Skip to main content
PMC home page
OncoTargets and Therapy logoLink to OncoTargets and Therapy
. 2019 Apr 16;12:2879–2890. doi: 10.2147/OTT.S190093

Leptin rs7799039 (G2548A) polymorphism is associated with cancer risk: a meta-analysis involving 25,799 subjects

Weifeng Tang 1,*, Mingqiang Kang 2,3,4,✉,*, Chao Liu 1, Hao Qiu 5
PMCID: PMC6489571  PMID: 31114233

Abstract

Background: Leptin (LEP) is a human analogous form of the mouse obese gene and plays a critical role in energy expenditure as well as the progression of carcinogenesis. Many studies exploring the relationship between the LEP rs7799039 (G2548A) polymorphism and cancer risk have observed controversial results. To extensively evaluate this potential association, we conducted this meta-analysis.

Methods: All eligible studies published up to August 2018 on the relationship between the LEP rs7799039 G>A polymorphism and cancer risk were obtained by searching PubMed, EMBASE, and the China Biology Medicine databases. The association of LEP rs7799039 G>A polymorphism with cancer risk was evaluated by crude ORs together with their 95% CI's.

Results: Thirty-one case–control studies involving 25,799 subjects were included for meta-analysis. We identify a significant correlation with an overall cancer risk when these eligible case–control studies were pooled for analysis: for AA vs GG: an OR = 1.22, 95% CI = 1.01–1.48, P = 0.042 and for AA/GA vs GG: an OR = 1.16, 95% CI = 1.02–1.33, P = 0.026. A significant association was also detected in Asians, prostate cancer, other cancers, and hematopoietic malignancy subgroups. Sensitivity analysis was conducted by deleting an individual study in turn and calculation of the pooled ORs and CIs of the remainders. The results of sensitivity analyses indicated that no eligible study influenced the pooled ORs and CIs materially. Begg’s and Egger’s tests revealed that there was no evidence of publication bias.

Conclusion: In conclusion, our study suggests that the LEP rs7799039 G>A polymorphism might contribute to the development of cancer. In order to further verify or refute our findings, large and well-designed epidemiological studies are needed.

Keywords: leptin, polymorphism, cancer, risk, energy, meta-analysis

Introduction

Cancer is one of the major public health burden with over 18.1 million new cancer cases and 9.6 million cancer deaths in 2018.1 According to assessments of World Health Organization in 2015, cancer is among the leading cause of death in most countries. The reasons may be very complex. Aging and growth of the population, as well as risk factors for cancer, might influence the development of cancer. Recently, accumulating evidence indicates that there is a connection between diabetes and obesity with cancer.2 Thus, any variation in diabetes and obesity-related genes may influence the risk of cancer.

LEP, a 16-kDa adipocyte-derived peptide hormone, is a mediator of obesity and homeostasis. LEP interacts with the LEP receptor and its function is mediated through this receptor. Previous studies have demonstrated that the LEP signal may be transmitted through several signaling pathways (eg JAK/STAT, MAPK, PI3K, Wnt/β-catenin, and ERK).3,4 It is also reported that LEP may affect angiogenesis, inflammation, thrombosis, and tumor growth, invasion, and metastasis.4–13 Hardwick et al reported that LEP was very important for phosphorylation of the p42/44 mitogen-activated protein kinase and for enhancing proliferation of colonic epithelial cells.14 It is well known that single-nucleotide polymorphisms (SNPs) in genes may be implicated in the pathogenesis of a number of cancers and can be used as an indicator of early screening, diagnostics, and prevention measures.15 The human LEP gene maps to chromosome 7 (location: 128241278–128257629, NCBI Build 38). The LEP gene is polymorphic. And LEP SNPs may influence the risk of cancer.16 The rs7799039 G>A (G2548A) polymorphism in the LEP gene is the most widely studied for its relationship between this locus and the risk of human diseases. Terrasi et al suggested that the occurrence of LEP rs7799039 G>A variants could promote LEP protein expression in breast cancer cells through a Sp1- and nucleolin-dependent pathway, resulting in the LEP overexpression in tumor tissue.17

Recently, many molecular epidemiological studies have been carried out to identify the relationship between the LEP rs7799039 G>A polymorphism and cancer risk, but the findings have been conflicting. Three meta-analyses have been performed to explore the relationship between this SNP and cancer risk.18–20 Results of these studies indicated that individuals carrying the LEP rs7799039 A allele might have an increased susceptibility of overall cancer. However, only a case–control study focusing on the association between the LEP rs7799039 G>A polymorphism and the risk of gastric cancer was included.21 The relationship of this polymorphism with cancer risk in Asians is unclear. Recently, several case–control studies conducted in Asians were carried out to explore the association between the LEP rs7799039 G>A polymorphism and cancer risk. To obtain a more precise assessment of the correlation of LEP rs7799039 G>A polymorphism with the risk of cancer, we performed an updated meta-analysis of all eligible studies focusing on the relationship of the rs7799039 G>A polymorphism to the susceptibility of developing cancer.

