) 1.575 (0.499-4.968) 0.439 94.9 < 0.001
IL17A rs8193036 C/T Hepatitis B Virus infection Asian 0.2656 6 2205 (1260/945) 1.650 (0.792-3.437) 0.181 89.9 < 0.001
IL17A rs2275913 G/A Hepatocellular carcinoma Asian 0.5100 4 912 (462/450) 1.074 (0.905-1.276) 0.414 65.8 0.054
IL17A rs2275913 G/A Inflammatory Bowel Disease Asian 0.4202 3 1344 (580/764) 1.244 (0.939-1.649) 0.129 71.4 0.030
IL17A rs8193036 C/T Inflammatory Bowel Disease Asian 0.2854 3 1613 (597/1016) 1.223 (0.887-1.685) 0.219 31.4 0.233
IL17F rs12203582 G/A Lung cancer Asian 0.5968 4 1752 (320/1432) 1.108 (0.755-1.626) 0.600 72.9 0.011
IL17A rs3819024 A/G Lung cancer Asian 0.4426 3 1420 (322/1098) 1.051 (0.783-1.412) 0.740 71.1 0.031
IL17A rs2275913 G/A Periodontitis Overall 0.3253 11 1906 (935/971) 1.012 (0.764-1.340) 0.936 65.1 0.057
IL17F rs763780 T/C Periodontitis Overall 0.0563 5 1007 (500/507) 1.103 (0.918-1.325) 0.293 0.0 0.790
IL17A rs2275913 G/A Periodontitis Overall 0.4129 3 4219 (1923/2296) 0.940 (0.784-1.127) 0.503 0.0 0.832
IL17F rs763780 T/C Periodontitis Overall 0.0979 3 4219 (1923/2296) 1.304 (0.892-1.908) 0.171 83.0 < 0.001
IL17A rs2275913 G/A Recurrent Miscarriage Overall 0.4725 3 599 (290/309) 1.251 (0.840-1.860) 0.270 0.0 0.520
IL17F rs2397084 T/C Rheumatoid arthritis Caucasian 0.1056 4 1495 (800/695) 1.009 (0.919-1.108) 0.848 0.0 0.860
IL17F rs763780 T/C Rheumatoid arthritis) Overall 0.0713 9 2561 (1297/1264) 0.995 (0.852-1.162) 0.947 54.4 0.111
IL17A rs8193036 C/T Rheumatoid arthritis Overall 0.3941 3 4313 (2052/4313) 1.148 (0.753-1.752) 0.520 65.6 0.055
IL17A rs3748067 C/T Tuberculosis Asian 0.1429 3 4670 (2365/2305) 1.575 (0.499-4.968) 0.439 94.9 < 0.001
IL17A rs2275913 G/A Type 1 diabetes mellitus Overall 0.3288 3 339 (155/184) 1.650 (0.792-3.437) 0.181 89.9 < 0.001
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OR, odds ratio; A, adenine; C, cytosine; G, guanine; T, thymine;

a

Major alleles (reference)/Minor alleles.

b

Frequency of minor allele in controls.

Heterogeneity, bias and sensitivity analysis

As shown in Table 1 , heterogeneity was investigated for 28 significant associations (7 SNPs for 18 human diseases). Mild heterogeneity (I2 < 25%) was assigned to 3 variants with risk of 2 cancers and 6 noncancerous diseases (10 associations); moderate heterogeneity (25% ≤ I2 ≤ 50%) was assigned to 3 variants with risk of 1 cancer and 3 noncancerous diseases (4 associations); high heterogeneity (I2 > 50%) was assigned to 4 variants with risk of 3 cancers and 9 noncancerous diseases (14 associations). Moreover, the results indicated that publication bias existed (p < 0.10) in associations for rs3748067 and rs2275913 with colorectal cancer risk. Apart from that, sensitivity analyses indicated that some significant summary ORs were lost, including rs8193036 in asthma and AITD, rs763780 in HBV infection (excess of significant findings); rs763780 in AITD and ITP (small study), and in IBD (HWE), and in leprosy (small study).

Cumulative evidence of association

As shown in Table 1 , our study firstly used the Venice guideline and FPRP tests to grade epidemiological credibility of 28 significant. In terms of Venice guideline, strong, moderate and weak evidence were assigned to 4, 7 and 17 associations, respectively. Then, the probability for a true association between the 28 positive associations was investigated based on FPRP tests. The FPRP value < 0.05 was observed for 13 associations, FPRP 0.05 to 0.2 for 6 associations, and FPRP > 0.2 was found for 9 associations, respectively. At last, combing Venice guideline and FPRP tests, strong evidence was assigned to 4 variants (IL-17F rs1889570, IL-17A rs2275913, IL-17F rs763780, IL-17A rs8193037) and 2 cancer (cervical and lung cancer) as well as 4 noncancerous diseases (asthma, MS, RA, SpA), moderate to 2 SNPs (IL-17A rs2275913, IL-17F rs763780) and colorectal and gastric cancer as well as 3 noncancerous diseases (ITP, leprosy, OA), weak to 5 SNPs (IL-17F rs2397084, IL-17F rs763780, IL-17A rs8193036, IL-17A rs3748067, IL-17A rs2275913) and 1 cancer (cervical cancer) as well as 9 noncancerous diseases (asthma, AITD, CAD, HBV infection, IBD, OA, psoriasis, SLE, TB).

