Hardy-Weinberg Equilibrium In Controls Research Articles

Association between tumor necrosis factor-alpha polymorphisms (rs361525, rs1800629, rs1799724, 1800630, and rs1799964) and risk of psoriasis in studies following Hardy-Weinberg equilibrium: A systematic review and meta-analysis

ObjectivePsoriasis is a disease with an immunogenetic background in which cytokines have important effects on its prevalence and incidence. The present meta-analysis evaluated the relationship between tumor necrosis factor-alpha (TNF-α) polymorphisms (rs361525, rs1800629, rs1799724, 1800630, and rs1799964) and psoriasis risk in studies following Hardy-Weinberg equilibrium (HWE). Materials and methodsFour databases were searched to retrieve relevant studies reporting the distributions of TNF-α polymorphisms in psoriasis cases compared to controls. The effect sizes were the 95% confidence intervals (CIs) and odds ratios (ORs). Subgroup analysis, sensitivity analyses, publication bias, trial sequential analysis (TSA), and meta-regression were performed on the initial pooled results of TNF-α polymorphisms. ResultsThirty-six articles with 71 studies were included in the meta-analysis (twenty-six: rs361525, twenty-seven: rs1800629, nine: rs1799724, four: 1800630, and five: rs1799964). The pooled ORs for −238 G/A rs361525 polymorphism were 2.33 (p < 0.00001), 2.79 (p < 0.0001), 2.35 (p < 0.00001), 2.44 (p < 0.00001), and 2.45 (p < 0.00001), as well as 1.57 (p < 0.00001), 1.98 (p = 0.01), 1.61 (p < 0.00001), 1.64 (p < 0.00001), and 1.79 (p < 0.00001) for −857 C/T rs1799724 polymorphism in allelic, homozygous, heterozygous, dominant, and recessive models, respectively. Ethnicity, psoriasis type, and sample size affected the pooled results of rs361525, rs1800629, and rs1799724 polymorphisms. Based on TSA, there were just sufficient cases for −238 G/A rs361525 polymorphism in five genetic models and −857C/T rs1799724 polymorphism in allelic, heterozygous, and dominant models. ConclusionsThe A allele and GA and GG genotypes of −238 G/A rs361525 polymorphism and T allele, TT and CT genotypes of −857C/T rs1799724 polymorphism were related to increased risks in psoriasis cases. Well-designed studies (with no deviation from HWE in controls) with more cases are recommended in the future.

Involvement of miR-126 rs4636297 and miR-146a rs2910164 polymorphisms in the susceptibility for diabetic retinopathy: a case-control study in a type 1 diabetes population.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. MiRNA-126 and miRNA-146a have been described as having abnormal expressions in diabetic retinopathy (DR) patients. Polymorphisms in genes codifying miRNAs (miRSNPs) may alter the expression of the corresponding miRNA and, thus, interfere with susceptibility to DR. Therefore, miRSNPs in miR-126 and miR-146a genes could be associated with DR susceptibility. The purpose of this study was to investigate the association between miR-126 rs4636297 (G/A) and miR-146a rs2910164 (G/C) miRSNPs and DR. This case-control study included 195 type 1 diabetes mellitus (T1DM) patients with DR (cases) and 215 patients without DR and with ≥10years of T1DM (controls). MiRSNPs were genotyped by real-time PCR. Genotype distributions of two analysed miRSNPs were in Hardy-Weinberg equilibrium in controls (p>0.050). Frequencies of the miR-126 rs4636297 miRSNP were not significantly different between case and control groups (p=0.169). However, after adjustment for age, glycated haemoglobin, triglycerides, estimated glomerular filtration rate and ethnicity, the A allele of this miRSNP was associated with protection for DR under additive [OR: 0.444 (95% CI: 0.211-0.936), p=0.033] and dominant [OR: 0.512 (95% CI: 0.303-0.865), p=0.012] inheritance models. Genotype and allele frequencies of miR-146a rs2910164 miRSNP did not differ between groups (p=0.368 and p=0.957), and this polymorphism was not associated with DR when assuming different inheritance models. Our results suggest an association between the A allele of miR-126 rs4636297 miRSNP and protection for DR in a Southern Brazilian population.

The association between the C-reactive protein gene +1444C/T polymorphism and Parkinson's disease susceptibility in a Chinese population.