Materials and methods

Search strategy

In this meta-analysis, we carried out an electronic literature retrieval in PubMed, Embase, and the China Biology Medicine databases up to August 2018 using the following search strategies: (‘LEP” or “leptin”) and (“carcinoma” or “cancer” or ‘malignancy ‘ or “neoplasms”) and (“polymorphism” or “SNP” or “variation”). There was no restriction on language. The references in included studies and reviewers were carefully checked for other potential data. When a publication involved some subgroups, it was treated separately. This study was reported based on the Preferred Reporting Items for Meta-analyses (PRISMA) guideline (Table S1: PRISMA checklist).22

Selection and exclusion criteria

The major selection criteria were as follows: (1) designed as case–control study that assessed the relationship between LEP rs7799039 G>A variants and cancer risk; (2) presented sufficient data (eg genotype number or other available data) to calculate the pooled-estimating; and (3) genotype distribution in controls did not violate Hardy–Weinberg equilibrium (HWE).

The exclusion criteria were defined as follows: (1) the publication was not designed as a case–control study; (2) the genotype data was not presented or could not be calculated; (3) genotype distribution in controls violated HWE; and (4) review articles and letters.

Data extraction

Two authors (W. Tang and C. Liu) independently extracted the information from each eligible study. If the extracted information was different, they would review the publication again and reached consensus. If they could not get a consistent assessment, another author (H. Qiu) would be invited to resolve the dispute and a final decision was made. The following data were extracted from each study: the surname of the first author, year of publication, country, ethnicity, numbers of participants, source of control, genotype frequencies, and genotyping method.

Statistical analysis

The strength of the correlation of the LEP rs7799039 G>A polymorphism with cancer susceptibility was determined by crude ORs with 95% CIs. The relationship between LEP rs7799039 G>A and cancer risk was evaluated using allele model (A vs G), homozygote model (AA vs GG), recessive model (AA vs GG/GA), and dominant model (AA/GA vs GG). We used the Q and I2 test to check the heterogeneity among the included studies. A P>0.1 and I2<50% indicated that there was low heterogeneity, and then the Mantel–Haenszel method (fixed-effects model) was used to calculate the ORs and CIs;23 otherwise, the DerSimonian and Laird method (random-effects model) was used to assess the association.24,25 The sources of heterogeneity were analyzed by subgroup analyses. Sensitivity analysis was analyzed by omitting an individual study in turn and re-calculating the ORs and CIs. Publication bias was checked by using Bgger’s and Egger’s test. An internet chi-square test was used to determine whether the distribution of the genotypes in controls conformed to HWE (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). All data were calculated and analyzed by using Stata 12.0 software (Stata Corp., College Station, TX). A P<0.05 (two-sided) was considered as statistical significance.

Results

Study characteristics

Based on the selection criteria, 30 publications focusing on the association of the LEP rs7799039 G>A polymorphism with cancer risk were included.21,26–53 One publication contained two independent case–control studies that we treated as two investigations.49 The detail selecting process is shown in Figure 1. A total of 31 case–control studies involving 25,799 subjects were included in this meta-analysis. Among them, 19 were conducted in Caucasians,26–44 eight performed in Asians,21,45–50,54 and four were in mixed populations.51–53 Nine were population-based,27,28,30,33,37,38,43,44,50 and 22 case–control were hospital-based studies.21,26,29,31,32,34–36,39–42,45–49,51–54 Of all the eligible studies, 11 focused on breast cancer,33,37–40,44,48,49,51,53 four focused on colorectal cancer (CRC),31,32,41,52 three focused on prostate cancer (PC),26,30,34 and 13 focused on other cancers.21,27–29,35,36,42,43,45–47,50,54 Other information includingd case–control studies in the pooled analysis is summarized in Table 1. The genotypes and alleles of LEP rs7799039 G>A polymorphism are shown in Table 2.

Figure 1.

Figure 1

Open in a new tab

Flow diagram of the meta-analysis of the association between LEP rs7799039 G>A polymorphism and overall cancer risk.

Table 1.

