Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort

It is well established that rare mutations in BRCA2 predispose to familial breast cancer, but whether common variants at this locus contribute more modest risk to sporadic breast cancer has not been thoroughly investigated. We performed a haplotype-based study of BRCA2 among women in the Multiethnic Cohort Study (MEC), genotyping 50 SNPs spanning 109.4 kb of the BRCA2 gene. Twenty-one haplotype-tagging SNPs (including seven missense SNPs) were selected to predict the common BRCA2 haplotypes and were genotyped in a breast cancer case-control study nested in the MEC (cases, n=1715; controls, n=2502). Compared to non-carriers, we observed nominally significant positive associations for homozygous carriers of specific haplotypes in blocks 2 (haplotype 2c: OR=1.50; 95% CI, 1.08-2.09) and 3 (haplotype 3d: OR=1.50; 95% CI, 1.01-2.24). These results could be explained on the basis of a single marker in intron 24 (SNP 42: rs206340) that was correlated with these haplotypes and the homozygous state was associated with a significantly increased risk of breast cancer (AA versus GG genotypes: OR=1.59, 95% CI, 1.18-2.16; nominal P=0.005). This association was modestly stronger among women with advanced disease (OR=2.00, 95% CI, 1.30-3.08; P=0.002). In this exploratory analysis, we found little indication that common variation in BRCA2 dramatically impacts sporadic breast cancer risk. However, a significant elevation in risk was observed among approximately 6% of women who carried a specific haplotype pattern and may harbor a susceptibility allele at the BRCA2 locus.     

Genetic polymorphisms in AURKA and BRCA1 are associated with breast cancer susceptibility in a Chinese Han population

Centrosome defects can result in aneuploidy and genomic instability, and have important implications for breast cancer development. The Aurora-A and BRCA1 proteins interact and both are strongly involved in centrosome regulation. Genetic variants in these two genes may have an effect on breast cancer development. Here, we report a comprehensive single nucleotide polymorphism (SNP) and haplotype-tagging association study on these two genes in 1334 breast cancer cases and 1568 unaffected controls among the Chinese Han population. Apart from a missense SNP, rs2273535 (Phe31Ile), and a probable risk SNP, rs2064863, six htSNPs were analysed in three high-LD blocks of AURKA spanning from 10 kb upstream to 2 kb downstream of AURKA. For BRCA1, six htSNPs were analysed in a large high-LD region covering 98 kb (10 kb was extended to each end of BRCA1). The results showed that four SNPs in AURKA (data in recessive model, rs2273535: OR = 2.19, 95% CI = 1.03-4.66, p = 0.0422; rs2298016: OR = 0.38, 95% CI = 0.18-0.82, p = 0.0141; rs6024836: OR = 1.54, 95% CI = 1.18-2.00, p = 0.0014; rs10485805: OR = 0.68, 95% CI = 0.47-0.98, p = 0.0380) and one SNP in BRCA1 (rs3737559, dominant model OR = 1.35, 95% CI = 1.11-1.64, p = 0.0030) were associated with breast cancer susceptibility. After correction for multiple comparisons (FDR = 0.05), only rs6024836 and rs3737559 remained significant. Two haplotypes (CC of block 2, OR = 20.74, 95% CI = 4.35-98.88, p = 0.0001; GG of block 3, OR = 1.32, 95% CI = 1.12-1.56, p = 0.0010) and one diplotype (AG-GG of block 3, OR = 1.63, 95% CI = 1.18-2.26, p = 0.0031) within AURKA showed strong associations with breast cancer risk. One haplotype of BRCA1 (CTGTTG, OR = 1.30, 95% CI = 1.06-1.59, p = 0.0118) was also associated with breast cancer risk. However, women harbouring both at-risk genotypes of Aurora-A and BRCA1 were at a slightly increased risk compared with those harbouring either at-risk variant alone. Common genetic variants in the AURKA and BRCA1 genes may contribute to breast cancer development.     