C-reactive protein (CRP) is increased in Parkinson's disease (PD). The CRP +1444C/T (rs1130864) polymorphism is located in the 3' untranslated region (3'-UTR) and is associated with serum CRP concentrations. We explored the relationship between the CRP +1444C/T polymorphism and susceptibility to PD. A total of 1000 subjects from a Chinese population were recruited into this case-control study, including 500 PD patients and 500 healthy controls. The genotype of the CRP +1444C/T polymorphism was tested by Sanger sequencing, and the Hardy-Weinberg equilibrium (HWE) was assessed in the groups. The odds ratios and 95% confidence intervals were calculated to evaluate the strength of any correlations in allelic, dominant, recessive, and additive genetic models. The genotypic distribution of the CRP +1444C/T polymorphism was consistent with HWE in controls, and markedly different with cases. The CRP +1444C/T polymorphism was associated with increased PD risk in allelic and dominant models in the overall and male population, but not the female subgroup. The presence of a CRP +1444C/T polymorphism may be associated with an increased risk of PD in our Chinese population. Given the missing support for a role of this SNP in PD in the pre-existing GWAS, the SNP may not be genuinely associated with PD despite some positive candidate gene studies.

Interaction between eNOS gene polymorphism and current smoking on susceptibility to coronary heart disease in Chinese people.

This study aims to explore the relation between endothelial nitric oxide synthase (eNOS) single-nucleotide polymorphisms (SNPs) and the risk of coronary heart disease (CHD). SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats) was performed to test Hardy-Weinberg equilibrium in controls. Generalized multifactor dimensionality reduction (GMDR) was adopted to screen the preferable interaction between eNOS SNPs and smoking. The frequency for the rs1799983-T allele was 31.1% in CHD patients, which was significantly higher than that of 19.8% in controls (P < 0.05). The frequency for the rs891512-A allele was 28.8% in cases, which was also significantly higher than that of 20.1% in controls (P < 0.05). Logistic regression analysis showed that both rs1799983-T and rs891512-A alleles were related with increased risk of CHD, and the odds ratios (ORs) [95% confidence interval (CI)] were 1.71 (1.31-2.15) and 1.57 (1.14-2.07), respectively. High-order interactions were investigated among SNPs and environmental factors using the GMDR method. The data showed that a two-locus model (rs1799983 × smoking) had a testing accuracy of 0.60 (P = 0.001). We found that current smokers with rs1799983-GT or TT within eNOS gene have the highest CHD risk, compared to never smokers with rs1799983-GG genotype, OR (95% CI) = 2.74 (1.78-3.85), after covariates adjustment for age, gender, BMI, and alcohol drinking. The rs1799983-T and rs891512-A alleles and interaction between rs1799983 and smoking were all risk factors of CHD.

Association of single-nucleotide polymorphisms in TLR4 gene and gene-environment interaction with primary open angle glaucoma in a Chinese northern population.

The present study aimed to investigate the association of several single nucleotide polymorphisms (SNPs) within the Toll-like receptor 4 (TLR4) gene and additional gene-environment interaction with primary open angle glaucoma (POAG) risk. Tests for Hardy-Weinberg equilibrium in controls and haplotype analysis were performed using SNPstats (https://www.snpstats.net). Generalized multifactor dimensionality reduction (GMDR) was performed to test the interaction effects among four SNPs within the TLR4 gene and environmental factors. Logistic regression was performed to calculate the odds ratios (ORs) (95% confidence interval [CI]) for association between four SNPs within the TLR4 gene and POAG risk. The POAG risk was significantly higher in carriers with the T allele of rs4986791 and the T allele of rs2149356 within the TLR4 gene than in those with the wild-type genotype, adjusted ORs (95% CI) were 1.65 (1.23-2.12) and 1.70 (1.16-2.31). The GMDR model suggested a significant two-locus model (p = 0.0010) involving rs2149356 and alcohol drinking. Alcohol drinkers with the rs2149356-GT+TT genotype within the TLR4 gene have the highest POAG risk compared to never alcohol drinkers with the rs2149356-GG genotype (OR = 2.62; 95% CI = 1.48-3.78) after covariates adjustment. However, the study did not find a significant any-locus model involving SNP and smoking. In all samples, the haplotype rs2149356-G-rs7873784-C was observed most frequently in two groups (47.47% and 48.21% for the POAG patients and controls, respectively). The results also indicated that no significant haplotype was associated with POAG risk. The minor alleles of rs4986791 and rs2149356 within the TLR4 gene, as well as interaction between rs2149356 and alcohol drinking, were associated with an increased POAG risk.

