Susceptibility To Male Infertility Research Articles

Pathway Analysis of Genome Wide Association Studies (GWAS) Data Associated with Male Infertility

Background: Infertility is a common condition affecting approximately 10–20% of the reproductive age population. Idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. However, the genetic basis underlying male infertility in humans is only partially understood. The Purpose of the study is to understand the current state of research on the genetics of male infertility and its association with significant biological mechanisms. Results: We performed an Identify Candidate Causal SNPs and Pathway (ICSN Pathway) analysis using a genome-wide association study (GWAS) dataset, and NCBI-PubMed search which included 632 SNPs in GWAS and 451 SNPs from the PubMed server, respectively. The ICSN Pathway analysis produced three hypothetical biological mechanisms associated with male infertility: (1) rs8084 and rs7192→HLA-DRA→inflammatory pathways and cell adhesion; rs7550231 and rs2234167→TNFRSF14→TNF Receptor Superfamily Member 14→T lymphocyte proliferation and activation; rs1105879 and rs2070959→UGT1A6→UDP glucuronosyltransferase family 1 member A6→Metabolism of Xenobiotics, androgen, estrogen, retinol, and carbohydrates. Conclusions: We believe that our results may be helpful to study the genetic mechanisms of male infertility. Pathway-based methods have been applied to male infertility GWAS datasets to investigate the biological mechanisms and reported some novel male infertility risk pathways. This pathway analysis using GWAS dataset suggests that the biological process related to inflammation and metabolism might contribute to male infertility susceptibility. Our analysis suggests that genetic contribution to male infertility operates through multiple genes affecting common inflammatory diseases interacting in functional pathways.

Association between polymorphisms in the XRCC1 gene and male infertility risk: A meta-analysis.

Background:X-ray repair cross-complementing group 1 (XRCC1) single nucleotide polymorphisms (SNPs) might correlate with male infertility susceptibility. This association has been described; however, the findings remain inconsistent. Consequently, this meta-analysis was conducted to characterize the relationship between XRCC1 SNPs and male infertility susceptibility.Methods/main results:Studies were systematically searched in databases to evaluate the association between SNPs of XRCC1 and infertility in males. The effect measures chosen were the 95% confidence intervals (95% CIs) and odds ratios (ORs). A total of 7 studies, including 6 case-controlled studies on XRCC1 Arg399Gln and 3 case-controlled studies on XRCC1 Arg194Trp, were included. Ultimately, the results of this analysis revealed that XRCC1 Arg399Gln SNPs were significantly associated with infertility in males in homozygote comparisons (GG vs GA+AA: OR = 0.614, 95% CI: 0.40–0.937, P = .024). This meta-analysis did not demonstrate a relationship between XRCC1 Arg194Trp and male infertility risk.Conclusions:Our study indicated that XRCC1 Arg399Gln polymorphism was associated with a significantly decreased male infertility risk, but not XRCC1 Arg194Trp.

Polymorphisms of protamine genes contribute to male infertility susceptibility in the Chinese Han population.

Protamine (PRM) plays important roles in the packaging of DNA within the sperm nucleus. To investigate the role of PRM1/2 and transition protein 1 (TNP1) polymorphisms in male infertility, 636 infertile men and 442 healthy individuals were recruited into this case-controlled study of the Chinese Han population, using MassARRAY technology to analyze genotypes. Our analysis showed that there were no significant differences between controls and infertile cases among the five single nucleotide polymorphisms identified in PRM1, PRM2 and TNP1 [rs737008 (G/A), rs2301365 (C/A), rs2070923 (C/A), rs1646022 (C/G) and rs62180545 (A/G)]. However, we found that the PRM1 and PRM2 haplotypes GCTGC, TCGCA and TCGCC exhibited significant protective effects against male infertility compared to fertile men, while TCGGA, GCTCC and TCGGC represented significant risk factors for spermatogenesis. Our data showed that rs737008 and rs2301365 in PRM1, and rs1646022 in PRM2, were significantly associated with male infertility and that gene–gene interaction played a role in male infertility. A linkage disequilibrium plot for the five SNPs showed that rs737008 was strongly linked with both rs2301365 and rs2070923. These findings are likely to help improve our understanding of the etiology of male infertility. Further studies should include a larger number of genes and SNPs, particularly growing critical genes; such studies will help us to unravel the effect of individual genetic factors upon male infertility.

XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T Gene Polymorphisms Associated with Male Infertility Risk: Evidences from Case-Control and In Silico Studies.

We evaluate the association between genetic polymorphisms of XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T with male infertility susceptibility. A total of 392 men including 178 infertile males (102 idiopathic azoospermia and 76 severe oligozoospermia) and 214 healthy controls were recruited. XRCC6 -61C>G and XRCC7 6721G>T genotyping was performed by PCR-RFLP whereas XRCC5 VNTR was performed by PCR. The 2R allele and 2R allele carriers of XRCC5 VNTR polymorphism significantly decreased risk of male infertility. The mutant GG genotypes and carriers of the CG and GG genotypes of XRCC6 -61C>G showed increased risk for the male infertility. Furthermore, the G allele of the XRCC6 -61C>G was correlated with increased susceptibility to male infertility. Likewise, the T allele of the XRCC7 6721G>T polymorphism was associated with increased susceptibility to male infertility in azoospermia. In silico analysis predicted that the presence of tandem repeats in XRCC5 gene prompter can be sequence to bind to more nuclear factors. Also, rs2267437 (C>G) variant was located in a well-conserved region in XRCC6 promoter and this variation might lead to differential allelic expression. The XRCC7 6721G>T gene polymorphism occurred in an acceptor-splicing site, but this polymorphism has no severe modification on XRCC7 mRNA splicing. Our results indicate the association of XRCC5 VNTR, XRCC6 -61C>G, and XRCC7 6721G>T gene polymorphisms with male infertility in Iranian men.

Association between Methionine Synthase Reductase A66G Polymorphism and Male Infertility: A Meta-Analysis

The aim of this meta-analysis was to assess the methionine synthase reductase (MTRR) gene 66A>G polymorphism and male infertility susceptibility. Studies were identified in PubMed and Embase databases. An odds ratio (OR) was used to assess the relationship between MTRR 66A>G polymorphism and male infertility risk. A total of seven case-control studies containing 1438 patients and 1363 controls were enrolled in the meta-analysis. Our results showed that no association exists between the MTRR 66A>G polymorphism and male infertility risk in the total population (GG vs. AA: OR = 1.29, 95% confidence interval [CI] = 1.00-1.66; GA vs. AA: OR = 1.09, 95% CI = 0.92-1.30; dominant model: OR = 1.13, 95% CI = 0.96-1.34; recessive model: OR = 0.83, 95% CI = 0.67-1.03). In a subgroup analysis by nationality, the 66A>G polymorphism was not associated with male infertility in both Asians and Caucasians. In a subgroup analysis stratified by male infertility type, significant association was found with oligoasthenozoospermia (OAT) (GG vs. AA: OR = 1.83, 95% CI = 1.24-269; GA vs. AA: OR = 1.36, 95% CI = 0.88-2.11; dominant model: OR = 1.51, 95% CI = 1.13-2.01; recessive model: OR = 0.62, 95% CI = 0.46-0.85). In summary, the present meta-analysis suggests that MTRR 66A>G polymorphism may be associated with OAT risk.

Genetic Association Between Androgen Receptor Gene CAG Repeat Length Polymorphism and Male Infertility: A Meta-Analysis.

The association between polymorphism of androgen receptor gene CAG (AR-CAG) and male infertility in several studies was controversial. Based on studies on association between AR-CAG repeat length and male infertility in recent years, an updated meta-analysis is needed. We aimed to evaluate the association between AR-CAG repeat length and male infertility in advantage of the data in all published reports.We searched for reports published before August 2015 using PubMed, CNKI, VIP, and WanFang. Data on sample size, mean, and standard deviation (SD) of AR-CAG repeat length were extracted independently by 3 investigators.Forty-four reports were selected based on criteria. The overall infertile patients and azoospermic patients were found to have longer AR-CAG repeat length (standard mean difference (SMD) = 0.19, 95% confidence interval (CI): 0.10-0.28, P < 0.01; SMD = 0.36, 95% CI: 0.10-0.61, P < 0.01). AR-CAG repeat length was longer in infertile men in Asian, Caucasian, and mixed races (SMD = 0.25, 95% CI: 0.08-0.43, P <0.01; SMD = 0.13, 95% CI: 0.02-0.25, P <0.05; SMD = 0.39, 95% CI: 0.15-0.63, P <0.01). The overall study shows that increased AR-CAG repeat length was associated with male infertility. The subgroup study on races shows that increased AR-CAG repeat length was associated with male infertility in Asian, Caucasian, and mixed races. Increased AR-CAG repeat length was also associated with azoospermia.This meta-analysis supports that increased androgen receptor CAG length is capable of causing male infertility susceptibility.

Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis

Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of 26 case–control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR = 2.32, 95%CI = 2.04–2.65 for TT vs. CC genotype; OR = 1.09, 95%CI = 1.00–1.19 for CT vs. CC genotype; OR = 1.19, 95%CI = 1.10–1.29 for CT/TT vs. CC genotype; OR = 1.54, 95%CI = 1.36–1.74 for TT vs. CC/TT genotype; OR = 1.22, 95%CI = 1.15–1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia.

AB210. The cytochrome P4501A1 gene polymorphisms and idiopathic male infertility risk: a meta-analysis

Meta-analysis Polymorphism Studies of the relationship between male infertility and CYP1A1 polymorphisms are inconclusive. To drive a more precise estimation, we performed a meta-analysis based on 1,060 cases and 1,225 controls from 7 published case-control studies. PubMed and CNKI literature search were conducted to identify all eligible studies investigating such a relationship. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the additive model, dominant model, recessive model, and allele-frequency genetic model. In the overall analysis, the frequency of CYP1A1*2A genotype was significantly associated with susceptibility to idiopathic male infertility. Further stratified analysis by ethnicity showed notable association between the polymorphism and risk of idiopathic male infertility in Asians. In conclusion, these results support that the CYP1A1*2A genotype polymorphism mainly contributes to idiopathic male infertility susceptibility in Asians but not in Caucasians.

Association of the Glutathione S-transferases M1 and T1 polymorphism with male infertility: a meta-analysis

Genes of different pathways regulate spermatogenesis, and the complexity of the spermatogenic process indicates that polymorphisms or mutations in these genes could cause male infertility. Published data on the association between the GSTM1 and GSTT1 polymorphism and male infertility risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 11 studies regarding GSTM1 and 9 studies regarding GSTT1 between 1999 and 2012 were identified through researching MEDLINE, EMBASE and the Chinese Biomedical Database. It was performed to obtain summary estimated odd ratios and 95 % confidence intervals of GSTM1 and GSTT1 for male infertility, with attention to study quality and publication bias. Overall, a significant association was seen between GSTM1 (OR=1.20, 95 % CI=1.02-1.40, P(heterogeneity) =0.000, P=0.027) genotypes and male infertility. Significant associations were also observed in subgroups of Caucasian populations (OR=1.65, 95 %CI=1.16-2.34, P(heterogeneity) =0.006, P=0.005), but were not observed in Asian populations (OR=1.09, 95 % CI=0.72-1.65, P(heterogeneity) =0.054, P=0.697) when stratified by ethnicity. While there was no significant association was seen between GSTT1 (OR=1.00, 95 % CI=0.74-1.35, P(heterogeneity) =0.000, P=0.980) null genotypes and male infertility. Simultaneously, significant associations were not observed in subgroups of Caucasian populations (OR=0.94, 95 %CI=0.44-2.00, P(heterogeneity) =0.000, P=0.867) and Asian populations (OR=0.93, 95 % CI=0.46-1.87, P(heterogeneity) =0.002, P=0.838) when stratified by ethnicity. Our results suggest the GSTM1 null genotype contributes to male infertility susceptibility, while GSTT1 gene polymorphisms are not associated with male infertility in our study.

