Association of GWAS-Identified Lung Cancer Susceptibility Loci with Survival Length in Patients with Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy

Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66–0.96; P = 0.0187) and 0.73 (95% CI, 0.55–0.96; P = 0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63–0.96; P = 0.0199) and 1.29 (95% CI, 1.08–1.55; P = 0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC.     

Genetic Variations in the Flanking Regions of miR-101-2 Are Associated with Increased Risk of Breast Cancer

Genetic variants in human microRNA (miRNA) genes may alter mature miRNA processing and/or target selection, and likely contribute to cancer susceptibility and disease progression. Previous studies have suggested that miR-101 may play important roles in the development of cancer by regulating key tumor-associated genes. However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in breast cancer susceptibility remains unclear. In this study, we genotyped 11 SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study of 1064 breast cancer cases and 1073 cancer-free controls. The results revealed that rs462480 and rs1053872 in the flank regions of pre-miR-101-2 were significantly associated with increased risk of breast cancer (rs462480 AC/CC vs AA: adjusted OR = 1.182, 95% CI: 1.030–1.357, P = 0.017; rs1053872 CG/GG vs CC: adjusted OR = 1.179, 95% CI: 1.040–1.337, P = 0.010). However, the remaining 9 SNPs were not significantly associated with risk of breast cancer. Additionally, combined analysis of the two high-risk SNPs revealed that subjects carrying the variant genotypes of rs462480 and rs1053872 had increased risk of breast cancer in a dose-response manner (P _trend = 0.002). Compared with individuals with “0–1” risk allele, those carrying “2–4” risk alleles had 1.29-fold risk of breast cancer. In conclusion, these findings suggested that the SNPs rs462480 and rs1053872 residing in miR-101-2 gene may have a solid impact on genetic susceptibility to breast cancer, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis.     

Gene Polymorphisms of ADIPOQ +45T>G,UCP2 -866G>A,and FABP2 Ala54Thr on the Risk of Colorectal Cancer: A Matched Case-Control Study

As insulin resistance (IR) is an established risk factor for colorectal cancer (CRC), we explored the association between each of the IR-related gene polymorphisms of adiponectin (ADIPOQ) rs2241766, uncoupling protein 2 (UCP2) rs659366, and fatty acid-binding protein (FABP2) rs1799883 and CRC risk. Genotyping of blood samples and collection of lifestyle and dietary habits were performed for 400 case-control pairs. Unconditional logistic regression (ULR) was applied to assess the effects of the three single nucleotide polymorphisms (SNP), environmental factors. Both ULR and generalized multifactor dimensionality reduction (GMDR) were used to test the gene-gene and gene-environment interactions on CRC risk. Subjects carrying the ADIPOQ rs2241766 TG+GG genotype had a higher CRC risk than those carrying the TT genotype (OR = 1.429, 95% CI 1.069–1.909). The additive and multiplicative interactions between ADIPOQ rs2241766 and FABP2 rs1799883 on CRC were found by ULR (RERI = 0.764, 95%CI 0.218∼1.311, AP = 0.514, 95%CI 0.165∼0.864, S = −1.745, 95%CI is unachievable, and P_multi = 0.017, respectively). Furthermore, the high order gene-gene interaction of the three SNPs were found by GMDR (P = 0.0107). A significant dosage effect with an increasing number of risk genotypes was observed as the risk of CRC increased (P_trend = 0.037). In GMDR, the gene-environment interaction among the three SNPs and red meat consumption on CRC risk was significant (P = 0.0107). Compared with subjects with low red meat consumption and null risk genotypes, those with high-red meat consumption and three risk genotypes had 3.439-fold CRC risk (95% CI 1.410–8.385). In conclusion, the results showed that the ADIPOQ rs2241766 TG+GG genotype increased CRC risk. Given the complexity of the carcinogen for CRC, ADIPOQ rs2241766, UCP2 rs659366, FABP2 rs1799883 and red meat consumption potentially worked together in affecting CRC risk.     

Genetic Variants at 12p11 and 12q24 Are Associated with Breast Cancer Risk in a Chinese Population

Background

A recent genome-wide association study (GWAS) has identified three new breast cancer susceptibility loci at 12p11, 12q24 and 21q21 in populations of European descent. However, because of the genetic heterogeneity, it is largely unknown for the role of these loci in the breast cancer susceptibility in the populations of non-European descent.