Evaluation of genetic association of 40 SNPs in candidate genes with cholesterol gallstone disease in north Indian population

BackgroundIn north Indian population, Gallbladder Stone Disease (GSD) affects 7% of population, with majority of stones containing >50% cholesterol. In general, GSD susceptibility has been suggested to include the combination of predisposing alleles of multiple lithogenic (LITH) genes and environmental factors. Materials and methodsStudy included 610 GSD patients (USG positive) and 315 healthy controls. A panel of 48 SNPs was prepared for candidate genes based on pathobiology of GSD, MAF in Hapmap and 1000 genome database, and Tagger SNPs in Linkage Disequilibrium. Genotyping was carried out by Sequenom Mass ARRAY platform and statistical analyses were performed using SPSS version 16.0, Bonferroni adjustment was applied for multiple testing corrections. Potential functional consequences of the exonic polymorphisms were determined using Polyphen2, SIFT score and interaction networks of associated genes by GENEMANIA. ResultsGenotypes of 40 out of 48 SNPs followed Hardy Weinberg Equilibrium in controls and subjected to present analysis. We observed significant associations of genotypes/alleles of FGFR4, CYP7A1, APOE, TM4SF4, NR1H2, IL10, PLCE1, CYP1A1, SLC10A2, MMP2, CYP8B1, Gab1 with GSD whereas remaining SNPs revealed no association.Analysis after gender stratification and Bonferroni correction revealed that in males SNPs in TM4SF4, PLCE1 and Gab1 were significantly associated with GSD while in females APOE and CYP8B1 polymorphisms were significantly associated with GSD.All but three significantly associated SNPs were intronic. The potential functional consequences of associated exonic SNPs by Polyphen2 predicted probable damaging effects of FGFR4 and APOE variants, while PLCE1 SNP showed benign effect. Further SIFT score predicted probable tolerated effects of FGFR4 and PLCE1, while APOE variant showed deleterious effect. ConclusionsOur study suggests that FGFR4, CYP7A1, APOE, TM4SF4, NR1H2, IL10, PLCE1, CYP1A1, SLC10A2, MMP2, CYP8B1 genetic variants confer significant risk for gallstone disease in North Indian population. The association of many genes with disease risk was found to be sex-specific.

SAT-346 POR Rs2286822 Polymorphism Is Associated with Clinical Features in Patients with Congenital Adrenal Hyperplasia Due to 21 Hydroxylase Deficiency

Patients with congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency present a strong genotype-phenotype correlation but variability in clinical features among patients carrying similar CYP21A2 mutations suggests that polygenic traits contribute to the phenotype. Aim of the present study is to evaluate whether polymorphisms in P450 oxoreductase (POR), a microsomal cofactor to 21 hydroxylase, contribute to the phenotype of patients with CYP21A2 mutations. Methods: Leukocyte DNA from 97 patients with CAH (49 classic, 48 non classic) due to CYP21A2 mutations and 43 control subjects were sequenced for POR, gene variants identified and their association with clinical features 21-hydroxylase deficiency assessed. Results: Several intronic and exonic variants in POR were identified, all in Hardy-Weinberg equilibrium in controls. Interestingly, patients with classic CAH carrying the rs2286822 polymorphism (CT/TT vs CC in intron 11) presented more severe Prader stage (81 vs 67%, p<0.05), higher prevalence of salt wasting (19 vs 0%, p<0.05), higher plasma ACTH levels (437 ± 85.3 vs 140 ± 18.1 pg/ml, p<0.05) at birth and both males and females were started earlier on steroid therapy (12 vs 23 days after birth, p<0.05) compared to wildtype. Conclusions: Our study shows that the POR rs2286822 polymorphism is associated with a more severe clinical presentation in patients with classic CAH due to 21 hydroxylase mutations. Of note, in vitro studies have shown that this polymorphism impacts POR activity in liver (1). Altogether, this evidence suggests that POR polymorphisms may contribute to clinical features in classic CAH. References (1) Zhang et al. Drug Metab Disp 44:1193-1200, 2016

Interaction between IL-33 Gene Polymorphisms and Current Smoking with Susceptibility to Systemic Lupus Erythematosus.