In addition, we attempted to pool the ORs and 95%CIs on the basis of two datasets and found that 9 variants (rs1889570, rs2275913, rs3819024, rs4711998, rs4819554, rs6973569, rs763780, rs8193036 and rs8193037) had significantly associated with susceptibility to 4 cancers (bladder, colorectal, papillary thyroid cancer and hepatocellular carcinoma) as well as 10 noncancerous diseases (ankylosing spondylitis, Behcet’s disease, bronchiolitis, brucellosis, chronic chagas cardiomyopathy, CAD, gastro-duodenal ulcer, recurrent miscarriage, silicosis and TB); of these, 5 SNPs (rs4819554, rs8193036, rs8193037, rs2275913, rs763780) and risk of 4 noncancerous diseases (ankylosing spondylitis, CAD, gastro-duodenal ulcer, recurrent miscarriage) were considered noteworthy (P < 0.2 for FPRP) (see Supplementary Table 4 ). Additionally, we calculated the ORs and 95% CI in the additive model to assess the relationships between 53 variants and susceptibility to 90 diseases (based on one dataset), yielding significant relationships between 22 variants and the risk of 47 types of carcinoma. Apart from that, P value of FPRP for the significant associations also be calculated. Finally, we considered the associations between 14 variants and susceptibility to 21 diseases noteworthy (see Supplementary Table 5 ).

Functional annotation for variants with strong evidence

As shown in Table 3 , we used the Encyclopedia of DNA Elements tool HaploReg v4.1 to assess the potential functional roles for strong evidence (4 variants with risk of 6 human diseases). For functional annotations, rs763780 was annotated as missense. The total 4 SNPs might be located in a region with strong promoter and enhancer activity, and two SNPs in alteration in regulatory motif. Subsequently, as the consequence of the function evaluation using the PolyPhen-2 web server (29), the unique non-synonymous variant rs763780 was qualitatively predicted to be “benign” with a naïve Bayes posterior probability of less than 0.15. As shown in Supplementary Figure 1 , the linkage disequilibrium (LD) plots presented that the regions represented by significant SNPs had distinct genetic structures among in European, Asian and African ancestry. The information extracted from the Genotype-Tissue Expression Project shows that rs2275913, rs763780, rs8193037, rs1889570 are eQTLs for the IL-17A, IL-17F, GSTA8P, MCM3. In addition, rs2275913 had an increased expression in GSTA8P, IL-17A genes in testis tissues; rs763780 and rs8193037 had an increased expression in MCM3,IL-17F genes in muscle and esophagus tissues, respectively ( Supplementary Table 6 ). In our study, rs2275913 and rs763780 had significantly associated with susceptibility to cervical cancer and SpA. The Phase 3 of the 1000 Genomes Project (30) ( Supplementary Table 7 ) indicated IL-17A rs2275913 is uncorrelated with IL-17F rs763780 in Europeans, East Asians and Africans (r 2< 0.05 for all tests). Moreover, IL-17A rs2275913 and IL-17A rs8193037 had associated with predisposition to lung cancer. We also found that rs2275913 is weak LD with rs8193037 in East Asians (r 2 = 0.1) and is uncorrelated with rs8193037 in Europeans and Africans (r 2< 0.05).

Table 3.

Summary of functional annotations for 4 SNPs in 6 human diseases (strong epidemiological credibility).

Variant Gene Positiona Annotation Promoter histone marksb Enhancer histone marksc DNAsed Proteins bounde Motifs changedf
rs763780 IL17F 52101739 missense ESDR, BLD BLD, HRT Lmo2-complex,Mtf1
rs1889570 IL17F 52110734 ESDR, IPSC, BRST GI, LIV HDAC2,NF-I,NRSF
rs2275913 IL17A 52051033 BLD BLD
rs8193037 IL17A 52051109 BLD, GI BLD
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a

chromosome position is based on NCBI Build 37.

b

Histone modification of H3K4me1 and H3K27ac (tissue types: if >3, only the number is included).

c

Histone modification of H3K4me3 (tissue types: if >3, only the number is included).

d

Levels of DNase I hypersensitivity (tissue types: if >3, only the number is included).

e

Alteration in transcription factor binding (disruptions: if >3, only the number is included).

f

Alteration in regulatory motif (disruptions: if >3, only the number is included).