Methodology/Principal Findings

Here, we genotyped three variants (rs10771399 at 12p11, rs1292011 at 12q24 and rs2823093 at 21q21) in an independent case–control study with a total of 1792 breast cancer cases and 1867 cancer-free controls in a Chinese population. We found that rs10771399 and rs1292011 were significantly associated with risk of breast cancer with per-allele odds ratios (ORs) of 0.85 (95% confidence interval (CI): 0.76–0.96; P = 0.010) and 0.84 (95% CI: 0.76–0.95; P = 4.50×10⁻³), respectively, which was consistent with those reported in populations of European descent. Similar effects were observed between ER/PR positive and negative breast cancer for both loci. However, we did not found significant association between rs2823093 and breast cancer risk (OR = 0.97, 95%CI = 0.76–1.24; P  = 0.795).

Conclusions/Significance

Our results indicate that genetic variants at 12p11 and 12q24 may also play an important role in breast cancer development in Chinese women.     

Metabotropic Glutamate Receptor 3 Is Associated with Heroin Dependence but Not Depression or Schizophrenia in a Chinese Population

Metabotropic glutamate receptor subtype 3 (mGluR3, encoded by GRM3) plays important roles in the pathophysiology of schizophrenia, depression, and drug dependence. GRM3 polymorphisms were reported to be associated with prefrontal activity, cognitive shifting, and memory capability in healthy subjects, as well as susceptibility to schizophrenia and depression. The goal of this study was to replicate the association of GRM3 with schizophrenia and depression and to explore GRM3’s potential association with heroin dependence (HD) in a Chinese population. Seventeen SNPs throughout the GRM3 gene were genotyped using MALDI-TOF within the MassARRAY system, and the allele and genotype distributions were compared between 619 healthy controls and 433 patients with schizophrenia, 409 patients with major depression, and 584 unrelated addicts. We found that GRM3 polymorphisms modulate the susceptibility to HD but do not significantly influence the risk for schizophrenia or depression. An increased risk of HD was significantly associated with the minor alleles of two GRM3 SNPs, including the T allele of rs274618 (Odds ratio (OR) = 1.631, 95% confidence interval (95%CI): 1.317–2.005), the T allele of rs274622 (OR = 1.652, 95% CI: 1.336–2.036), compared with the major alleles. The addicts carrying the minor allele of rs274618 or rs274622 had a shortened duration for transition from first use to dependence (DTFUD) in comparison to homozygote for major allele (P<0.0001 for each SNP using log rank test). Additionally, a 6-SNP haplotype within 5′ region of the GRM3 including the minor alleles of the two aforementioned SNPs was significantly associated with an increased risk of HD (P = 0.00001, OR = 1.668, 95% CI: 1.335–2.084). Our data indicated that GRM3 polymorphisms do not contribute to genetic susceptibility to schizophrenia and depression, but they confer an increased risk of HD in a Chinese population.     

Associations of Two Common Genetic Variants with Breast Cancer Risk in a Chinese Population: A Stratified Interaction Analysis

Recent genome-wide association studies (GWAS) have identified a series of new genetic susceptibility loci for breast cancer (BC). However, the correlations between these variants and breast cancer are still not clear. In order to explore the role of breast cancer susceptibility variants in a Southeast Chinese population, we genotyped two common SNPs at chromosome 6q25 (rs2046210) and in TOX3 (rs4784227) in a case-control study with a total of 702 breast cancer cases and 794 healthy-controls. In addition, we also evaluated the multiple interactions among genetic variants, risk factors, and tumor subtypes. Associations of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (95% CI). The results indicated that both polymorphisms were significantly associated with the risk of breast cancer, with per allele OR = 1.35, (95%CI = 1.17–1.57) for rs2046210 and per allele OR = 1.24 (95%CI = 1.06–1.45) for rs4784227. Furthermore, in subgroup stratified analyses, we observed that the T allele of rs4784227 was significantly associated with elevated OR among postmenopausal populations (OR = 1.44, 95%CI 1.11–1.87) but not in premenopausal populations, with the heterogeneity P value of P = 0.064. These findings suggest that the genetic variants at chromosome 6q25 and in the TOX3 gene may play important roles in breast cancer development in a Chinese population and the underlying biological mechanisms need to be further elucidated.     

Identification of a Functional Genetic Variant at 16q12.1 for Breast Cancer Risk: Results from the Asia Breast Cancer Consortium

Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA) study in over 28,000 cases and controls recruited from 12 studies conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals) of 1.25 (1.20−1.31) per allele (P = 3.2×10⁻²⁵) in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR  = 1.19, 95% CI  = 1.09−1.31, P = 1.3×10⁻⁴, 2,797 cases and 2,662 controls). SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures.     