Aims This study is aimed at exploring the relation between IL-33 single-nucleotide polymorphisms (SNPs) and the risk of systemic lupus erythematosus (SLE). Methods SNPStats (online software) was used to test the Hardy-Weinberg equilibrium in controls. Generalized multifactor dimensionality reduction (GMDR) was adopted to screen the preferable interaction between IL-33 SNPs and current smoking. Results Logistic regression analysis based on the fundamental data of age, gender, BMI, current smoking, and alcohol drinking showed that both rs1929992-G and rs1891385-C alleles were correlated with an increasing risk of SLE, the ORs (95% CI) of which were 1.62 (1.21-2.05) and 1.64 (1.22-2.10), respectively. One two-locus model (rs1929992×current smoking) had a testing accuracy of 60.11% (P = 0.0010). Through an overall multidimensional model, optimum cross-validation consistency was obtained. The analysis indicated that current smoking status influenced the SLE risk depending on the genotypes at rs1929992. Pairwise LD analysis indicated that haplotype rs1929992G-rs7044343T was statistically related to the elevating risk of SLE (P < 0.05). Those subjects with the G-T haplotype had a higher SLE risk than those with other haplotypes, after correction with factors, including gender, alcohol drinking, age, BMI, and current smoking. Conclusions The rs1929992-G and rs1891385-C allele, interaction between the rs1929992 gene and current smoking, and haplotype rs1929992G-rs7044343T were all risk factors of SLE.

Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus.

Skin blisters of pemphigus foliaceus (PF) present concomitant deposition of autoantibodies and components of the complement system (CS), whose gene polymorphisms are associated with susceptibility to different autoimmune diseases. To investigate these in PF, we evaluated 992 single-nucleotide polymorphisms (SNPs) of 44 CS genes, genotyped through microarray hybridization in 229 PF patients and 194 controls. After excluding SNPs with minor allele frequency <1%, out of Hardy–Weinberg equilibrium in controls or in strong linkage disequilibrium (r2 ≥ 0.8), 201 SNPs remained for logistic regression. Polymorphisms of 11 genes were associated with PF. MASP1 encodes a crucial serine protease of the lectin pathway (rs13094773: OR = 0.5, p = 0.0316; rs850309: OR = 0.23, p = 0.03; rs3864098: OR = 1.53, p = 0.0383; rs698104: OR = 1.52, p = 0.0424; rs72549154: OR = 0.55, p = 0.0453). C9 (rs187875: OR = 1.46, p = 0.0189; rs700218: OR = 0.12, p = 0.0471) and C8A (rs11206934: OR = 4.02, p = 0.0323) encode proteins of the membrane attack complex (MAC) and C5AR1 (rs10404456: OR = 1.43, p = 0.0155), a potent anaphylatoxin-receptor. Two encode complement regulators: MAC-blocking CD59 (rs1047581: OR = 0.62, p = 0.0152) and alternative pathway-blocking CFH (rs34388368: OR = 2.57, p = 0.0195). One encodes opsonin: C3 (rs4807895: OR = 2.52, p = 0.0239), whereas four encode receptors for C3 fragments: CR1 (haplotype with rs6656401: OR = 1.37, p = 0.0382), CR2 (rs2182911: OR = 0.23, p = 0.0263), ITGAM (CR3, rs12928810: OR = 0.66, p = 0.0435), and ITGAX (CR4, rs11574637: OR = 0.63, p = 0.0056). Associations reinforced former findings, regarding differential gene expression, serum levels, C3, and MAC deposition on lesions. Deregulation of previously barely noticed processes, e.g., the lectin and alternative pathways and opsonization-mediated phagocytosis, also modulate PF susceptibility. The results open new crucial avenues for understanding disease etiology and may improve PF treatment through additional therapeutic targets.

Interaction Between XRCC1 Gene Polymorphisms and Obesity on Susceptibility to Papillary Thyroid Cancer in Chinese Han Population

Background/Aims: To investigate the association of several single nucleotide polymorphisms (SNPs) within XRCC gene and additional gene- environment interaction with papillary thyroid cancer (PTC) risk. Methods: Testing for Hardy-Weinberg equilibrium in controls was conducted using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among 5 SNPs within XRCC gene and obesity. Results: Logistic regression analysis showed that the C allele of rs861539 and T allele of rs1799782 were associated with increased PTC risk Adjusted ORs (95%CI) were 1.65 (1.23-2.12) and 1.61 (1.20-2.04). However There was no relation of rs25489 Rs25487 and rs13181 with PTC. The cross-validation consistency and the testing accuracy for each of the models were determined by GMDR analysis. One two-locus model (rs1799782 and obesity) had a testing accuracy of 62.11% Which was significant at the p < 0.01 level. The D’ value between rs1799782 and rs13181 within ERCC1 gene was more than 0.75 (0.825). So haplotype analysis was just conducted for rs1799782 and rs13181 using the SHEsis online haplotype analysis software. In all samples The haplotype C- A was observed most frequently in two groups With 49.46% and 55.79% in the PTC patients and controls Respectively. The results also indicated that haplotype T- C was significantly associated with increased PTC risk. Conclusion: The C allele of rs861539 and T allele of rs1799782 Interaction between rs1799782 and obesity and haplotype T- C were all associated with increased PTC risk.