Association of PTEN gene polymorphisms with liver cancer risk

Objective: To find out if there are any relationship between three single nucleotide polymorphisms (SNPs) of phosphatase and tensin homolog (PTEN) gene (rs1234213, rs1234220, and rs2299939) and the susceptibility of liver cancer. Methods: Genotypes of the three SNPs in the PTEN gene were achieved utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Comparison of genotypes and alleles distribution differences between the case and the control subjects was accomplished with χ² test. The analysis of linkage disequilibrium (LD) and haplotypes of the three SNPs was performed using SHEsis software. We adopted odds ratios (ORs) with 95% confidence intervals (95% CIs) to show the relative risk of liver cancer. Results: TC genotype and C allele of rs1234220 polymorphism showed much more frequently in cases than in controls, reflecting that the TC genotype and the C allele may be linked to the increased risk of liver cancer (OR=2.225, 95% CI=1.178-4.204; OR=1.941, 95% CI=1.124-3.351). Rs2299939 polymorphism showed an opposite result that the GT genotype probably reduce the risk of liver cancer (OR=0.483, 95% CI=0.259-0.900). Statistical significance was not found in the distribution differences of the genotypes of rs1234213 between two groups. LD and haplotype analysis results of the three SNPs showed that the T-C-G haplotype frequency was much higher in cases than in healthy objects, which proved that the T-C-G haplotype might be a susceptibility haplotype for liver cancer (OR=3.750, 95% CI=1.396-10.077). Conclusions: PTEN gene polymorphisms might relate to liver cancer risk.     

Haplotype patterns in cancer-related genes with long-range linkage disequilibrium: no evidence of association with breast cancer or positive selection

The average length of linkage disequilibrium (LD) blocks in European populations is about 22 kb. In this study, we have selected 20 genes with LD blocks larger than 60 kb (with a median length of 88 kb) from a total of 121 cancer-related genes. We observed limited haplotype diversity, with an average of three haplotypes per gene accounting for more than 90% of the diversity, two of these being a Yin-Yang pair in 95% of the LD blocks. The mean frequency of the most common haplotype in the Spanish population was just below 50%, similar to those for the HapMap CEU and African samples, but lower than the 60% observed in Asian samples. Genes involved in the regulation of nucleobases and nucleic acid metabolism were overrepresented among these 20 genes with long LD blocks (eight genes ATM, BRCA1, BRCA2, ERCC6, MLH1, MSH3, RAD54B and XRCC4) relative to the other 101 cancer-related genes studied (P=1.23 x 10(-6)). The ancestral haplotype was observed at a frequency greater than 3 in 67% of the genes either in the Spanish or one of the HapMap sampled populations. When observed, the ancestral haplotype had an average 15% frequency in the Spanish sample, less than half that observed in Asian and African samples. The Spanish Yin-Yang haplotype pair represented over 35% of haplotypes in African samples and over 65% in non-African samples. We detected differences in SNP frequencies between populations for five genes (ALDH2, APC, PIK3CB, RB1 and XRCC4, all with Fst>0.4); however, these genes did not show evidence of positive selection. Finally, we found no evidence that the haplotypes formed by SNPs in the 20 genes are associated with breast cancer.     

Correlation between LSP1 polymorphisms and the susceptibility to breast cancer

Objective: The present study aimed at assessing the relationship between Leukocyte-specific protein 1 gene (LSP1) polymorphisms (rs569550 and rs592373) and the pathogenesis of breast cancer (BC). Methods: 70 BC patients and 72 healthy subjects were enrolled in the study. Rs569550 and rs592373 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratio (OR) with 95% confidence interval (CI) were calculated by the chi-squared test to assess the relationship between LSP1 polymorphisms and BC risk. Linkage disequilibrium (LD) and haplotypes were also analyzed by HaploView software. Results: Genotype distribution of the control was in accordance with Hardy-Weinberg equilibrium (HWE). The homozygous genotype TT and T allele of rs569550 could significantly increase the risk of BC (TT vs. GG: OR=3.17, 95% CI=1.23-8.91; T vs. G: OR=1.63, 95% CI=1.01-2.64). For rs592373, mutation homozygous genotype CC and C allele were significantly associated with BC susceptibility (CC vs. TT: OR=4.45, 95% CI=1.38-14.8; C vs. T: OR=1.70, 95% CI=1.03-2.81). LD and haplotypes analysis of rs569550 and rs592373 polymorphisms showed that T-C haplotype was a risk factor for BC (T-C vs. G-T: OR=1.74, 95% CI=1.04-2.92). Conclusion: LSP1 rs569550 and rs592373 polymorphisms are both risk factors for BC.     