Characteristics of the studies in meta-analysis

Study Publication year Country Ethnicity Cancer type Sample size (case/control) Source of control Genotype method
Ribeiro et al.26 2004 Portugal Caucasians Prostate cancer 150/118 HB PCR-RFLP
Skibola et al.27 2004 USA Caucasians Lymphoma 376/805 PB TaqMan
Willett et al.28 2005 UK Caucasians Lymphoma 593/754 PB TaqMan
Snoussi et al.51 2006 Tunisia Mixed Breast cancer 308/222 HB PCR-RFLP
Slattery et al.52 2008 USA Mixed Colorectal cancer 1565/1965 HB TaqMan
Chovanec et al.29 2009 Czech Caucasians Endometrial cancer 66/543 HB PCR
Moore et al.30 2009 Finland Caucasians Prostate cancer 1053/1053 PB TaqMan
Pechlivanis et al.31 2009 Czech Caucasians Colorectal cancer 702/752 HB TaqMan
Vasku et al.32 2009 Czech Caucasians Colorectal cancer 102/101 HB PCR-sequencing
Cleveland et al.33 2010 USA Caucasians Breast cancer 1059/1101 PB PCR
Kim et al.21 2012 Korea Asians Gastric cancer 48/48 HB PCR-RFLP
Ribeiro et al.34 2012 Portugal Caucasians Prostate cancer 449/557 HB TaqMan
Tavil et al.35 2012 Turkey Caucasians Leukemia 72/70 HB PCR-RFLP
Garcia-Robles et al.53 2013 Mexico Mixed Breast cancer 130/189 HB PCR
Unsal et al.36 2014 Turkey Caucasians Lung cancer 162/130 HB PCR-RFLP
Zhang et al.45 2018 China Asians Hepatocellular carcinoma 584/923 HB SNPscan
Hussain et al.46 2015 India Asians Oral cancer 306/228 HB PCR-RFLP
Karakus et al.37 2015 Turkey Caucasians Breast cancer 199/185 PB PCR
Mahmoudi et al.38 2015 Iran Caucasians Breast cancer 45/41 PB PCR-RFLP
Mohammadzadeh et al.39 2015 Iran Caucasians Breast cancer 100/100 HB PCR-RFLP
Rostami et al.40 2015 Iran Caucasians Breast cancer 203/171 HB PCR-RFLP
Mahmoudi et al.41 2016 Iran Caucasians Colorectal cancer 261/339 HB PCR-RFLP
Amer et al.42 2017 Egypt Caucasians Hepatocellular carcinoma 150/100 HB PCR-RFLP
Ali et al.43 2017 Pakistan Caucasians Bladder carcinoma 200/200 PB PCR
Qiu et al.47 2017 China Asians Esophageal cancer 507/1496 HB SNPscan
Rodrigo et al.44 2017 Sri Lanka Caucasians Breast cancer 80/80 PB PCR
Cao et al.54 2015 China Asians Lung cancer 162/200 HB PCR-RFLP
Yuan et al.48 2017 China Asians Breast cancer 703/805 HB MALDI-TOF MS
Liu et al.49 2018 China Asians Breast cancer 434/440 HB MALDI-TOF MS
Liu et al.49 2018 China Asians Breast cancer 334/331 HB MALDI-TOF MS
Zhang et al.50 2014 USA Mixed Pancreatic cancer 173/476 PB TaqMan
Open in a new tab

Abbreviations: PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; PCR, polymerase chain reaction; MALDI-TOF MS, Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry.

Table 2.

Distribution of LEP rs7799039 G>A polymorphism genotype and allele

Study Publication year Case AA Case AG Case GG Control AA Control AG Control GG Case A Case G Control A Control G HWE
Ribeiro et al.26 2004 24 89 30 12 62 44 137 149 86 150 Yes
Skibola et al.27 2004 91 167 118 167 376 259 349 403 710 894 Yes
Willett et al.28 2005 127 294 170 145 348 260 548 634 638 868 Yes
Snoussi et al.51 2006 37 152 119 11 99 112 226 390 121 323 Yes
Slattery et al.52 2008 284 782 499 393 938 634 1350 1780 1724 2206 Yes
Chovanec et al.29 2009 20 33 13 131 255 149 73 59 517 553 Yes
Moore et al.30 2009 281 453 213 216 437 210 1015 879 869 857 Yes
Pechlivanis et al.31 2009 120 309 230 150 334 227 549 769 634 788 Yes
Vasku et al.32 2009 24 41 35 20 44 36 89 111 84 116 Yes
Cleveland et al.33 2010 226 492 341 180 561 360 944 1174 921 1281 Yes
Kim et al.21 2012 29 18 1 33 14 1 76 20 80 16 Yes
Ribeiro et al.34 2012 73 212 164 84 268 203 358 540 436 674 Yes
Tavil et al.35 2012 26 31 15 27 29 14 83 61 83 57 Yes
Garcia-Robles et al.53 2013 22 71 37 46 95 48 115 145 187 191 Yes
Unsal et al.36 2014 50 86 26 27 63 40 186 138 117 143 Yes
Zhang et al.45 2014 AA+AG:122 - 51 AA+AG:318 - 158 - - - - Yes
Hussain et al.46 2015 50 154 102 23 92 113 254 358 138 318 Yes
Karakus et al.37 2015 49 105 45 47 98 40 203 195 192 178 Yes
Mahmoudi et al.38 2015 27 11 7 17 19 5 65 25 53 29 Yes
Mohammadzadeh et al.39 2015 36 55 9 52 45 3 127 73 149 51 Yes
Rostami et al.40 2015 115 64 24 63 77 31 294 112 203 139 Yes
Cao et al.54 2015 57 75 30 33 80 87 189 135 146 254 Yes
Mahmoudi et al.41 2016 76 135 50 113 154 72 287 235 380 298 Yes
Amer et al.42 2017 60 69 21 49 47 4 189 111 145 55 Yes
Ali et al.43 2017 61 103 36 61 100 39 225 175 222 178 Yes
Qiu et al.47 2017 291 184 29 797 591 101 766 242 2185 793 Yes
Rodrigo et al.44 2017 32 43 5 53 24 3 107 53 130 30 Yes
Yuan et al.48 2017 416 GG+GA:276 - 426 GG+GA:347 - - - - - Yes
Zhang et al.50 2018 295 221 59 505 360 56 811 339 1370 472 Yes
Liu et al.49 2018 252 GG+GA:182 - 236 GG+GA:206 - - - - - Yes
Liu et al.49 2018 201 GG+GA:133 - 190 GG+GA:141 - - - - - Yes
Open in a new tab

Abbreviation: HWE, Hardy–Weinberg equilibrium.