Association of interleukin-10 gene promoter polymorphisms with recurrent pregnancy loss: a meta-analysis.

It has been reported single-nucleotide polymorphisms (SNPs) of the IL-10 promoter might be associated with the susceptibility to recurrent pregnancy loss (RPL). Owing to the inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the IL-10 promoter SNPs and RPL risk. A systematic search of studies on the association of the three SNPs with RPL was conducted in PubMed and Embase. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. Eleven case-control studies on rs1800896, seven studies on rs1800871, and eight studies on rs1800872 were included. A significant association was identified between IL-10 rs1800896 with RPL risk (G versus A: OR = 1.21, 95% CI 1.09-1.35). No evidence of association was found between rs1800871 and RPL when restricted to those studies in Hardy-Weinberg equilibrium in controls (T versus C: OR = 1.25, 95% CI 0.76-2.06). No statistical association was demonstrated between rs1800872 and RPL (C versus A: OR = 1.08, 95% CI 0.83-1.42). IL-10 rs1800896 significantly increases the risk of RPL, while rs1800872 is not correlated with RPL risk. No significant association is demonstrated between rs1800871 and RPL risk but this requires further investigation.

Renin gene rs1464816 polymorphism contributes to chronic kidney disease progression in ADPKD.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder and is a common genetic cause of chronic renal failure in children and adults. The enzyme renin plays a key role in the RAAS cascade and an important role in the development of hypertension and progression of renal disease in ADPKD. The present study is aimed to investigate the potential modifier effect of REN gene polymorphisms on the progression of chronic kidney disease (CKD) in ADPKD.MethodsWe analyzed 102 ADPKD patients and 106 healthy controls from the same geographic area. FRET-based KASPar single-nucleotide polymorphism (SNP) genotyping assays for REN gene tag-SNPs (rs2887284, rs2368564, rs1464816, rs7521667, rs10900555, rs6693954, rs6676670 and rs11571078) were performed. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Haplotype frequencies and LD measures were estimated by using the software Haploview. Mantel-Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms.ResultsOf the eight tag-SNPs genotyped, the rs10900555 polymorphism deviated from the Hardy-Weinberg equilibrium in controls. The presence of ADPKD in general was not significantly associated with the REN tag-SNPs included in this study. Linkage disequilibrium analysis yielded three haplotype blocks and the haplotypes of the respective blocks are not statistically different between ADPKD and controls. In multivariate analysis, the rs1464816 TG genotype showed a significant association with the advancement of CKD in ADPKD (OR = 4.80; 95 % CI = 1.30–17.82; p = 0.019).ConclusionsThe present study provides evidence that the rs1464816 polymorphism in REN is associated with CKD progression in ADPKD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0217-0) contains supplementary material, which is available to authorized users.

Case-control study on peroxisome proliferator-activated receptor gamma polymorphism and interaction with HDL on essential hypertension in Chinese Han.

To investigate the association of single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors gamma (PPARG) with essential hypertension (EH) and additional role of gene- high-density lipoprotein cholesterol (HDL) interaction. A total of 1640 patients with EH (806 males, 834 females), with a mean age of 52.5±12.6 years, were selected, including 816 EH patients and 824 controls, who were enrolled from the community. Three SNPs were selected for genotyping in the case-control study: rs10865710, rs709158, rs1805192. Logistic regression model was used to examine the interaction between SNP and HDL on EH, odds ratio (OR) and 95% confidence interval (95% CI) were also calculated. All genotypes were distributed according to Hardy-Weinberg equilibrium in controls. Logistic regression analysis showed an association between genotypes of variants in rs1805192 and decreased EH risk, EH risk was significantly lower in carriers of Ala allele of the rs1805192 polymorphism than those with Pro/Pro (Pro/Ala+ Ala/Ala versus Pro/Pro, adjusted OR (95% CI) =0.65 (0.53-0.83), after covariate adjustment. In addition, the Ala allele of the rs1805192 polymorphism was also associated with diastolic blood pressure (DBP), but not systolic blood pressure (SBP), we also found, by interaction analysis, combined effect of rs1805192 and HDL on EH risk after covariate adjustment. Our results support an important association between rs1805192 minor allele (Ala allele) of PPARG and lower EH risk, the interaction analysis showed a combined effect of Ala- HDL on lower EH risk.