Discussion

Our study performs a comprehensive research synopsis and meta-analysis, summarizes and updates the associations between SNPs in IL-17 family genes and predisposition to human diseases for the first time, which offers precise results for the SNPs and provides more variants and diseases that never been investigated before. Our study included 227 papers with 73,509 cases and 93,253 controls and performed a meta-analysis using 135 papers with available information to assess relationships of 10 variants with susceptibility to 25 diseases (5 cancers as well as 20 non-cancer diseases); 7 SNPs had positively associated with 18 human disease predisposition. Our study used the Venice guidelines and FPRP tests to grade the cumulative evidence of significant relationships. At last, 4 SNPs were assigned to strong evidence with predisposition to 6 human diseases (9 associations: IL-17F rs1889570 in asthma; IL-17A rs2275913 in lung cancer, cervical cancer, RA, SpA; IL-17F rs763780 in cervical cancer, MS, SpA; IL-17A rs8193037 in lung cancer), moderate to 2 SNPs and 2 cancer as well as 3 noncancerous diseases, weak to 5 SNPs and 1 cancer as well as 9 noncancerous diseases. Moreover, we attempted to construct functional annotations for these 4 variants with strong evidence using data from the Encyclopedia of DNA Elements Project and other public databases and then uncovered that the SNPs with strong evidence might fall in several putative regulatory regions. In summary, this study provides updated evidence that SNPs in the IL-17 family genes had significant associations with predisposition to lung, cervical cancer, asthma, RA, SpA and MS.

The IL-17, a kind of proinflammatory cytokine, plays a crucial role in both innate and acquired immune responses (31). Previous papers demonstrated that IL-17 is activated by microbial products, and may accelerate carcinoma occurrence and development by angiogenic functions (32). The IL-17A gene (Gene ID: 3605) is located at chromosome 6p12.2, and the encoded protein is a proinflammatory cytokine produced by activated T cells, which might involve in the development of human diseases (31). In the previous paper, it was pointed out that IL-17A rs2275913 acted as risk factor for multiple cancers (gastric, cervical, colorectal and oral carcinoma) (15) and non-cancerous diseases (RA) (33). Consistent with our meta-analysis, strong evidence was assigned to IL-17A rs2275913 in lung cancer, cervical cancer, RA, SpA, and IL-17A rs8193037 in lung cancer. LD analysis indicates that IL-17A rs2275913 and IL-17A rs8193037 were associated with susceptibility to lung cancer. We also found that rs2275913 is weak LD with rs8193037 in East Asians and is uncorrelated with rs8193037 in Europeans and Africans, indicating that the functional mechanisms of the two variants associated with lung cancer risk may be distinct in different ethnic groups and partly explain why some variants are found to be associated with a cancer site in one ethnic group but not in others. Current evidence presents that high expression of IL-17A is linked with the development and progression of cancers, and IL-17A could be regulated at the transcriptional level (34). IL-17A rs2275913 could influence the expression of the IL-17A protein and trigger cell transformation and maintain the autonomous proliferation of the transformed cells, and thus increase the susceptibility of cervical cancer, especially in HPV infection individuals (35). IL-17A could influence the transcriptional activity of NFAT and trigger the stimulation of T lymphocytes cells, which might increase risk of lung cancer (36). Moreover, a recent study indicated that the G allele polymorphism of IL-17A rs2275913 (a change from glutamic acid to lysine) was protective in RA individuals (37), which is consistent with our results; IL-17A and TNF-α had been considered as a predictor of a poor outcome in RA individuals; interestingly, previous study concluded that therapies targeting IL-17 in autoimmune diseases ameliorated the inadequate response to anti-TNF-α therapy (38), which indicated that SNP rs2275913 could be considered as a novel target for gene therapy of RA and promote drug developments against RA. Moreover, the SNP rs2275913 A allele is linked with high IL-17 expression, which has an elevated susceptibility to autoimmune and inflammatory diseases, including SpA (39). Moreover, previous papers found that drugs target other molecules of the immune system, such as anti-IL-17A (ixekizumab and secukinumab) and anti-IL-17A receptor (brodalumab). The efficacy of anti-IL-17R and anti-IL-17 agents has been shown in Phase II (40) and III trials (41, 42), indicating that IL-17A might have impact on the pathogenesis of psoriasis.