Meta-analysis results

Table 3 summarizes the results of this meta-analysis. We found that the LEP rs7799039 G>A polymorphism was associated with overall cancer risk (Figure 2). The A vs G genetic model has an OR = 1.10 with a 95% CI = 1.00–1.21 and a P = 0.051. The AA vs GG genetic model has an OR = 1.22 with a 95% CI = 1.01–1.48, and a P = 0.042. When we compared AA/GA vs GG model, we found an OR = 1.16 with a 95% CI = 1.02–1.33 and P = 0.026. Comparing the AA genotype with GA/GG, we calculated an OR =1.12 with a 95% CI = 1.00–1.26 and a P = 0.059.

Table 3.

Results of the meta-analysis from different genetic models

No. of cases/controls A vs G AA vs GG AA+GA vs GG AA vs.GA+GG
OR (95% CI) P I2 P (Q-test) OR (95% CI) P I2 P (Q-test) OR (95% CI) P I2 P (Q-test) OR (95% CI) P I2 P (Q-test)
Total 11,276/14,523 1.10(0.1.00–1.21) 0.051 79.1% <0.001 1.22(1.01–1.48) 0.042 74.9% <0.001 1.16(1.02–1.33) 0.026 68.3% <0.001 1.12(1.00–1.26) 0.059 69.6% <0.001
Ethnicity
 Caucasians 6,022/7,200 1.07(0.96–1.18) 0.216 69.5% <0.001 1.18(0.98–1.41) 0.088 58.5% 0.001 1.11(0.97–1.27) 0.122 49.2% 0.008 1.09(0.92–1.28) 0.314 67.2% <0.001
 Mixed 2,176/2,852 1.07(0.78–1.47) 0.687 83.9% 0.002 1.17(0.55–2.48) 0.676 83.9% 0.002 1.14(0.90–1.45) 0.279 56.4% 0.076 1.08(0.58–2.00) 0.816 81.0% 0.005
 Asians 3,078/4,471 1.27(0.87–1.87) 0.216 91.7% <0.001 1.60(0.67–3.80) 0.287 90.6% <0.001 1.42(0.71–2.85) 0.326 89.6% <0.001 1.23(1.01–1.49) 0.044 70.0% 0.001
Cancer type
 Prostate cancer 1,652/1,728 1.17(0.97–1.40) 0.098 59.5% 0.085 1.36(0.94–1.97) 0.106 56.8% 0.099 1.24(0.89–1.72) 0.208 70.7% 0.033 1.24(1.04–1.47) 0.014 0.0% 0.470
 Breast cancer 3,595/3,665 1.02(0.79–1.31) 0.878 82.4% <0.001 1.11(0.70–1.75) 0.669 71.3% 0.001 1.07(0.84–1.38) 0.576 46.1% 0.072 1.12(0.87–1.43) 0.385 78.3% <0.001
 Colorectal cancer 2,630/3,157 0.95(0.88–1.03) 0.203 0.0% 0.671 0.90(0.77–1.05) 0.169 0.0% 0.675 0.99(0.88–1.11) 0.849 0.0% 0.615 0.88(0.77–1.00) 0.046 0.0% 0.699
 Others 3,399/5,973 1.17(0.98–1.40) 0.081 82.7% <0.001 1.34(0.92–1.94) 0.127 81.1% <0.001 1.25(0.95–1.65) 0.104 78.2% <0.001 1.18(0.98–1.42) 0.083 63.0% 0.002
System of cancer
 Reproductive and breast cancer 5,313/5,936 1.10(0.95–1.29) 0.207 75.9% <0.001 1.28(0.98–1.68) 0.074 63.0% 0.002 1.15(0.97–1.37) 0.105 47.9% 0.032 1.17(0.97–1.40) 0.096 70.7% <0.001
 Hematopoietic malignancy 1,041/1,629 1.13(1.01–1.26) 0.038 0.0% 0.595 1.25(1.00–1.55) 0.049 0.0% 0.680 1.17(0.99–1.39) 0.068 0.0% 0.399 1.15(0.95–1.39) 0.140 0.0% 0.730
 Digestive system cancer 4,398/6,428 0.99(0.86–1.13) 0.838 73.4% <0.001 0.94(0.70–1.25) 0.658 70.4% 0.001 1.01(0.81–1.27) 0.928 71.7% <0.001 0.95(0.82–1.09) 0.454 47.5% 0.055
 Others 524/530 1.60(0.96–2.66) 0.070 88.2% <0.001 2.48(0.99–6.23) 0.053 85.1% 0.001 2.06(1.05–4.02) 0.035 80.3% 0.006 1.66(0.90–3.03) 0.102 78.6% 0.009
Sample size
 <1000 3,685/4,312 1.13(0.94–1.37) 0.200 81.6% <0.001 1.32(0.92–1.90) 0.129 74.8% <0.001 1.29(1.03–1.62) 0.027 64.3% <0.001 1.15(0.92–1.43) 0.224 73.3% <0.001
 ≥1000 7,591/10,211 1.04(0.96–1.12) 0.378 62.4% 0.006 1.05(0.88–1.26) 0.559 67.9% 0.002 1.01(0.90–1.13) 0.836 51.2% 0.037 1.09(0.97–1.23) 0.135 61.6% 0.005
Source of control
 Hospital-based 7,498/9,828 1.13(0.98–1.30) 0.087 83.6% <0.001 1.26(0.94–1.68) 0.118 81.3% <0.001 1.21(0.98–1.49) 0.073 77.7% <0.001 1.13(0.98–1.31) 0.100 71.1% <0.001
 Population-based 3,778/4,695 1.08(0.97–1.19) 0.151 47.6% 0.064 1.24(1.09–1.42) 0.001 0.0% 0.731 1.10(0.99–1.21) 0.069 0.0% 0.811 1.11(0.90–1.37) 0.314 65.2% 0.005
Open in a new tab

Figure 2.