DNA polymorphisms and haplotypes of apolipoprotein A5's attribution to the plasma triglyceride levels in Koreans

PURPOSE: Recent studies using human and mice reported that apolipoprotein A-V (APOA5) gene plays an important role in controlling triglyceride (TG) concentrations. The purpose of the present study was to investigate the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in the APOA5 gene and TG in subjects and to search for possible associations of the APOA5 gene variants and common haplotypes with hypertriglyceridemia (HTG). MATERIALS AND METHODS: We examined the case-control subjects including 100 HTG patients and 243 unrelated healthy control. The genes were screened for SNPs by direct sequencing in 48 genetically unrelated individuals. Six SNPs (-1390C>T, -1020G>A, -3A>G, V150M, G182C and 1259T>C) were genotyped in case and control populations. RESULTS: In this study, our results indicated a strong association between APOA5 SNP -3A>G and G182C and elevated TG levels (p<0.001). Analysis of the SNPs from APOA5 gene has identified major haplotype showing very strong association with HTG, CGGGTT (p<0.001). Likelihood ratio test (LRT) of these six SNPs revealed that haplotypes were strong independent predictors of HTG (p<0.001). Haplotype-trend logistic regression (HTR) analysis revealed a significant association between the CGGGGC (haplotype 2) and CGGGTT (haplotype 4) and HTG (OR=2.48, 95% CI=1.06-5.76 and OR=8.54, 95% CI=2.66-27.42, respectively). CONCLUSION: We confirm that the APOA5 variants are associated with triglyceride levels and the haplotype may be strong independent predictors of HTG among Koreans.     

Multiple sclerosis and hepatitis C virus infection are associated with single nucleotide polymorphisms in interferon pathway genes.

We have studied 35 single nucleotide polymorphisms (SNPs) in the interferon (IFN) pathway to determine their contribution to multiple sclerosis (MS) and hepatitis C virus (HCV) infection. A total of 182 patients with MS, 103 patients with chronic hepatitis C, and 118 control subjects were enrolled in the study. Of the 35 SNPs studied, 3 were in IFN-alpha receptor (IFNAR-1), 10 in IFN-alpha/beta receptor (IFNAR-2), 9 in Stat1, 5 in Stat2, and 8 in IFN regulatory factor-1 (IRF-1). Compared to controls, Stat1 gene polymorphisms were significantly more frequent in MS patients (rs# 2066802 OR = 7.46, 95% CI = 2.22-25.10; rs# 1547550 OR = 1.69, 95% CI = 1.01-2.81) and in HCV patients (rs# 2066802 OR = 5.95, 95% CI = 1.55-22.81; rs# 1547550 OR = 2.30, 95% CI = 1.24-4.24). Also one IRF-1 gene SNP was associated with MS (rs# 2070721 OR = 2.05, 95% CI = 1.03-4.09), and four IRF-1 gene SNPs were associated with HCV infection (rs# 2070721 OR = 2.59, 95% CI = 1.23-5.43; rs# 2070723 OR = 4.8, 95% CI = 1.26-18.20; rs# 2070728 OR = 9.81, 95% CI = 1.21-79.4; rs# 2070729 OR = 3.6, 95% CI = 1.23-10.48; rs# 839 OR = 4.67, 95%CI = 1.29-16.87). Characteristic nucleotide combinations on single chromosomes (haplotype) generated block structures, including SNPs, that differed between patients and controls. Using a permutation test to detect differences in haplotype distribution between groups, the CCATTGA and the CCGAA haplotypes in the IRF-1 gene were more frequent in MS (p = 0.03) and in HCV patients (p = 0.001) than in controls. In conclusion, our data show that genetic variants in the IRF-1 and Stat1 genes of the IFN pathway are associated with MS and HCV infection.     

