LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four‐centre case‐control study

Neuroblastoma ranks the most common seen solid tumour in childhood. Overexpression of LIN28A gene has been linked to the development of multiple human malignancies, but the relationship between LIN28A single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility is still under debate. Herein, we evaluated the correlation of four potentially functional LIN28A SNPs (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) and neuroblastoma susceptibility in 505 neuroblastoma patients and 1070 controls from four independent hospitals in China. The correlation strengths were determined by using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Among these SNPs, rs34787247 G>A exhibited a significant association with increased susceptibility in neuroblastoma (GA vs GG: adjusted OR = 1.30, 95% CI = 1.03‐1.64; AA vs GG: adjusted OR = 2.51, 95% CI = 1.36‐4.64, AA/GA vs GG: adjusted OR = 1.42, 95% CI = 1.12‐1.80, AA vs GG/GA: adjusted OR = 2.39, 95% CI = 1.29‐4.42). Furthermore, the combined analysis of risk genotypes revealed that subjects carrying three risk genotypes (adjusted OR = 1.64, 95% CI = 1.02‐2.63) are more inclined to develop neuroblastoma than those without risk genotype, and so do carriers of 1‐4 risk genotypes (adjusted OR = 1.26, 95% CI = 1.01‐1.56). Stratification analysis further revealed risk effect of rs3811464 G>A, rs34787247 G>A and 1‐4 risk genotypes in some subgroups. Haplotype analysis of these four SNPs yields two haplotypes significantly correlated with increased neuroblastoma susceptibility. Overall, our finding indicated that LIN28A SNPs, especially rs34787247 G>A, may increase neuroblastoma risk.     

Association between METTL3 gene polymorphisms and neuroblastoma susceptibility: A nine‐centre case‐control study

Neuroblastoma ranks as the most commonly seen and deadly solid tumour in infancy. The aberrant activity of m⁶A‐RNA methyltransferase METTL3 is involved in human cancers. Therefore, functional genetic variants in the METTL3 gene may contribute to neuroblastoma risk. In the current nine‐centre case‐control study, we aimed to analyse the association between the METTL3 gene single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility. We genotyped four METTL3 gene SNPs (rs1061026 T>G, rs1061027 C>A, rs1139130 A>G, and rs1263801 G>C) in 968 neuroblastoma patients and 1814 controls in China. We found significant associations between these SNPs and neuroblastoma risk in neither single‐locus nor combined analyses. Interestingly, in the stratified analysis, we observed a significant risk association with rs1061027 AA in subgroups of children ≤ 18 months of age (adjusted OR = 1.87, 95% CI = 1.03‐3.41, P = .040) and females (adjusted OR = 1.86, 95% CI = 1.07‐3.24, P = .028). Overall, we identified a significant association between METTL3 gene rs1061027 C>A polymorphism and neuroblastoma risk in children ≤18 months of age and females. Our findings provide novel insights into the genetic determinants of neuroblastoma.     

Association of potentially functional variants in the XPG gene with neuroblastoma risk in a Chinese population

XPG gene plays a critical role in the nucleotide excision repair pathway. However, the association between XPG gene polymorphisms and neuroblastoma risk has not been investigated. In this study with 256 neuroblastoma cases and 531 cancer‐free controls, we investigated the effects of five potentially functional polymorphisms ( rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601G>A) on neuroblastoma risk. We calculated odds ratio (OR) and 95% confidence interval (CI) to evaluate the association between the five selected polymorphisms and neuroblastoma risk. False‐positive report probability (FPRP) was utilized to determine whether significant findings were noteworthy or because of a chance. We also performed genotype–phenotype association analysis to explore the biological plausibility of our findings. We found that the rs2094258 T allele was significantly associated with decreased neuroblastoma risk (CT versus CC: adjusted OR = 0.65, 95% CI = 0.47–0.90, P = 0.010; and CT/TT versus CC: adjusted OR = 0.71, 95% CI = 0.53–0.97, P = 0.030) after adjusting for age and gender. The association was more prominent for subjects with retroperitoneal tumour or early‐stage tumour. We also found that carriers of the 2–3 risk genotypes had a significantly increased neuroblastoma risk when compared to carriers of the 0–1 risk genotypes. The association with risk genotypes was more predominant in older children, females and subjects with retroperitoneal tumour or early stage. Our results were further supported by FPRP analysis and genotype–phenotype association analysis. In conclusion, our study verified that the XPG gene rs2094258 C>T polymorphism may contribute to neuroblastoma susceptibility. Our findings require further validation by studies with larger sample size and concerning different ethnicities.     