Figure 2

Open in a new tab

Meta-analysis of the association between LEP rs7799039 G>A polymorphism and overall cancer risk (dominant model, random-effects model).

In a subgroup analysis by ethnicity, we found an association in Asian populations with AA/GA vs GG having an OR = 1.23, a 95% CI = 1.01–1.49 and a P = 0.044, Table 3.

In a subgroup analysis by cancer type, we found that the LEP rs7799039 G>A polymorphism moderately increased the risk of PC; AA vs GA/GG: OR =1.24, 95%CI = 1.04–1.470, P = 0.014. However, we found that this G>A polymorphism might actually confer a decreased the risk to CRC, AA vs GA/GG: OR =0.88, 95%CI = 0.77–1.00, P = 0.046. When we conducted a subgroup analysis by cancer system, we found that this G>A polymorphism might increase the susceptibility of hematopoietic cancer; A vs G: OR = 1.13, 95% CI = 1.01–1.26, P = 0.038; AA vs GG: OR = 1.25, 95% CI = 1.00–1.55, P = 0.049) and other system cancers (AA/GA vs GG: OR = 2.06, 95% CI = 1.05–4.02, P = 0.035.

Heterogeneity analysis

For this meta-analysis, we found that there was significant heterogeneity among the included case–control studies (Table 3). To identify the major sources of heterogeneity, we carried out subgroup analyses. The results indicated that Asians, small sample size studies (<1000), and hospital-based studies might lead to the major heterogeneity in this meta-analysis.

Sensitivity analysis

Sensitivity analysis was conducted by deleting an individual study in turn and calculating the pooled ORs and CIs of the remaining studies. For this SNP, the results under all genetic comparisons were not influenced by removing any eligible study (Figure 4).

Figure 4.

Figure 4

Open in a new tab

Sensitivity analysis of the influence of dominant model (random-effects estimates).

Publication bias

Begg’s test and Egger’s test were used to determine whether there was publication bias in genetic comparisons. The shapes of the Begg’s funnel plot revealed that they were symmetrical; A vs G had a P Begg’s= 0.588, AA vs GG had a P Begg’s= 0.802; AA/GA vs GG had a P Begg’s = 0.953; and AA vs GA/GG had a P Begg’s= 0.887 (Figure 3). The results of Egger’s test also highlighted that there was no evidence of publication bias (A vs G: PEgger’s = 0.559; AA vs GG: PEgger’s = 0.579; AA/GA vs GG: PEgger’s = 0.639 and AA vs GA/GG: PEgger’s = 0.660).

Figure 3.

Figure 3

Open in a new tab

Begg’s funnel plot of meta-analysis of the association between LEP rs7799039 G>A polymorphism and cancer risk (dominant genetic model, random-effects model).

Discussion

The adipocyte-derived peptide hormone LEP has a well-known influence on inflammation, tumor growth, and metastasis. Rs7799039 G>A is a common promoter SNP in the LEP gene, that may affect the transcriptional level and LEP expression.55 We therefore hypothesized that the LEP rs7799039 G>A polymorphism might be closely related to the susceptibility of cancer. Although a number of studies have focused on the relationship between the LEP rs7799039 G>A polymorphism and cancer risk, the observed results have been inconsistent. Three meta-analyses carried out by Liu et al18, He et al19, and Yang et al20, including 12, 15, and 15 eligible case–control studies, respectively, yielded conflicting results in some subgroups. Of late, some new data regarding the relationship of the LEP rs7799039 G>A polymorphism and cancer risk have been reported.36–50,53,54 Therefore, an updated meta-analysis is needed to address this issue. In our meta-analysis, data of 31 independent case–control studies including 11,276 cancer cases and 14,523 controls were pooled, which is more participants than were in the meta-analyses mentioned above. Thus, this updated analysis should be more comprehensive. To the best of our knowledge, the present study is the most convincing pooled analysis to explore the association between the LEP rs7799039 G>A polymorphism and cancer risk. Results of our meta-analysis did indicate that the LEP rs7799039 G>A polymorphism was associated with an increased risk of overall cancer, especially in Asians, PC, hematopoietic malignancy, and other system cancer subgroups.

With the accumulating evidence of genetic association investigations, it is urgent to synthesize all available data to obtain a robust result. According to the findings, the association of increased cancer risk with the LEP rs7799039 G>A polymorphism was found in overall populations. Race also could be a critical biological factor for the genetic comparison. In previous meta-analyses,18–20 most of the eligible studies contained only Caucasians. In the current study, more case–control studies included Asians.21,45–50,54 The results suggest that the LEP rs7799039 G>A polymorphism might increase the risk of cancer in Asians. We are the first to report the relationship between this SNP and cancer risk in this ethnicity.