Association of canine anal furunculosis with TNFA is secondary to linkage disequilibrium with DLA-DRB1*

Anal furunculosis (AF) is a chronic inflammatory disease of perianal tissues that particularly affects German Shepherd dogs (GSD). An immune-mediated aetiopathogenesis is suggested by T-cell infiltration, upregulated cytokine gene expression, clinical response to ciclosporin therapy and a strong genetic association with the DLA-DRB1*00101 allele. Given the close proximity of TNFA and DLA-DRB1 in the canine major histocompatibility complex (MHC), together with the strong linkage disequilibrium (LD) observed across this region, the primary disease association could be with either locus. We have investigated whether there may be an association of AF with TNFA gene polymorphism in GSDs. Cohorts of AF-affected and AF-unaffected GSDs of known dog leucocyte antigen (DLA) class II profile were genotyped for 10 single nucleotide polymorphisms (SNPs) in the canine TNFA locus using Sequenom iPLEX technology. Seven discrete TNFA haplotypes were identified in GSDs for combinations of these SNPs. TNFA haplotype frequencies were compared in cases and controls. The TNFA haplotype 3 (ATCGTTACGG), was at significantly increased frequency in cases (29% vs 15%, OR 2.5, 95% CI 1.4–4.8; P  = 0.003). All seven discrete TNFA SNP haplotypes were examined for their association with DLA-DRB1/DQA1/DQB1 established haplotypes. TNFA haplotype 3 was preferentially associated with both DLA-DRB1*00101(3A)- and DLA-DRB1*00102(3B)-positive haplotypes. The DLA-DRB1* 00101/TNFA-3A haplotype was significantly associated with AF (19.3% vs 5.8%; OR 3.7, 95% CI: 1.5–8.9; P  = 0.003), whereas the DLA-DRB1*00102/TNFA-3B haplotype was not ( P  = NS). These findings suggest that susceptibility to AF in GSDs is primarily associated with DLA-DRB1*00101 and any association with the TNFA locus is secondary and is likely to be because of LD.     

Inducible nitric oxide synthase gene (NOS2A) haplotypes and the outcome of hepatitis C virus infection

Inducible nitric oxide synthase (iNOS) is an important molecule involved in the host defense against infectious agents. iNOS is encoded by the NOS2A gene and well-defined haplotypes exist with respect to this gene. We examined whether these haplotypes were associated with the outcome of hepatitis C virus (HCV) infection in 619 Caucasian patients from seven European liver centres. We observed five major haplotypes: (-277A)+(-1026G)+(-1659C): haplotype 1; (-277G)+(-1026T)+(-1659C): haplotype 2; (-277G)+(-1026G)+(-1659C): haplotype 3; (-277G)+(-1026T)+(-1659T): haplotype 4; and (-277A)+(-1026T)+(-1659C): haplotype 5. Distributions of these haplotypes are comparable with those of previous studies. Homozygotes for haplotype 2 or those with haplotypes 2/4 were more likely than those with the 1/1 (wild type) combination to have self-limiting infections (odds ratios (OR)=3.43; 95% confidence intervals (95% CI): 1.10-8.0; P=0.0206 and OR=5.15; 95% CI: 1.32-14.32; P=0.0018, respectively). Conversely, carriage of haplotype 1 was associated with the lack of self-limiting disease (OR=0.48; 95% CI: 0.27-0.83; P=0.009). The effect was mainly among males (OR=0.41; 95% CI: 0.182-0.942; P=0.031 for males, and OR=0.55; 95% CI: 0.24-1.37; P=0.136 for women). Carriage of haplotype 1 was not associated with initial response (P=0.268) or sustained response (P>0.171). Combinations of haplotypes 1/4 were more likely to respond to interferon monotherapy in comparison of initial responders to nonresponders (OR=2.25; 95% CI: 1.05-5.68; P=0.0275).     

Genetic variation in CXCL12 and risk of cervical carcinoma: a population‐based case–control study

CXCL12 provides a chemotactic signal‐directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population‐based case–control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56–0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5′‐flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56–0.93; recessive model OR = 0.35, 95% CI: 0.12–0.97; and log‐additive model OR = 0.72, 95% CI: 0.57–0.90). A stepwise procedure identified rs17885289, rs266085 and 3′‐untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3′‐UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population‐based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.     

Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2

Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.     