Evidence for STAT4 as a Common Autoimmune Gene: rs7574865 Is Associated with Colonic Crohn's Disease and Early Disease Onset

Background

Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort.

Methodology/Principal Findings

Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn''s disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74–0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63–12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74–1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75–1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction.

Conclusions/Significance

Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.     

A Study on Genetic Variants of Fibroblast Growth Factor Receptor 2 (FGFR2) and the Risk of Breast Cancer from North India

Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694), respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0–1 risk loci, those with 2–4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152–2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was associated with a significantly increased risk compared to the common (ACA) haplotype (OR = 1.365, 95% CI = 1.086–1.717, P = 0.008). Our results suggest that intron 2 SNPs of FGFR2 may contribute to genetic susceptibility of breast cancer in North India population.     

RNASEL and MIR146A SNP-SNP Interaction as a Susceptibility Factor for Non-Melanoma Skin Cancer

Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (OR_GC = 0.73, [95%CI = 0.52–1.03]; OR_CC = 0.29, [95% CI = 0.14–0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (OR_AG = 0.88, [95%CI = 0.65–1.19]; OR_AA = 0.68, [95%CI = 0.43–1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (OR_SCC = 0.56, [95%CI = 0.38–0.81], p-interaction = 0.012) and BCC (OR_BCC = 0.57, [95%CI = 0.40–0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology.     

Rs7206790 and rs11644943 in FTO Gene Are Associated with Risk of Obesity in Chinese School-Age Population

To evaluate the associations between candidate FTO single nucleotide polymorphisms (SNPs) and obesity, a case-control study was conducted among Chinese school-age children, which included 500 obese cases and 500 matched controls (age, gender and location). We selected 24 candidate FTO tag-SNPs via bio-informatics analysis and performed genotyping using SNPScan technology. Results indicated that rs7206790 and rs11644943 were significantly associated with obesity among school-age children in both additive and recessive models (P<0.05) after adjusting confounders. Comparing rs7206790 CC and CG genotype of carriers, those carrying the GG genotype had an increased risk of obesity (adjusted odds ratio [OR], 3.76; 95% Confidence interval [CI], 1.24–11.43). Carriers of the AA allele of rs11644943 had a lower risk of obesity (adjusted OR, 0.16; 95% CI, 0.04–0.72) compared with those of the T allele (TT and TA). These two SNPs (rs7206790 and rs11644943) were not Linkage Disequilibrium (LD) with previous reported obesity-associated SNPs. Under the recessive model adjusted for age and gender and location, rs7206790 GG allele carriers had significantly increased BMIs (P = 0.012), weight (P = 0.012), waist circumferences (WC) (P = 0.045) and hip circumferences (HC) (P = 0.033). Conversely, rs11644943 AA allele carriers had significantly decreased BMIs (P = 0.006), WC (P = 0.037) and Waist-to-height ratios (WHtR) (P = 0.012). A dose-response relationship was found between the number of risk alleles in rs7206790, rs11644943 and rs9939609 and the risk of obesity. The Genetic Risk Score (GRS) of the reference group was 3; in comparison, those of 2, 4, and ≥5 had ORs for obesity of 0.24 (95%CI, 0.05–1.13), 1.49 (95%CI, 1.10–2.01), and 5.20 (95%CI, 1.75–15.44), respectively. This study confirmed the role of FTO variation on genetic susceptibility to obesity. We reported two new obesity-related FTO SNPs (rs7206790 and rs11644943) among Chinese school-age children.     

A Functional TNFAIP2 3'-UTR rs8126 Genetic Polymorphism Contributes to Risk of Esophageal Squamous Cell Carcinoma

Background

Accumulated evidences demonstrated that single nucleotide polymorphisms (SNPs) in mRNA 3''-untranslated region (3''-UTR) may impact microRNAs (miRNAs)-mediated expression regulation of oncogenes and tumor suppressors. There is a TNFAIP2 3''-UTR rs8126 T>C genetic variant which has been proved to be associated with head and neck cancer susceptibility. This SNP could disturb binding of miR-184 with TNFAIP2 mRNA and influence TNFAIP2 regulation. However, it is still unclear how this polymorphism is involved in development of esophageal squamous cell carcinoma (ESCC). Therefore, we hypothesized that the functional TNFAIP2 rs8126 SNP may affect TNFAIP2 expression and, thus, ESCC risk.