An interesting phenomenon observed during stratified analysis was that the LEP rs7799039 G>A polymorphism decreased the risk of CRC, while this SNP increased the risk of PC, other cancers, and hematopoietic malignancy. One possible explanation is that there were insufficient sample sizes for subgroup analysis. Although our findings were stable by one-way sensitivity analysis, publication bias was not found.

Among the included studies, significant heterogeneity was found in four genetic models for overall analysis. Stratified analyses indicated that heterogeneity was significant in some subgroups (eg Asians, small sample sizes, and hospital-based studies). These factors may contribute to the major heterogeneity in this study.

Several limitations, in this meta-analysis, should be acknowledged. First, although the Begg’s funnel plot and Egger’s test suggested no significant publication bias, it is possible that certain unpublished data are yet to be included. Selection bias for this study might have existed. Second, for lack of detailed information in the included studies, only crude ORs and CIs were calculated. We did not carry out the analysis adjusted for other potential risk factors (eg smoking, alcohol consumption, body mass index, and vegetable intake). Finally, heterogeneity among the eligible case–control studies was statistically significant in multiple genetic models. These findings should be considered with caution.

In conclusion, this study performed an extensive assessment based on a larger sample size than the previous pooled analysis. Our study indicates that the LEP rs7799039 G>A polymorphism may contribute to the development of cancer. In order to further verify or refute our findings, large well-designed epidemiological studies are warranted. As investigations among Asian populations are limited, further well-designed epidemiological studies involving a wider spectrum of subjects to explore the potential role of this SNP in Asians are needed.

Disclosure

The authors report no conflicts of interest in this work.