Association between XPG polymorphisms and stomach cancer susceptibility in a Chinese population

Xeroderma pigmentosum group G (XPG) protein plays an important role in the DNA repair process by cutting the damaged DNA at the 3′ terminus. Previous studies have indicated some polymorphisms in the XPG gene are associated with stomach cancer susceptibility. We performed this hospital‐based case–control study to evaluate the association of four potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C and rs873601G>A) with stomach cancer susceptibility. The four single nucleotide polymorphisms (SNPs) were genotyped in 692 stomach cancer cases and 771 healthy controls. Logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association of interest. Of the studied SNPs, XPG rs873601G>A polymorphism was found to significantly associate with stomach cancer susceptibility (AA versus GG/AG: OR = 1.31, 95% CI = 1.03–1.66, P = 0.027). Combined analysis of all SNPs revealed that the individuals with two of risk genotypes had a significantly increased stomach cancer risk (OR = 1.52, 95% CI = 1.13–2.06). In the stratification analysis, the association between the rs873601AA genotype and stomach cancer risk was observed in older group (>59 year), as well as patients with non‐cardia stomach cancer. Further combined analysis indicated men, smokers, or non‐drinkers more than one risk genotypes had a significantly increased stomach cancer risk. Our results indicate that XPG rs873601G>A polymorphism may be associated with the risk of stomach cancer. Further prospective studies with different ethnicities and large sample sizes are needed to validate our findings.     

Genetic Variations of GWAS-Identified Genes and Neuroblastoma Susceptibility: a Replication Study in Southern Chinese Children

Neuroblastoma is one of the most commonly diagnosed solid cancers for children, and genetic factors may play a critical role in neuroblastoma development. Previous genome-wide association studies (GWASs) have identified nine genes associated with neuroblastoma susceptibility in Caucasians. To determine whether genetic variations in these genes are also associated with neuroblastoma susceptibility in Southern Chinese children, we genotyped 25 polymorphisms within these genes by the TaqMan method in 256 cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. We performed a meta-analysis to further evaluate the associations. Furthermore, we calculated the area under the receiver-operating characteristic curves (AUC) to assess which gene/genes may better predict neuroblastoma risk. We confirmed that CASC15 rs6939340 A > G, rs4712653 T > C, rs9295536 C > A, LIN28B rs221634 A > T, and LMO1 rs110419 A > G were associated with significantly altered neuroblastoma susceptibility. We also confirmed that rs6939340 A > G (G versus A: OR = 1.30, 95% CI = 1.13-1.50) and rs110419 G > A (A versus G: OR = 1.37, 95% CI = 1.19-1.58) were associated with increased neuroblastoma risk for all subjects. We also found that the combination of polymorphisms in CASC15, LIN28B, and LMO1 may be used to predict neuroblastoma risk (AUC = 0.63, 95% CI = 0.59-0.67). Overall, we verified five GWAS-identified polymorphisms that were associated with neuroblastoma susceptibility alteration for Southern Chinese population; however, these results need further validation in studies with larger sample sizes.     

Effect of FASN gene on milk yield and milk composition in the Chinese Holstein dairy population

Fatty acid synthase (FASN) is a multifunctional protein that catalyzes de novo synthesis of fatty acids in cells. It plays a key role in the lipid biosynthesis as well as in the general metabolism of all living animals. We herein investigated polymorphisms of FASN. As a result, six single nucleotide polymorphisms (SNPs) were found and then genotyped in 752 Chinese Holstein cows. It was found that g.17924A>G was non‐synonymous, g.13965 C>T, g.16907 T>C and g.18663T>C were synonymous mutations and two other two SNPs, g.8948 C>T (ss491228481) and g.14439T>C (rs133498277), were in intronic sequences of the gene. All such identified SNPs were found to be associated with milk yield and composition traits (P = 0.0441 to <0.0001). Significant additive and allele substitution effects were observed for three yield traits at all six loci as well (P < 0.05 to <0.01). Complete linkage disequilibrium among the five SNPs, with the exception of g.8948 C>T, was observed.     