Association of RIP2 gene polymorphisms and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of receptor interacting protein 2 (RIP2) single-nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. A case-control study was performed on the SNPs rs16900617 and rs16900627 in 590 Chinese SLE patients and 660 healthy controls. These SNPs were typed by TaqMan allele discrimination assays. We found a significant association of rs16900617 G allele [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.41-0.72] and rs16900627 G allele (OR = 1.28, 95% CI 1.04-1.58) with SLE. Significant differences in genotype frequency distribution were also found in SLE and control individuals (rs16900617: AG versus AA, OR = 0.59, 95% CI 0.44-0.81; GG versus AA, OR = 0.08, 95% CI 0.01-0.65; AG + GG versus AA, OR = 0.55, 95% CI 0.41-0.75; rs16900627: AG versus AA, OR = 1.51, 95% CI 1.17-1.93; AG + GG versus AA, OR = 1.43, 95% CI 1.13-1.82). Analysis of the haplotypes revealed that two haplotypes of AG and GA were also significantly associated with SLE (OR = 1.37, 95% CI 1.11-1.70; OR = 0.60, 95% CI 0.45-0.79). Our findings suggest that the RIP2 gene polymorphisms may be associated with susceptibility to SLE in the Chinese population.     

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility

Aim: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. Methods: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. Results: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). Conclusion: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.     

Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism

Linkage studies have provided evidence that one or more loci on chromosome 9q influence Alzheimer disease (AD). The gene encoding the ATP-binding cassette A1 transporter (ABCA1) resides within proximity of previously identified linkage peaks and represents a plausible biological candidate for AD due to its central role in cellular lipid homeostasis. Several single nucleotide polymorphisms (SNPs) spanning ABCA1 have been genotyped and haplotype-based association analyses performed in four independent case-control samples, consisting of over 1,750 individuals from three European populations representing both early and late-onset AD. Prominent effects were observed for a common (H2) and rarer haplotype (H5) that were enriched in AD cases across studied populations (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.36-1.82; P<0.00001 and OR 2.90; 95% CI 2.54-3.27; P<0.00001, respectively). Two other common haplotypes in the studied region (H1 and H3) were significantly under-represented in AD cases, suggesting that they may harbor alleles that decrease disease risk (OR 0.79, 95% CI 0.64-0.94; P=0.0065 and OR 0.70, 95% CI 0.46-0.93; P=0.011, respectively). While findings were significant in both early and late-onset samples, haplotype effects were more distinct in early-onset materials. For late-onset samples, ancillary evidence was obtained that both single marker alleles and haplotypes of ABCA1 contribute to variable cerebrospinal fluid tau and beta amyloid (Abeta42) protein levels, and brain Abeta load. Results indicate that variants of ABCA1 may affect the risk of AD, providing further support for a genetic link between AD and cholesterol metabolism.     

Comparative study of the haplotype structure and linkage disequilibrium of chromosome 1p36.2 region in the Korean and Japanese populations

The patterns of linkage disequilibrium (LD) in the human genome provide important information for disease gene mapping. LDs may vary depending on chromosomal regions and populations. We have compared LD and haplotypes defined by SNPs in the chromosome 1p36.2 region of the Korean and Japanese populations. Fifty-eight SNPs in about 418 kb ranging from tumor necrosis factor receptor 2 (TNFR2:TNFRSF1B) to procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) gene were examined in 96 healthy Koreans and Japanese each by direct sequencing and fluorescence correlation spectroscopy combined with the PCR-sequence specific primer method (PCR-SSP-FCS), respectively. Upon pair-wise LD analysis, a total of 25 and 16 out of 58 SNPs greater than MAF 10% were included in LD blocks, encompassing almost 81 kb and 55 kb in total, in Koreans and Japanese, respectively. Both similarities and differences were observed in LD strength and haplotype frequencies between the populations. Considerable similarities were observed in the telomeric region where a long-range block of approximately 80 kb including three genes was found to have strong LDs in both Koreans and Japanese. Significant difference in LD strength was present near the TNFR2 region between the Japanese and Korean populations.     