References

  • 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492 [DOI] [PubMed] [Google Scholar]
  • 2.Garg SK, Maurer H, Reed K, Selagamsetty R. Diabetes and cancer: two diseases with obesity as a common risk factor. Diabetes Obes Metab. 2014;16(2):97–110. doi: 10.1111/dom.2014.16.issue-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Saxena NK, Sharma D, Ding X, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67(6):2497–2507. doi: 10.1158/0008-5472.CAN-06-3075 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Liang X, Wang S, Wang X, Zhang L, Zhao H, Zhang L. Leptin promotes the growth of breast cancer by upregulating the Wnt/beta-catenin pathway. Exp Ther Med. 2018;16(2):767–771. doi: 10.3892/etm.2018.6212 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Nwadozi E, Ng A, Stromberg A, et al. Leptin is a physiological regulator of skeletal muscle angiogenesis and is locally produced by PDGFRalpha and PDGFRbeta expressing perivascular cells. Angiogenesis. 2019;22(1):103–115. doi:10.1007/s10456-018-9641-6 [DOI] [PubMed] [Google Scholar]
  • 6.Sun X, Wei J, Tang Y, et al. Leptin-induced migration and angiogenesis in rheumatoid arthritis is mediated by reactive oxygen species. FEBS Open Bio. 2017;7(12):1899–1908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Clements VK, Long T, Long R, Figley C, Smith DMC, Ostrand-Rosenberg S. Frontline science: high fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells. J Leukoc Biol. 2018;103(3):395–407. doi: 10.1002/JLB.4HI0517-210R [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Ray A, Cleary MP. The potential role of leptin in tumor invasion and metastasis. Cytokine Growth Factor Rev. 2017;38:80–97. doi: 10.1016/j.cytogfr.2017.11.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Ye XL, Lu CF. Association of polymorphisms in the leptin and leptin receptor genes with inflammatory mediators in patients with osteoporosis. Endocrine. 2013;44(2):481–488. doi: 10.1007/s12020-013-9899-9 [DOI] [PubMed] [Google Scholar]
  • 10.Patraca I, Martinez N, Busquets O, et al. Anti-inflammatory role of Leptin in glial cells through p38 MAPK pathway inhibition. Pharmacol Rep. 2017;69(3):409–418. doi: 10.1016/j.pharep.2016.12.005 [DOI] [PubMed] [Google Scholar]
  • 11.Santos CL, Bobermin LD, Souza DO, Quincozes-Santos A. Leptin stimulates the release of pro-inflammatory cytokines in hypothalamic astrocyte cultures from adult and aged rats. Metab Brain Dis. 2018. doi: 10.1007/s11011-018-0311-6 [DOI] [PubMed] [Google Scholar]
  • 12.Lu W, Zhou S, Xue L, et al. High preoperative serum leptin level is an independent risk factor for deep vein thrombosis after total knee arthroplasty in osteoarthritis patients: a prospective and cross-sectional study. Medicine. 2018;97(21):e10884. doi: 10.1097/MD.0000000000010884 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Petrini S, Neri T, Lombardi S, et al. Leptin induces the generation of procoagulant, tissue factor bearing microparticles by human peripheral blood mononuclear cells. Biochim Biophys Acta. 2016;1860(6):1354–1361. doi: 10.1016/j.bbagen.2016.03.029 [DOI] [PubMed] [Google Scholar]
  • 14.Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP. Leptin is a growth factor for colonic epithelial cells. Gastroenterology. 2001;121(1):79–90. [DOI] [PubMed] [Google Scholar]
  • 15.Yuzhalin AE, Kutikhin AG. Integrative systems of genomic risk markers for cancer and other diseases: future of predictive medicine. Cancer Manag Res. 2012;4:131–135. doi: 10.2147/CMAR.S30855 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Yang J, Zhong Z, Tang W, Chen J. Leptin rs2167270 G > A (G19A) polymorphism may decrease the risk of cancer: A case-control study and meta-analysis involving 19 989 subjects. J Cell Biochem. 2019. doi: 10.1002/jcb.28378 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Terrasi M, Fiorio E, Mercanti A, et al. Functional analysis of the −2548G/A leptin gene polymorphism in breast cancer cells. Int J Cancer. 2009;125(5):1038–1044. doi: 10.1002/ijc.24372 [DOI] [PubMed] [Google Scholar]
  • 18.Liu Y, Wu H, Zhu Y, Gao Y. Genetic association between leptin-2548G/A polymorphism and risk of cancer: a meta analysis. Int J Clin Exp Med. 2015;8(1):448–455. [PMC free article] [PubMed] [Google Scholar]
  • 19.He J, Xi B, Ruiter R, et al. Association of LEP G2548A and LEPR Q223R polymorphisms with cancer susceptibility: evidence from a meta-analysis. PLoS One. 2013;8(10):e75135. doi: 10.1371/journal.pone.0075135 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Yang Y, Liu P, Guo F, et al. Genetic G2548A polymorphism of leptin gene and risk of cancer: a meta-analysis of 6860 cases and 7956 controls. J BUON. 2014;19(4):1096–1104. [PubMed] [Google Scholar]
  • 21.Kim EY, Chin HM, Park SM, et al. Susceptibility of gastric cancer according to leptin and leptin receptor gene polymorphisms in Korea. J Korean Surg Soc. 2012;83(1):7–13. doi: 10.4174/jkss.2012.83.1.7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–269, W264. [DOI] [PubMed] [Google Scholar]
  • 23.Mantel NHW, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748. [PubMed] [Google Scholar]
  • 24.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Bmj. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. [DOI] [PubMed] [Google Scholar]
  • 26.Ribeiro R, Vasconcelos A, Costa S, et al. Overexpressing leptin genetic polymorphism (−2548 G/A) is associated with susceptibility to prostate cancer and risk of advanced disease. Prostate. 2004;59(3):268–274. doi: 10.1002/pros.20004 [DOI] [PubMed] [Google Scholar]
  • 27.Skibola CF, Holly EA, Forrest MS, et al. Body mass index, leptin and leptin receptor polymorphisms, and non-hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2004;13(5):779–786. [PubMed] [Google Scholar]
  • 28.Willett EV, Skibola CF, Adamson P, et al. Non-Hodgkin’s lymphoma, obesity and energy homeostasis polymorphisms. Br J Cancer. 2005;93(7):811–816. doi: 10.1038/sj.bjc.6602762 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Chovanec J, Bienertova-Vasku JA, Dostalova Z. Leptin–2548 g/A polymorphism in endometrial cancer. Klinicka. 2009;22(5):223–227. [PubMed] [Google Scholar]
  • 30.Moore SC, Leitzmann MF, Albanes D, et al. Adipokine genes and prostate cancer risk. Int J Cancer. 2009;124(4):869–876. doi: 10.1002/ijc.24043 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Pechlivanis S, Bermejo JL, Pardini B, et al. Genetic variation in adipokine genes and risk of colorectal cancer. Eur j endocrinol. 2009;160(6):933–940. doi: 10.1530/EJE-09-0039 [DOI] [PubMed] [Google Scholar]