The glutathione-S-transferase gene polymorphisms (GSTM1 and GSTT1) and idiopathic male infertility risk: A meta-analysis

Published data on the association between male infertility and the glutathione-S-transferase (GST) gene polymorphism are inclusive. To drive a more precise estimation, we performed a meta-analysis based on 1897 cases and 1785 controls from 15 published case–control studies. PubMed and CBMdisc literature research were conducted to identify all eligible studies investigating such a relationship. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.In the overall analysis, the frequency of glutathione-S-transferase Mu-1 (GSTM1) null genotype was significantly associated with susceptibility to idiopathic male infertility. In further stratified analysis by sperm concentration of the case group, no significantly increased risk of azoospermia was found in either GSTM1 null or glutathione-S-transferase Theta-1 (GSTT1) null genotype. Compared with a significant relationship between GSTM1 null genotype and oligoasthenoteratozoospermia (OAT), GSTT1 null genotype was not associated with the OAT risk. Additionally, a subgroup analysis on ethnicity showed no notable association between the polymorphism and the risk of idiopathic male infertility in any of GSTM1 null and GSTT1 null genotype, neither in Asian nor in European populations. In conclusion, these results support that the GSTM1 null genotype mainly contributes to idiopathic male infertility susceptibility, particularly to OAT.

Follicle stimulating hormone receptor G-29A, 919A>G, 2039A>G polymorphism and the risk of male infertility: A meta-analysis

Studies of the relationship between male infertility and polymorphisms in the regions of FSHR G-29A (rs1394205), 919A>G (Thr307Ala, rs6165) and 2039A>G (Asn680Ser, rs6166) have reported inconsistent results. To assess the association between them, a meta-analysis was conducted. PubMed and CBMdisc literature search were conducted to identify all eligible studies investigating such a relationship. The pooled ORs were performed for co-dominant model, dominant model and recessive model in FSHR G-29A, Thr307Ala and Asn680Ser respectively to assess the strength of association.A total of 1644 male infertility cases and 1748 controls were collected from seven case–control studies. In the overall analysis, no significant association between the three polymorphisms and risk of male infertility was observed. Stratified analysis showed that there were no significantly increased risks of azoospermia and oligoasthenoteratozoospermia (OAT) in any of the genetic models. This meta-analysis supports that FSHR G-29A, Thr307Ala and Asn680Ser polymorphisms may not be capable of causing male infertility susceptibility.

Association of the Methylenetetrahydrofolate Reductase Gene A1298C Polymorphism with Male Infertility: A Meta‐Analysis

Published data on the association between the methylenetetrahydrofolate reductase (MTHFR) gene A1298C (rs1801131) polymorphism and male infertility risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of seven case-control studies including 1633 cases and 1735 controls were selected to evaluate the possible association. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the additive model, dominant model, recessive model, and allele-frequency genetic model. In the overall analysis, the frequency of the C1298 allele (C vs. A) was significantly associated with susceptibility to male infertility (OR = 1.12, 95% CI = 1.00-1.26). A subgroup analysis of the subjects showed that MTHFR 1298C was associated with significant increased risk of azoospermia in homozygote comparison (CC vs. AA) and recessive mode (CC vs. AA/AC) (OR = 1.66 for CC vs. AA genotype; OR = 1.67 for CC vs. AA/AC genotype). However, no statistically significant increased risk of oligoasthenoteratozoospermia was found in any of the genetic models. In conclusion, this meta-analysis supports that the MTHFR A1298C polymorphism is capable of causing male infertility susceptibility, especially azoospermia.

Methylenetetrahydrofolate reductase C677T polymorphism and the risk of male infertility: a meta‐analysis

Several molecular epidemiological studies have been conducted to examine the association between MTHFR C677T polymorphism and male infertility susceptibility, but the results remain inconsistent. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 10 case-control studies, including 2275 cases and 1958 controls, were selected. Crude odds ratios (ORs) with 95% confidence intervals were used to assess the strength of association in the additive model, dominant model and recessive model. In the overall analysis, no significant association between the polymorphism and risk of male infertility was observed. Stratified analysis showed that significantly strong association between MTHFR C677T polymorphism and male infertility were present only in Asians (OR = 1.79 for TT vs. CC genotype; OR = 1.42 for CT/TT vs. CC genotype; OR = 1.50 for TT vs. CC/CT genotype; OR = 1.36 for T vs. C allele), but not in Caucasians. Additionally, MTHFR 677T was associated with a significant increase in the risk of azoospermia in all genetic models. No significantly increased risks of oligoasthenoteratozoospermia were found in any of the genetic models. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing male infertility susceptibility in Asians, but not in Caucasians.