Association of genetic polymorphisms in PTEN and additional gene-gene interaction with risk of esophageal squamous cell carcinoma in Chinese Han population.

This study aims to investigate the association of five single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homologue (PTEN) gene and additional role of gene-gene interaction with esophageal squamous cell carcinoma (ESCC), based on a Chinese case-control study. A total of 871 subjects (420 males and 451 females) were selected, including 425 ESCC cases and 446 controls. Five SNPs were selected for genotyping in the case-control study: rs2735343, rs555895, rs2299939, rs17431184 and rs701848. Logistic regression model was used to examine the association between five SNP and ESCC, and additional interaction among five SNP, odds ratio (OR) and 95% confident interval (95%CI) were calculated. All genotypes were distributed according to Hardy-Weinberg equilibrium in controls. The carriers of homozygous mutant of rs2735343 and rs701848 polymorphism revealed increased ESCC risk than those with wild-type homozygotes, and OR (95%CI) were 1.27 (1.09-2.08) and 1.45 (1.17-1.98), respectively. We also found a potential gene-gene interaction between rs2735343 and rs701848 (P = 0.0010), and a potential gene-gene interaction among all five SNP (P = 0.0107) after covariates adjustment. Subjects with TC or CC of rs2735343 and TC or CC of rs701848 genotype have highest ESCC risk, compared to subjects with TT of rs2735343 and TT of rs701848 genotype, OR (95% CI) was 2.76 (1.37-3.45) after covariates adjustment. The carriers of homozygous mutant of rs2735343 and rs701848 polymorphism revealed increased ESCC risk. We also found a potential gene-gene interaction between rs2735343 and rs701848 and a potential gene-gene interaction among all five SNPs.

Angiotensinogen gene polymorphisms and progression of chronic kidney disease in ADPKD patients.

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic and progressive disorder characterized by cyst formation and kidney enlargement and ultimately renal failure. Reduction of CKD progression in the ADPKD by pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) using ACE inhibitors indicated the involvement of RAAS pathway in the progression of CKD. The aim of the present study is to investigate the role of angiotensinogen tag-single nucleotide polymorphisms (AGT tag-SNPs) in progression of CKD. Twelve AGT tag-SNPs were genotyped in 102 ADPKD patients and 106 non-ADPKD subjects using FRET-based KASPar method. Genotypes and haplotypes were compared between ADPKD and controls. The effect of genotypes and hypertension on CKD progression was assessed using univariate and multivariate logistic regression. Mantel-Haenszel (M-H) stratified analysis was performed to study the interaction between CKD stages and hypertension. Of the twelve tag-SNPs analyzed, only rs11122578 SNP deviated Hardy-Weinberg equilibrium in controls. Significant association between two AGT polymorphisms (rs11122577 and rs4762) and ADPKD was observed. Analysis of linkage disequilibrium revealed two haplotype blocksand haplotypes are not associated with ADPKD. The univariate analysis revealed that the age, hypertension, family history of diabetes and AGT rs4762 contributed to the progression of CKD in ADPKD. The modifier effect of these factors remained even after controlling other variables in multivariate analysis. The results of our study suggest significant association between Thr207Met polymorphism of AGT and CKD progression and acts as an effect modifier of renal disease progression in ADPKD.

Lack of association between Hsa-Mir-499 rs3746444 polymorphism and cancer risk: meta-analysis findings.