FOXO3 gene polymorphisms influence the risk of acute lymphoblastic leukemia in Chinese children

Acute lymphoblastic leukemia (ALL) is the most frequently diagnosed cancer in children and single-nucleotide polymorphisms (SNPs) in certain genes influence risk of ALL. Although FOXO3 had been demonstrated to be involved leukemia, the role of FOXO3 polymorphisms was still not clear. In the present study, we explored the association of FOXO3 SNPs with ALL risk in Chinese children. We genotyped four polymorphisms (rs17069665 A>G, rs4945816 T>C, rs4946936 C>T, and rs9400241 A>C) of FOXO3 in 425 ALL cases and 1339 health controls. The associations were estimated by odds ratios (ORs) with their 95% confidence intervals (CIs). Further analyses were performed to explore associations of rs17069665 and rs9400241 with ALL susceptibility in terms of age, gender, immunophenotype, minimal residual disease (MRD), and other clinical characteristics. We found rs17069665 related to the increased ALL risk (OR = 1.76; 95% CI = 1.02-3.04), rs9400241 related to decreased ALL risk (OR = 0.80; 95% CI = 0.64-0.99). The effects of rs17069665 on ALL risk were more predominant in males and children < 10 years, and patients with lower rates of platelet or neutrophil. As for rs9400241, the effects were more predominant in children < 10 years, and in patients with pre B ALL, positive MRD, anemia, or hepatomegaly. In conclusion, FOXO3 gene polymorphisms influence the risk of ALL in children and might be a potential biomarker for ALL susceptibility.     

Genetic and environmental contributions to age at menarche: Interactive effects of father absence and LIN28B

Substantial research and theory over a number of years have linked father absence to earlier age at menarche (AAM). More recent work has centered on explaining the relative genetic and environmental contributions to this correlation. The purpose of the current study was to evaluate the combined effects of father absence and variation in the LIN28B gene on AAM. A sample of 300 women (age 18–25) successfully genotyped for two LIN28B single nucleotide polymorphisms (SNPs; rs364663 and rs314273) were used to test gene-environment interaction models. Results for both SNPs were consistent with the hypothesis that father absence would attenuate later AAM associated with LIN28B. Genetic index analysis of combined LIN28B SNPs showed that girls with at least one copy of the T/T genotype had later AAM if they were father present. Study strengths and the implications of GxE research for life history models are discussed.     

Detection of exonic variants within the melanocortin 1 receptor (MC1R) gene in Black Silky,White Leghorn and Golden duckwing Araucana chicken

The melanocortin 1 receptor (MC1R) gene can be considered a candidate functional gene for the pigmentation of plumage color. The aim of this study was to investigate the association between the genotype frequencies of g.69 T>C, g.376 G>A and g.427 A>G SNPs within the MC1R gene in Black silky (O), Golden duckwing Araucana (GA) and White Leghorn (W). The CC and AA genotype frequencies of g.69 T>C and g.427 A>G SNPs in White Leghorn (W) were both 1.000, and the TT genotype frequency of the g.69 T>C SNP in Golden duckwing Araucana (GA) was also 1.000. The GG and AA genotype frequencies of g.376 G>A and g.427 A>G SNPs in Black silky (O) were both 0.100. When a haplotype is observed using a combination of markers, a Golden duckwing Araucana (GA) can especially be distinguished when it is a TAG, TGG and TAA type in the SNP combination of the MC1R gene. In case of the CAA types, only White Leghorn (W) could specifically be distinguished. Therefore, three SNPs in MC1R may provide identification in chicken breeds.     