  • 32.Vasku A, Vokurka J, Bienertova-Vasku J. Obesity-related genes variability in Czech patients with sporadic colorectal cancer: preliminary results. Int J Colorectal Dis. 2009;24(3):289–294. doi: 10.1007/s00384-008-0553-6 [DOI] [PubMed] [Google Scholar]
  • 33.Cleveland RJ, Gammon MD, Long CM, et al. Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival. Breast Cancer Res Treat. 2010;120(3):745–752. doi: 10.1007/s10549-009-0503-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ribeiro RJ, Monteiro CP, Azevedo AS, et al. Performance of an adipokine pathway-based multilocus genetic risk score for prostate cancer risk prediction. PLoS One. 2012;7(6):e39236. doi: 10.1371/journal.pone.0039236 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Tavil B, Balta G, Ergun EL, et al. Leptin promoter G-2548A genotypes and associated serum leptin levels in childhood acute leukemia at diagnosis and under high-dose steroid therapy. Leuk Lymphoma. 2012;53(4):648–653. doi: 10.3109/10428194.2011.626881 [DOI] [PubMed] [Google Scholar]
  • 36.Unsal M, Kara N, Karakus N, Tural S, Elbistan M. Effects of leptin and leptin receptor gene polymorphisms on lung cancer. Tumour Biol. 2014;35(10):10231–10236. doi: 10.1007/s13277-014-2293-2 [DOI] [PubMed] [Google Scholar]
  • 37.Karakus N, Kara N, Ulusoy AN, Ozaslan C, Tural S, Okan I. Evaluation of CYP17A1 and LEP gene polymorphisms in breast cancer. Oncol Res Treat. 2015;38(9):418–422. doi: 10.1159/000438940 [DOI] [PubMed] [Google Scholar]
  • 38.Mahmoudi R, Noori Alavicheh B, Nazer Mozaffari MA, Fararouei M, Nikseresht M. Polymorphisms of leptin (−2548 G/A) and leptin receptor (Q223R) genes in Iranian women with breast cancer. Int J Genomics. 2015;2015:132720. doi: 10.1155/2015/132720 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Mohammadzadeh G, Ghaffari MA, Bafandeh A, Hosseini SM, Ahmadi B. The relationship between −2548 G/A leptin gene polymorphism and risk of breast cancer and serum leptin levels in Ahvazian women. Iran J Cancer Prev. 2015;8(2):100–108. [PMC free article] [PubMed] [Google Scholar]
  • 40.Rostami S, Kohan L, Mohammadianpanah M. The LEP G-2548A gene polymorphism is associated with age at menarche and breast cancer susceptibility. Gene. 2015;557(2):154–157. doi: 10.1016/j.gene.2014.12.021 [DOI] [PubMed] [Google Scholar]
  • 41.Mahmoudi T, Farahani H, Nobakht H, Dabiri R, Zali MR. Genetic variations in leptin and leptin receptor and susceptibility to colorectal cancer and obesity. Iran J Cancer Prev. 2016;9(3):e7013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Amer T, El-Baz R, Mokhtar AR, El-Shaer S, Elshazli R, Settin A. Genetic polymorphisms of IL-23R (rs7517847) and LEP (rs7799039) among Egyptian patients with hepatocellular carcinoma. Arch Physiol Biochem. 2017;123(5):279–285. doi: 10.1080/13813455.2017.1320680 [DOI] [PubMed] [Google Scholar]
  • 43.Ali SHB, Bangash KS, Rauf A, et al. Identification of novel potential genetic predictors of urothelial bladder carcinoma susceptibility in Pakistani population. Fam Cancer. 2017;16(4):577–594. doi: 10.1007/s10689-017-9991-z [DOI] [PubMed] [Google Scholar]
  • 44.Rodrigo C, Tennekoon KH, Karunanayake EH, De Silva K, Amarasinghe I, Wijayasiri A. Circulating leptin, soluble leptin receptor, free leptin index, visfatin and selected leptin and leptin receptor gene polymorphisms in sporadic breast cancer. Endocr J. 2017;64(4):393–401. doi: 10.1507/endocrj.EJ16-0448 [DOI] [PubMed] [Google Scholar]
  • 45.Zhang S, Jiang J, Chen Z, et al. Investigation of LEP and LEPR polymorphisms with the risk of hepatocellular carcinoma: a case-control study in Eastern Chinese Han population. Onco Targets Ther. 2018;11:2083–2089. doi: 10.2147/OTT.S153931 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Hussain SR, Naqvi H, Gupta S, et al. A study on oncogenic role of leptin and leptin receptor in oral squamous cell. Tumour Biol. 2015;36(8):6515–6523. doi: 10.1007/s13277-015-3342-1 [DOI] [PubMed] [Google Scholar]
  • 47.Qiu H, Lin X, Tang W, et al. Investigation of TCF7L2, LEP and LEPR polymorphisms with esophageal squamous cell carcinomas. Oncotarget. 2017;8(65):109107–109119. doi: 10.18632/oncotarget.22619 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Yuan XL, Xu ZP, Liu CR, et al. [Study of the association between polymorphism of persistent obesity, human leptin gene/leptin receptor gene and molecular subtypes of breast cancer]. Zhonghua Yu Fang Yi Xue Za Zhi. 2017;51(6):533–538. doi: 10.3760/cma.j.issn.0253-9624.2017.06.015 [DOI] [PubMed] [Google Scholar]
  • 49.Liu CR, Li Q, Hou C, et al. Changes in body mass index, leptin, and leptin receptor polymorphisms and breast cancer risk. DNA Cell Biol. 2018;37(3):182–188. doi: 10.1089/dna.2017.4047 [DOI] [PubMed] [Google Scholar]
  • 50.Zhang J, Dhakal IB, Zhang X, Prizment AE, Anderson KE. Genetic variability in energy balance and pancreatic cancer risk in a population-based case-control study in Minnesota. Pancreas. 2014;43(2):281–286. doi: 10.1097/MPA.0b013e3182a7c829 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Helal AN, Chouchane L. Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer. 2006;6:38. doi: 10.1186/1471-2407-6-38 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Slattery ML, Wolff RK, Herrick J, Caan BJ, Potter JD. Leptin and leptin receptor genotypes and colon cancer: gene-gene and gene-lifestyle interactions. Int J Cancer. 2008;122(7):1611–1617. doi: 10.1002/ijc.23135 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Luan H, Zhang H, Li Y, et al. Association of two obesity-related gene polymorphisms LEPG2548A rs7799039 and LEPRQ223R rs1137101 with the risk of breast cancer. Oncotarget. 2017;8(35):59333–59344. doi: 10.18632/oncotarget.19580 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Cao FJWG, Yu YD, Yu XJ, Die QS, Lei JH, Deng SH. Chen P association of leptin gene −2548 G/A polymorphism with the susceptibility and prognosis of non-small cell lung cancer. Chin J Exp Surg. 2015;32(3):621–623. [Google Scholar]
  • 55.Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P. A polymorphism in the leptin promoter region (−2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res. 2002;34(7):355–359. doi: 10.1055/s-2002-33466 [DOI] [PubMed] [Google Scholar]

Articles from OncoTargets and therapy are provided here courtesy of Dove Press

RESOURCES