Epidemiologic findings concerning the association between the hsa-mir-499 rs3746444 A>G polymorphism and cancer risk have yielded mixed results. We aimed to investigate the association by performing a meta-analysis of all available studies. We searched PubMed and EMBASE for studies published up to November 2014, using odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of any association. The Benjamini- Hochberg (BH) method was used to correct the p values for multiple comparisons. We included 39 studies, including 14,136 cases and 16,937 controls. The results of overall meta-analysis suggested a borderline association between hsa-mir-499 rs3746444 polymorphism and cancer susceptibility (AG+GG vs. AA: OR=1.15, 95% CI= 1.04-1.26, corrected p value=0.04). After removing studies not conforming to Hardy-Weinberg equilibrium (HWE), however, this association disappeared (AG+GG vs AA: OR=1.18, 95% CI=1.03-1.34, corrected p value=0.21). When stratified analysis by ethnicity, cancer type or HWE in controls, although some associations between hsa-mir-499 rs3746444 polymorphism and cancer susceptibility were detected, these associations no longer existed after adjustment using BH method. In conclusion, our meta-analysis suggests that hsa-mir-499 rs3746444 A>G polymorphism is not associated with risk of cancer based on current evidence.

Association of TNF-alpha, IL-6 and IL-1beta gene polymorphisms with polycystic ovary syndrome: a meta-analysis.

BackgroundSeveral studies on the association of TNF-alpha (−308 G/A), IL-6 (−174 G/C) and IL-1beta (−511 C/T) polymorphisms with polycystic ovary syndrome (PCOS) risk have reported conflicting results. The aim of the present study was to assess these associations by meta-analysis.ResultsA total of 14 eligible articles (1665 cases/1687 controls) were included in this meta-analysis. The results suggested that there was no obvious association between the TNF-alpha (−308 G/A) polymorphism and PCOS in the overall population or subgroup analysis by ethnicity, Hardy–Weinberg equilibrium (HWE) in controls, genotyping method, PCOS diagnosis criteria, and study sample size. Also, no obvious association was found between the TNF-alpha (−308 G/A) polymorphism and obesity in patients with PCOS (body mass index [BMI] ≥ 25 kg/m2 vs. BMI < 25 kg/m2). Regarding the IL-6 (−174 G/C) polymorphism, also no association was found in the overall population in heterozygote comparison, dominant model, and recessive model. Even though an allelic model (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.41–0.96) and a homozygote comparison (OR = 0.52, 95% CI = 0.30–0.93) showed that the IL-6 (−174 G/C) polymorphism was marginally associated with PCOS. Further subgroup analysis suggested that the effect size was not significant among HWE in controls (sample size ≤ 200) and genotyping method of pyrosequencing under all genetic models. Similarly, there was no association between the IL-1beta (−511 C/T) polymorphism and PCOS in the overall population or subgroup analysis under all genetic models. Furthermore, no significant association was found between the IL-1beta (−511 C/T) polymorphism and several clinical and biochemical parameters in patients with PCOS.ConclusionsThe results of this meta-analysis suggest that the TNF-alpha (−308 G/A), IL-6 (−174 G/C), and IL-1beta (−511 C/T) polymorphisms may not be associated with PCOS risk. However, further case–control studies with larger sample sizes are needed to confirm our results.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0165-4) contains supplementary material, which is available to authorized users.

The Relationship between Seven Common Polymorphisms from Five DNA Repair Genes and the Risk for Breast Cancer in Northern Chinese Women

BackgroundConverging evidence supports the central role of DNA damage in progression to breast cancer. We therefore in this study aimed to assess the potential interactions of seven common polymorphisms from five DNA repair genes (XRCC1, XRCC2, XRCC3, XPA and APEX1) in association with breast cancer among Han Chinese women.Methodology/Principal FindingsThis was a case-control study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched cancer-free controls. The polymerase chain reaction - ligase detection reaction method was used to determine genotypes. All seven polymorphisms were in accordance with Hardy-Weinberg equilibrium in controls. Differences in the genotypes and alleles of XRCC1 gene rs25487 and XPA gene rs1800975 were statistically significant between patients and controls, even after the Bonferroni correction (P<0.05/7). Accordingly, the risk for breast cancer was remarkably increased for rs25487 (OR = 1.28; 95% CI: 1.07–1.51; P = 0.006), but decreased for rs1800975 (OR = 0.77; 95% CI: 0.67–0.90; P = 0.001) under an additive model at a Bonferroni corrected alpha of 0.05/7. Allele combination analysis showed higher frequencies of the most common combination C-G-G-C-G-G-G (alleles in order of rs1799782, rs25487, rs3218536, rs861539, rs1800975, rs1760944 and rs1130409) in controls than in patients (PSim = 0.002). In further interaction analysis, two-locus model including rs1800975 and rs25487 was deemed as the overall best model with the maximal testing accuracy of 0.654 and the cross-validation consistency of 10 out of 10 (P = 0.001).ConclusionOur findings provide clear evidence that XRCC1 gene rs25487 and XPA gene rs1800975 might exert both independent and interactive effects on the development of breast cancer among northern Chinese women.