Gender‐Specific Association of a Perilipin Gene Haplotype with Obesity Risk in a White Population

Objective: Perilipin is a class of protein‐coating lipid droplets in adipocytes and steroidogenic cells. Our purpose was to examine the association between common single‐nucleotide polymorphisms (SNPs) at the perilipin (PLIN) locus and obesity, as well as related phenotypes, in unrelated American adults. Research Methods and Procedures: Four PLIN SNPs (PLIN 6209T>C, 11482G>A, 13041A>G, and 14995A>T) were typed in 734 white subjects (373 men and 361 women) attending a residential lifestyle intervention program. The baseline anthropometric and biochemical measures were used. Obesity was defined as BMI ≥ 30 kg/m². Results: Multivariate analysis demonstrated that, in women, two of the SNPs (13041A>G, and 14995A>T) were significantly associated with percentage body fat (p = 0.016 for 13041A>G and p = 0.010 for 14995A>T) and waist circumference (p = 0.020 for 13041A>G and p = 0.045 for 14995A>T). Moreover, haplotype analysis using these two SNPs indicated that haplotypes A/T and G/T were both associated with significantly increased obesity risk (odds ratio = 1.76, 95% confidence interval 1.07 to 2.90 for haplotype A/T, and odds ratio = 1.73, 95% confidence interval 1.06 to 2.82 for haplotype G/T) when compared with haplotype A/A. No significant associations between PLIN variations and obesity were found in men. Discussion: Our data support the hypothesis that the PLIN locus may be a significant genetic determinant for obesity risk in whites and that women are more sensitive to the genetic effects of perilipin than men.     

Haplotype combinations of <Emphasis Type="Italic">AdPLA</Emphasis> gene polymorphisms associate with growth traits in Chinese cattle

Ablation of AdPLA in mice could prevent obesity, which implicated AdPLA was a new candidate gene for growth traits. In this study, we screened the polymorphisms of AdPLA gene and revealed three novel SNPs (NC_007330.4:g.43638506 C>T, 43658457 T>C and 43661404 T>C) by DNA sequencing and forced PCR-RFLP methods in 1340 individuals from six breeds. A preliminary single SNP-traits association analysis demonstrated that CC genotype was significantly higher than TT genotype at two growth traits in P6-EcoRII locus (P < 0.05). Moreover, the P8-FbaI locus had a significant association with some growth traits, individuals with TT genotype were higher than CC genotype (P < 0.05). A further analysis confirmed that these two SNPs were in linkage disequilibrium, and haplotype H2, both advantage allelic in P6-EcoRII and P8-FbaI loci, was better than the others for bovine growth traits, which was consistent with single SNP-traits association results. Therefore, this study not only proved that these SNPs were in association with bovine growth traits, but also contributed to evaluate them as genetic markers in bovine genetics and breeding and had potential application in breeding programs.     

Association study of single nucleotide polymorphisms in JAK2 and STAT5B genes and their differential mRNA expression with mastitis susceptibility in Chinese Holstein cattle

The JAK–STAT pathway plays a key role in mediating immune responses. The genetic effects of single nucleotide polymorphisms (SNPs) in JAK2 and STAT5B were investigated for serum cytokines, mastitis indicators and productions traits in a population of 468 Chinese Holstein cattle. Pooled DNA sequencing revealed one SNP (BTA8:g.39645396A>G) in JAK2 and two SNPs (BTA19:g.43673888A>G and BTA19:g.43660093T>C) in STAT5B. A fixed effect model considering the effects of SNPs, parity, herd, season and year of calving was used by way of the general linear model procedure of sas . Genotype frequencies of these SNPs in the population were in Hardy–Weinberg equilibrium (P > 0.05). A novel SNP (g.39645396A>G) in JAK2 was predicted to change the amino acid from lysine to asparagine and was significantly associated with the somatic cell count (SCC) and somatic cell score (SCS), whereas g.43673888A>G in STAT5B was significantly associated with SCC, SCS and interleukin‐4 (IL‐4) (P < 0.05). The dominant effect of g.39645396A>G in JAK2 was significant for SCS, and its additive effect was significant for SCC, whereas the dominant effect of g.43673888A>G in STAT5B was significant for SCS and IL‐4 (P < 0.05). The combination of g.39645396A>G in JAK2 and g.43673888A>G in STAT5B showed a significant effect on SCC, SCS, IL‐4 and TNF‐α (P < 0.05). As for mRNA expression analysis, the AA genotype g.39645396A>G and GG genotype g.43673888A>G indicated higher mRNA expression level and were significantly different from other genotypes (P < 0.05). The results imply that JAK2 and STAT5B genes could be useful candidate genes, and the identified polymorphisms might potentially be strong genetic markers for selection of dairy cattle against mastitis development.     