Association between COX-2 polymorphisms and non-small cell lung cancer susceptibility

Aim: To explore the association between COX-2 polymorphisms and non-small cell lung cancer (NSCLC) susceptibility. Methods: We collected fasting peripheral venous blood from 60 cases with NSCLC and 62 healthy controls through physical examinations, and applied PCR-RFLP to analyze COX-2 polymorphisms of two groups. Results: With respect to detecting COX-2 rs689466 and rs5275 polymorphisms, the distribution frequency of mutant genotype AA of COX-2 rs689466 in case group was higher than that in control group, which possessed significant difference between two groups (P < 0.05). Carriers with AA genotype were 4.05 times at risk of NSCLC than those with GG genotype (P = 0.04, OR=4.05, 95% CI = 1.14-14.43). The distribution of mutant genotype CC of COX-2 rs5275 was different between two groups, and carriers with genotype CC were at 5.70 times higher risk of NSCLC than those with genotype TT. After corrected by sex, gender, smoking and drinking factors, AA genotype of COX-2 rs689466 and CC genotype of COX-2 rs5275 still contributed to increased risk of NSCLC (OR=4.22, 95% CI=1.10-16.17, OR=6.95, 95% CI=1.27-38.11). After analyzed of linkage disequilibrium (LD) and haplotypes of alleles in two SNPs, the distribution frequency of A-C haplotype in case group was higher than that in control group, with significant difference between two groups (P < 0.05). After corrected by sex, gender, smoking and drinking factors, statistical difference was still found in the total distribution of A-C haplotype between two groups (P = 0.03, OR=6.11, 95% CI=1.16-32.2). Conclusions: COX-2 rs689466 and rs5275 polymorphisms may be related to NSCLC susceptibility. And A-C haplotype might be a susceptibility haplotype for NSCLC.     

Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk

The ataxia telangiectasia mutated (ATM) gene is known to be activated by DNA damage and involved in cell cycle arrest, apoptosis and DNA repair. Therefore, ATM gene polymorphisms may act as important factors predicting individual susceptibility to lung cancer. To evaluate the role of ATM gene polymorphisms in lung cancer development, genotypes of the ATM polymorphisms, -4518A>G, IVS21-77C>T, IVS61-55T>C, and IVS62+60G>A, were determined in 616 lung cancer patients and 616 cancer-free controls. When the effects of selected ATM genotypes were evaluated separately, only one ATM genotype (IVS62+60G>A) showed an association with lung cancer risk. Subjects with the A allele at the site (IVS62+60G>A) have significantly higher risk of lung cancer than those with the G allele [odds ratio (OR)=1.6, 95% confidence interval (CI) 1.1-2.1]. When the haplotypes of four ATM single nucleotide polymorphism sites (-4518A>G, IVS21-77C>T, IVS61-55T>C and IVS62+60G>A) were studied, the ATTA haplotype showed significantly increased risk of lung cancer compared with the GCCA haplotype, the most common haplotype (OR=7.6, 95% CI 1.7-33.5). Furthermore, subjects with the (NN)TA haplotype showed highly significant and increased risk of lung cancer when compared with those without the (NN)TA haplotype (OR=13.2, 95% CI 3.1-56.1). Therefore, our results suggest that polymorphisms or haplotypes of the ATM gene play an important role in the development of lung cancer.     

Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study

Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer.     

Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case–control study with meta-analysis

Folate deficiency due to the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) variants leads to carcinogenesis by affecting DNA synthesis, repair, and methylation. We hypothesized that the MTHFR C677T, A1298C, and MS A2756G polymorphisms are associated with risk of bladder cancer. In a case-control study of 239 bladder cancer cases and 250 cancer-free controls, we found that the MTHFR 677TT genotype was statistically significantly associated with an increased risk of bladder cancer compared with the 677CC genotype (OR = 2.06, 95% CI = 1.16-3.64). Furthermore, the TA haplotype was associated with a significantly increased bladder cancer risk (OR = 1.38, 95% CI = 1.05-1.81) than was the most common haplotype, CA (e.g., CA denotes MTHFR 677C -1298A). We also found that the combined genotypes with 4-6 variant (risk) alleles (i.e., MTHFR 677T, 1298A, and MS 2756G alleles) were associated with an increased risk of bladder cancer (OR = 1.62, 95% CI = 1.03-2.53) compared with those with 0-3 variants, and this increased risk was more pronounced among subgroup of older people (OR = 1.71, 95% CI = 1.03-2.83). A meta-analysis of seven studies did not show a significant risk of bladder cancer in the MTHFR polymorphisms. The MTHFR polymorphisms and their haplotypes appear to jointly contribute to risk of bladder cancer.