The IL-17F gene (Gene ID:112744) is located at chromosome 6p12.2, and the protein encoded by IL-17F gene is a cytokine activated by T cells. It could stimulate the production of other cytokines, such as IL-6, IL-8, and CSF2/GM_CSF (31, 43). These cytokines might have similar synergistic effects on risk of human diseases (44). In the previous paper, it was pointed out that IL-17F rs763780 might trigger the development of cervical and oral carcinoma (15) and non-cancerous diseases (such as asthma) (45). Consistent with our meta-analysis, strong evidence was assigned to IL-17F rs1889570 in asthma, and IL-17F rs763780 in cervical cancer, MS, SpA. In our study, rs2275913 and rs763780 had positive association with susceptibility to SpA and cervical cancer. LD analysis indicates that IL-17A rs2275913 is uncorrelated with IL-17F rs763780 in Europeans, East Asians and Africans, demonstrating that there might be different causal variants and functional mechanisms involved in relationships of variants in the IL-17A-IL-17F genes with risk of cervical cancer and SpA. Current evidence presents that IL-17F rs1889570 could increase risk of asthma by influencing the expression of proinflammatory cytokines, chemokines, and growth factors associated with leukocyte activation and airway remodeling (46). Additionally, a previous study found that the IL-17F rs763780, a missense located in the IL-17F exon3 region, could trigger high IL-17 expression which influenced cervical cancer cell growth, and thus increased risk of cervical cancer (47). Moreover, the SNP rs763780 C allele is linked with high IL-17 expression, which has proved to increase risk of SpA (39).

Additionally, we calculated the ORs and 95% CI in the additive model to assess the relationships between 53 variants and susceptibility to 90 diseases (based on one dataset), yielding significant relationships between 22 variants and the risk of 47 types of carcinoma. For example, our results found that some non-cancerous diseases including autoimmune diseases (such as autoimmune thyroid diseases), alopecia areata, and some type of autoimmune blistering diseases (such as bullous pemphigoid), which have presented in our supplementary Tables (see Supplementary Table 1 ). Moreover, in our study, we performed meta-analysis based on at least three datasets. However, we found that alopecia areata and bullous pemphigoid only contained 1 dataset for each SNP, which could not be assessed by meta-analysis. Therefore, we just presented these information in our supplementary files (see Supplementary Table 1 and Supplementary Table 5 ). Finally, we hope to attempt to collect more information in order to solve this issue in our study in the future. Apart from that, P value of FPRP for the significant associations also be calculated. In summary, we considered the associations between 14 variants and susceptibility to 21 diseases noteworthy (see Supplementary Table 5 ). Further, well-designed studies are recommended to clarify the association with multiple diseases for these variants.

Additionally, 8 SNPs had no association with susceptibility to 14 human diseases in additive model. Of these, 3 SNPs had no association with 3 diseases (rs3748067 and rs763780 for gastric cancer; rs2275913 for HBV infection; rs3748067 for TB) with at least 2,300 cases and 2,300 controls, which presented over 80% statistical power to detect an OR of 1.15 for a variant with MAF 0.20 (Type 1 error 0.05). Further study less than current individuals on these 3 variants for these 3 diseases will not yield fruitful results ( Supplementary Table 3 ). Apart from that, our study identified that significant relationships for 5 variants with risk of 4 diseases (based on two datasets) and 14 variants with risk of 21 diseases (based on one dataset) were considered noteworthy, which might be required to confirm or refute these associations by large-scale studies in the future.

Some limitations apply to this research: (i) even though we conducted a comprehensive search to screen eligible papers, some articles may have been missed. Also, some malignancies and non-cancer diseases could not be completely assessed by meta-analysis owing to insufficient information (for example, lack of genotype amount, fewer than 3 datasets in some associations); (ii) only ethnicity was assessed by subgroup, other factors (such as pathological/clinical type, gene-gene or gene-environment associations and interactions) might be required to confirm or refute the relationships with susceptibility to disease; (iii) the unreasonable data, like errors in genotype, could not be investigated, and (iv) moderate and weak evidence should be explained with caution.

In summary, this large-scale meta-analysis identified that 4 SNPs in the IL-17 family genes were graded as demonstrating strong association to 2 cancer and 4 non-cancer disease risk. Apart from that, these findings provide a foundation for further demonstrating the variations in the IL-17 family genes are positively linked with susceptibility to cervical cancer, lung cancer, asthma, MS, RA, SpA, and highlight that the variants in IL-17 family genes might become a valuable genetic tool to investigate the pharmacological targeting potential of IL-17 family genes. We should further understand its biological pathway and apply these clues to clinical practice and public health for risk assessment and management.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Author contributions

TL, LY, and HC designed this work. TL and LY integrated and analyzed the data. TL, LY, and HC wrote this manuscript. TL, LY, XL, CZ, CJ, ZY, CF, and HC finished the related Tables and Figures. TL, LY, and HC edited and revised the manuscript. All authors approved this manuscript.

Funding

This study was supported by funding from the Chongqing Natural Science Foundation (grant No. cstc2020jcyj-msxmX0257).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2022.1008184/full#supplementary-material

Click here for additional data file. (2.5MB, pdf)

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Data Availability Statement

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