Association study of four variants in <Emphasis Type="Italic">KCNQ1</Emphasis> with type 2 diabetes mellitus and premature coronary artery disease in a Chinese population

Four single nucleotide polymorphisms (SNPs, rs2237892, rs2237895, rs2237897, rs2283228) in KCNQ1 are associated with type 2 diabetes mellitus in different ancestral groups. We investigated whether these 4 genetic markers are determinants of type 2 diabetes and premature coronary artery disease (CAD) in a Chinese population. We studied 398 consecutive patients, including 180 with coronary stenosis ≥50% or previous myocardial infarction (male <55 years, female <65 years) and 218 controls without documented CAD. CAD cases and controls were genotyped for 4 SNPs by using the ligase detection reaction method. The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, TT were present in rs2237897 and rs2237892. No differences were found in genotype distribution and allele frequencies of these 4 SNPs between subjects with and without type 2 diabetes. Logistic regression showed that the risk of premature CAD in subjects carrying the CC genotype at rs2237892 was reduced by 90% in relation to individuals carrying the TT genotype (OR = 0.100, 95% CI: 0.018–0.564, P = 0.009). The association of other 3 SNPs with premature CAD could not be detected, nor did there exist any association of these 4 SNPs among groups of patients with 0, 1, 2, and 3-vessel disease (all P > 0.05). Our data implicate rs2237892 in KCNQ1 as a protective gene variant against premature CAD and we couldn’t replicate any association of these 4 SNPs with T2DM or extent of coronary lesions in a Chinese population.     

Association of the variants and haplotypes in the DOCK7, PCSK9 and GALNT2 genes and the risk of hyperlipidaemia

Little is known about the association between the single nucleotide polymorphisms (SNPs) and haplotypes of the dedicator of cytokinesis 7 (DOCK7), pro‐protein convertase subtilisin/kexin type 9 (PCSK9) and polypeptide N‐acetylgalactosaminyltransferase 2 (GALNT2) and serum lipid traits in the Chinese populations. This study was to determine the association between nine SNPs in the three genes and their haplotypes and hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG), and to identify the possible gene–gene interactions among these SNPs. Genotyping was performed in 733 HCH and 540 HTG participants. The haplotype of C‐C‐G‐C‐T‐G‐C‐C‐G [in the order of DOCK7 rs1168013 (G>C), rs10889332 (C>T); PCSK9 rs615563 (G>A), rs7552841 (C>T), rs11206517 (T>G); and GALNT2 rs1997947 (G>A), rs2760537 (C>T), rs4846913 (C>A) and rs11122316 (G>A) SNPs] was associated with increased risk of HCH and HTG. The haplotypes of C‐C‐G‐C‐T‐G‐C‐C‐A and G‐C‐G‐T‐T‐G‐T‐C‐G were associated with a reduced risk of HCH and HTG. The haplotypes of G‐C‐G‐C‐T‐G‐C‐C‐A and G‐C‐G‐C‐T‐G‐T‐C‐G were associated with increased risk of HCH. The haplotypes of C‐T‐G‐C‐T‐G‐C‐C‐G, G‐C‐A‐C‐T‐G‐C‐C‐G and G‐C‐G‐C‐T‐G‐C‐C‐A were associated with an increased risk of HTG. The haplotypes of G‐C‐G‐C‐T‐G‐T‐C‐A and G‐C‐G‐T‐T‐G‐T‐C‐G were associated with a reduced risk of HTG. In addition, possible inter‐locus interactions among the DOCK7, PCSK9 and GALNT2 SNPs were also noted. However, further functional studies of these genes are still required to clarify which SNPs are functional and how these genes actually affect the serum lipid levels.     