Methods

We investigated the association between the TNFAIP2 rs8126 variant and ESCC risk as well as the functional relevance on TNFAIP2 expression in vivo. Genotypes were determined in a case-control set consisted of 588 ESCC patients and 600 controls. The allele-specific regulation on TNFAIP2 expression by the rs8126 SNP was examined in normal and cancerous tissue specimens of esophagus.

Results

We found that individuals carrying the rs8126 CC or CT genotype had an OR of 1.89 (95%CI  = 1.23–2.85, P = 0.003) or 1.38 (95%CI  = 1.05–1.73, P = 0.017) for developing ESCC in Chinese compared with individual carrying the TT genotype. Carriers of the rs8126 CC and CT genotypes had significantly lower TNFAIP2 mRNA levels than those with the TT genotypes in normal esophagus tissues (P<0.05).

Conclusions

Our data demonstrate that functional TNFAIP2 rs8126 genetic variant is a ESCC susceptibility SNP. These results support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of cancer risk.     

Type II Transmembrane Serine Protease Gene Variants Associate with Breast Cancer

Type II transmembrane serine proteases (TTSPs) are related to tumor growth, invasion, and metastasis in cancer. Genetic variants in these genes may alter their function, leading to cancer onset and progression, and affect patient outcome. Here, 464 breast cancer cases and 370 controls were genotyped for 82 single-nucleotide polymorphisms covering eight genes. Association of the genotypes was estimated against breast cancer risk, breast cancer–specific survival, and survival in different treatment groups, and clinicopathological variables. SNPs in TMPRSS3 (rs3814903 and rs11203200), TMPRSS7 (rs1844925), and HGF (rs5745752) associated significantly with breast cancer risk (P _trend = 0.008–0.042). SNPs in TMPRSS1 (rs12151195 and rs12461158), TMPRSS2 (rs2276205), TMPRSS3 (rs3814903), and TMPRSS7 (rs2399403) associated with prognosis (P = 0.004–0.046). When estimating the combined effect of the variants, the risk of breast cancer was higher with 4–5 alleles present compared to 0–2 alleles (P = 0.0001; OR, 2.34; 95% CI, 1.39–3.94). Women with 6–8 survival-associating alleles had a 3.3 times higher risk of dying of breast cancer compared to women with 1–3 alleles (P = 0.001; HR, 3.30; 95% CI, 1.58–6.88). The results demonstrate the combined effect of variants in TTSPs and their related genes in breast cancer risk and patient outcome. Functional analysis of these variants will lead to further understanding of this gene family, which may improve individualized risk estimation and development of new strategies for treatment of breast cancer.     

A Genetic Variant in pre-miR-27a Is Associated with a Reduced Renal Cell Cancer Risk in a Chinese Population

Background

MicroRNAs (miRNAs) are a class of small non-coding RNAs to regulate cell differentiation, proliferation, development, and apoptosis. The single nucleotide polymorphism (SNP) rs895819 is located at the terminal loop of pre-miR-27a. Here, we aimed to investigate whether SNP rs895819 was associated with the development of renal cell cancer (RCC) in a Chinese population.

Methods

In this case-control study, we recruited 594 RCC patients and 600 cancer-free controls with frequency matched by age and sex. We genotyped this polymorphism using the TaqMan assay and assessed the effect of this polymorphism on RCC survival. Logistic regression model was used to assess the genetic effects on the development of RCC and interactions between rs895819 polymorphism and risk factors.

Results

Compared with AA homozygote, individuals carrying AG/GG genotypes had a statistically significant reduced susceptibility to RCC (adjusted OR = 0.71, 95% CI = 0.56–0.90). Furthermore, AG/GG genotypes were associated with reduced RCC susceptibility in localized clinical stage (adjusted OR = 0.71, 95% CI = 0.55–0.91), and similar effects were observed in well differentiated and poorly differentiated RCC (adjusted OR = 0.71, 95% CI = 0.55–0.93 for well differentiated, adjusted OR = 0.51, 95% CI = 0.28–0.93 for poorly differentiated). We also observed that rs895819 had multiplicative interactions with age and hypertension. However, the polymorphism did not influence the survival of RCC.

Conclusion

Our results suggest that the pre-miR-27a rs895819 polymorphism can predict RCC risk in a Chinese population. Larger population-based prospective studies should be used to validate our findings.     

Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma

Background

The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).

Methods

In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI).

Results

We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16–2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23–3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57–7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011).

Conclusions

Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts.     

Genome-Wide Association Study of Breast Cancer in the Japanese Population

Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P<1.0×10⁻⁵) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31×10⁻¹², OR = 1.23; 95% CI = 1.16–.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79×10⁻¹¹, OR = 1.21; 95% CI = 1.15–.28) and rs12922061 (combined P-value of 3.97×10⁻¹⁰, OR = 1.23; 95% CI = 1.15–.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer.     

Genetic Polymorphisms of the Glycine N-Methyltransferase and Prostate Cancer Risk in the Health Professionals Follow-Up Study

Purpose

Glycine N-methyltransferase (GNMT) affects genetic stability by regulating the ratio of S-adenosylmethionine to S-adenosylhomocysteine, by binding to folate, and by interacting with environmental carcinogens. In Taiwanese men, GNMT was found to be a tumor susceptibility gene for prostate cancer. However, the association of GNMT with prostate cancer risk in other ethnicities has not been studied. It was recently reported that sarcosine, which is regulated by GNMT, increased markedly in metastatic prostate cancer. We hereby explored the association of GNMT polymorphisms with prostate cancer risk in individuals of European descent from the Health Professionals Follow-up Study (HPFS).

Methods

A total of 661 incident prostate cancer cases and 656 controls were identified from HPFS. The GNMT short tandem repeat polymorphism 1 (STRP1), 4-bp insertion/deletion polymorphisms (INS/DEL) and the single nucleotide polymorphism rs10948059 were genotyped to test for their association with prostate cancer risk.

Results

The rs10948059 T/T genotype was associated with a 1.62-fold increase in prostate cancer risk (95% confidence interval (CI): 1.18, 2.22) when compared with the C/C genotype. The STRP1 ≥16GAs/≥16GAs genotype was associated with decreased risk of prostate cancer when compared with the <16GAs/<16GAs genotype (odds ratio (OR) = 0.68; 95% CI: 0.46, 1.01). INS/DEL was not associated with prostate cancer risk. Haplotypes containing the rs10948059 T allele were significantly associated with increased prostate cancer risk.

Conclusion

In men of European descent, the GNMT rs10948059 and STRP1 were associated with prostate cancer risk. Compared to the study conducted in Taiwanese men, the susceptibility GNMT alleles for prostate cancer had a reverse relationship. This study highlights the differences in allelic frequencies and prostate cancer susceptibility in different ethnicities.     

Association of Aminoacyl-tRNA Synthetases Gene Polymorphisms with the Risk of Congenital Heart Disease in the Chinese Han Population

Aminoacyl-tRNA synthetases (ARSs) are in charge of cellular protein synthesis and have additional domains that function in a versatile manner beyond translation. Eight core ARSs (EPRS, MRS, QRS, RRS, IRS, LRS, KRS, DRS) combined with three nonenzymatic components form a complex known as multisynthetase complex (MSC).We hypothesize that the single-nucleotide polymorphisms (SNPs) of the eight core ARS coding genes might influence the susceptibility of sporadic congenital heart disease (CHD). Thus, we conducted a case-control study of 984 CHD cases and 2953 non-CHD controls in the Chinese Han population to evaluate the associations of 16 potentially functional SNPs within the eight ARS coding genes with the risk of CHD. We observed significant associations with the risk of CHD for rs1061248 [G/A; odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.81–0.99; P = 3.81×10⁻²], rs2230301 [A/C; OR = 0.73, 95%CI = 0.60–0.90, P = 3.81×10⁻²], rs1061160 [G/A; OR = 1.18, 95%CI = 1.06–1.31; P = 3.53×10⁻³] and rs5030754 [G/A; OR = 1.39, 95%CI = 1.11–1.75; P = 4.47×10⁻³] of EPRS gene. After multiple comparisons, rs1061248 conferred no predisposition to CHD. Additionally, a combined analysis showed a significant dosage-response effect of CHD risk among individuals carrying the different number of risk alleles (P _trend = 5.00×10⁻⁴). Compared with individuals with “0–2” risk allele, those carrying “3”, “4” or “5 or more” risk alleles had a 0.97-, 1.25- or 1.38-fold increased risk of CHD, respectively. These findings indicate that genetic variants of the EPRS gene may influence the individual susceptibility to CHD in the Chinese Han population.