Measurement Errors in Polymerase Chain Reaction Are a Confounding Factor for a Correct Interpretation of 5-HTTLPR Polymorphism Effects on Lifelong Premature Ejaculation: A Critical Analysis of a Previously Published Meta-Analysis of Six Studies

ObjectiveTo analyze a recently published meta-analysis of six studies on 5-HTTLPR polymorphism and lifelong premature ejaculation (PE).MethodsCalculation of fraction observed and expected genotype frequencies and Hardy Weinberg equilibrium (HWE) of cases and controls. LL,SL and SS genotype frequencies of patients were subtracted from genotype frequencies of an ideal population (LL25%, SL50%, SS25%, p = 1 for HWE). Analysis of PCRs of six studies and re-analysis of the analysis and Odds ratios (ORs) reported in the recently published meta-analysis.ResultsThree studies deviated from HWE in patients and one study deviated from HWE in controls. In three studies in-HWE the mean deviation of genotype frequencies from a theoretical population not-deviating from HWE was small: LL(1.7%), SL(−2.3%), SS(0.6%). In three studies not-in-HWE the mean deviation of genotype frequencies was high: LL(−3.3%), SL(−18.5%) and SS(21.8%) with very low percentage SL genotype concurrent with very high percentage SS genotype. The most serious PCR deviations were reported in the three not-in-HWE studies. The three in-HWE studies had normal OR. In contrast, the three not-in-HWE studies had a low OR.ConclusionsIn three studies not-in-HWE and with very low OR, inadequate PCR analysis and/or inadequate interpretation of its gel electrophoresis resulted in very low SL and a resulting shift to very high SS genotype frequency outcome. Consequently, PCRs of these three studies are not reliable. Failure to note the inadequacy of PCR tests makes such PCRs a confounding factor in clinical interpretation of genetic studies. Currently, a meta-analysis can only be performed on three studies-in-HWE. However, based on the three studies-in-HWE with OR of about 1 there is not any indication that in men with lifelong PE the frequency of LL,SL and SS genotype deviates from the general male population and/or that the SL or SS genotype is in any way associated with lifelong PE.

Relationship between rs2274223 and rs3765524 polymorphisms of PLCE1 and risk of esophageal squamous cell carcinoma in a Kazakh Chinese population

To investigate the association between the rs2274223 and rs3765524 polymorphism of phospholipase C epsilon 1 (PLCE1) gene and the susceptibility to develop esophageal squamous cell carcinoma (ESCC) in a pure Kazakh Chinese population. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) was utilized to genotype the potentially functional single nucleotide polymorphism rs2274223 A>G and rs3765524 C>T of PLCE1 in an ongoing hospital-based and case-control study of 200 ESCC cases with 300 cancer-free age ( ± 5 years) and sex matched controls. Statistical analyses were performed with Statistical Products and Services Solutions software (version 13.0). Adjusted odds ratios (OR) and 95% confidence evaluation intervals (95%CI) measured by multivariate logistic regression analysis were adopted to study the correlation of the gene polymorphism with the susceptibility to ESCC. The genotype frequencies observed for rs2274223 was consistent with Hardy-Weinberg equilibrium in controls. Univariate analysis revealed significant differences between cases and controls with respect to genotype distribution for rs2274223 (P = 0.006). The variants of rs2274223 were found to confer significantly increased risk of ESCC (GG vs AA: OR = 3.17, 95%CI = 1.45-6.93; AG/GG vs AA: OR = 1.55, 95%CI = 1.08-2.22) in the Kazakh Chinese population. Moreover, AG/GG genotype of rs2274223 was found to be significantly associated with poorly-differentiated ESCC (OR = 2.48, 95%CI = 1.10-5.60). When the ESCC patients were divided into two subgroups, stage I/II and stage III/IV according to the AJCC TNM classification, the GT/GG genotype of rs2274223 was significantly associated with stage III/IV ESCC (OR = 1.85, 95%CI = 1.05-3.25). No significant association was found between rs3765524 and Kazakh ESCC. These results indicate that rs2274223 site polymorphism of the PLCE1 gene is strongly associated with risk of ESCC in a Kazakh Chinese population, especially the poorly-differentiated and stage III/IV ESCC.