Association between single nucleotide polymorphisms of TPH1 and TPH2 genes,and depressive disorders

Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to confirm the association between the presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected: c.804‐7C>A (rs10488682), c.‐1668T>A (rs623580), c.803+221C>A (rs1800532), c.‐173A>T (rs1799913)—TPH1, c.‐1449C>A (rs7963803), and c.‐844G>T (rs4570625)—TPH2. A total of 510 DNA samples (230 controls and 280 patients) were genotyped using TaqMan probes. Among the studied polymoorphisms, the G/G genotype and G allele of c.804‐7C>A—TPH1, the T/T homozygote of c.803+221C>A—TPH1, the A/A genotype and A allele of c.1668T>A—TPH1, the G/G homozygote and G allele of c.‐844G>T—TPH2, and the C/A heterozygote and A allele of c.‐1449C>A—TPH2 were associated with the occurrence of depression. However, the T/T homozygote of c.‐1668T>A—TPH1, the G/T heterozygote and T allele of c.‐844G>T—TPH2, and the C/C homozygote and C allele of c.‐1449C>A—TPH2 decreased the risk of development of depressive disorders . Each of the studied polymorphisms modulated the risk of depression for selected genotypes and alleles. These results support the hypothesis regarding the involvement of the pathway in the pathogenesis of depression.     

Functional polymorphisms of the TET1 gene increase the risk of neuroblastoma in Chinese children

Common genetic mutations are absent in neuroblastoma, one of the most common childhood tumours. As a demethylase of 5-methylcytosine (m5C) modification, TET1 plays an important role in tumourigenesis and differentiation. However, the association between TET1 gene polymorphisms and susceptibility to neuroblastoma has not been reported. Three TET1 gene polymorphisms (rs16925541 A > G, rs3998860 G > A and rs12781492 A > C) in 402 Chinese patients with neuroblastoma and 473 cancer-free controls were assessed using TaqMan. Multivariate logistic regression analysis was used to evaluate the association between TET1 gene polymorphisms and susceptibility to neuroblastoma. The GTEx database was used to analyse the impact of these polymorphisms on peripheral gene expression. The relationship between gene expression and prognosis was analysed using Kaplan–Meier analysis with the R2 platform. We found that both rs3998860 G > A and rs12781492 A > C were significantly associated with increased neuroblastoma risk. Stratified analysis further showed that rs3998860 G > A and rs12781492 A > C significantly increased neuroblastoma risk in certain subgroups. In the combined risk genotype model, 1–3 risk genotypes significantly increased risk of neuroblastoma compared with the 0 risk genotype. rs3998860 G > A and rs12781492 A > C were significantly associated with increased STOX1 mRNA expression in adrenal and whole blood, and high expression of STOX1 mRNA in adrenal and whole blood was significantly associated with worse prognosis. In summary, TET1 gene polymorphisms are significantly associated with increased neuroblastoma risk; further research is required for the potential mechanism and therapeutic prospects in neuroblastoma.     

Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population

Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms (SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42–0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43–0.94) and non‐drinkers (OR = 0.79, 95% CI = 0.64–0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37–0.83) and non‐drinker (adjusted OR = 0.75, 95% CI = 0.60–0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene–gene interactions among three AKT1 SNPs (P < 0.015). A three‐AKT1 SNP haplotype (C‐A‐C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52–0.94). Multifactor dimensionality reduction analysis confirmed a high‐order gene–environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene–environment interplay in ESCC carcinogenesis.     

Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease‐specific survival

Single nucleotide polymorphisms (SNPs) in the vitamin D pathway genes have been implicated in cutaneous melanoma (CM) risk, but their role in CM disease‐specific survival (DSS) remains obscure. We comprehensively analyzed the prognostic roles of 2669 common SNPs in the vitamin D pathway genes using data from a published genome‐wide association study (GWAS) at The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated the SNPs of interest in another GWAS from the Nurses’ Health Study and Health Professionals Follow‐up Study. Among the 2669 SNPs, 203 were significantly associated with DSS in MDACC dataset (P < 0.05 and false‐positive report probability < 0.2), of which 18 were the tag SNPs. In the replication, two of these 18 SNPs showed nominal significance: the VDBP rs12512631 T > C was associated with a better DSS [combined hazards ratio (HR) = 0.66]; and the same for RXRA rs7850212 C > A (combined HR = 0.38), which were further confirmed by the Fine and Gray competing‐risks regression model. Further bioinformatics analyses indicated that these loci may modulate corresponding gene methylation status.