[Show abstract][Hide abstract] ABSTRACT: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,8 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4950 at q32. (in intron 2 of the ZC3H11A gene; P = 8.82 × 0 −9), rs0474352 at 5q4.3 (near the ARRDC3 gene; P = .67 × 0 −9) and rs2290203 at 5q26. (in intron 4 of the PRC1 gene; P = 4.25 × 0 −8). We replicated these associations in 6,003 cases and 4,335 controls of European ancestry (P = 0.030, 0.004 and 0.00, respectively). Data from the ENCODE Project suggest that variants rs4950 and rs0474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have a substantial role in breast cancer etiology 1,2 . Thus far, genome-wide association studies (GWAS) have identified approximately 75 genetic loci associated with breast cancer risk 2–5 . With the exception of the studies we have conducted among East Asian women 6–9 and one study conducted among women of African ancestry 10 , all other published GWAS have been conducted among women of European ancestry. Genetic risk variants identified thus far from GWAS explain only about 10% of familial risk for breast cancer in East Asian women 3 . Given the dif-ferences in genetic architecture and environmental exposures for women of European and East Asian ancestry, additional GWAS need to be conducted among East Asian women to study the genetic basis of breast cancer risk. The current study was conducted as part of the Asia Breast Cancer Consortium (ABCC) to search for additional susceptibility loci for breast cancer. Included in this study are data obtained from 22,780 breast cancer cases and 24,181 controls who were recruited in 14 studies conducted in multiple Asian countries (Supplementary Table 1). The discovery stage (stage 1) included 2 GWAS in which 5,285 Chinese women (SBCGS-1) and 4,777 Korean women (SeBCS1) were scanned primarily using Affymetrix Genome-Wide Human SNP Array 6.0, which consists of 906,602 SNPs. After applying quality control filters described previously 6,9,11 , 5,152 Chinese women (2,867 cases and 2,285 controls; 677,157 SNPs) and 4,298 Korean women (2,246 cases and 2,052 controls; 555,117 SNPs) remained in the cur-rent analysis. Imputation was conducted for each study following the MACH algorithm 12 using HapMap 2 release 22 CHB (Han Chinese in Beijing, China) and JPT (Japanese in Tokyo, Japan) data (2,416,663 SNPs) as the reference. Only SNPs with a high imputation quality score (RSQR ≥ 0.50) were analyzed for associations with breast can-cer risk. In the analyses of data from Chinese and Korean women, a total of 1,930,412 and 1,907,146 SNPs, respectively, were included. A meta-analysis of these GWAS data was conducted using a fixed-effects, inverse variance meta-analysis with the METAL program 13 . There was little evidence of inflation in the association test statis-tics for the studies included in stage 1 (genomic inflation factors (λ): λ = 1.0426 for SBCGS-1, λ = 1.0431 for SeBCS1 and λ = 1.0499 for both studies combined; Supplementary Fig. 1). When scaled to a study of 1,000 cases and 1,000 controls, λ 1,000 values were 1.02, 1.02 and 1.01, respectively. To select SNPs for stage 2 replication, we used the following criteria: (i) association P < 0.05 in the stage 1 meta-analysis results; (ii) the
[Show abstract][Hide abstract] ABSTRACT: ecent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and approximately 2.5 million genotyped or imputed SNPs among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488 to 47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P=9.29×10-13), ALDH2/MYL2 (rs671, P=3.40×10-11; rs12229654, P=4.56×10-9), ITIH4 (rs2535633, P=1.77×10-10), and NT5C2 (rs11191580, P=3.83×10-8) genes. The association of BMI with rs2237892, rs671, and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed 8 loci at the genome-wide significance level (P<5.0×10-8) and an additional 14 at P<1.0×10-3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.
Human Molecular Genetics 05/2014; · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown. METHODS: In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. RESULTS: No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81-0.94, p-value = 4.4x10-4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 (OR = 1.32, 95% CI 1.18-1.47, p-value = 1.1x10-6). CONCLUSIONS: This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies. Impact: These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 05/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown.
In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.
No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81-0.94, p-value = 4.4x10-4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 (OR = 1.32, 95% CI 1.18-1.47, p-value = 1.1x10-6).
This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies. Impact: These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 05/2013; · 4.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.Methods
We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.ResultsOf the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10(-4)) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10(-22)). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10(-24)).Conclusions
We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION: Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? SUMMARY ANSWER: Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. PARTICIPANTS AND SETTING: We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. MAIN RESULTS: For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10(-6), binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. STUDY FUNDING/COMPETING INTERESTS: This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: As breast and ovarian cancers may have similar etiologies, this study aimed to evaluate the hypothesis that breast cancer shares common genetic susceptibility variants with ovarian cancer. METHODS: Ten genetic variants in 9 loci were previously identified to be associated with ovarian cancer risk among Caucasian women; an additional 353 variants in high linkage disequilibrium (r2≥0.6) among Han Chinese were identified. Data were available from the Affymetrix Genome Wide Array (6.0) or MACH imputation for 25 and 78 common genetic variants (minor allele frequency (MAF) ≥0.05), respectively. Associations with breast cancer risk were evaluated by additive logistic regression models among 2,918 breast cancer cases and 2,324 controls. RESULTS: No associations with breast cancer risk were evident for 103 ovarian cancer susceptibility variants in five loci. Four loci were not evaluated, as they included only rare variants (MAF<0.05). CONCLUSIONS: Ovarian cancer susceptibility variants identified in Caucasian women were not associated with breast cancer risk among 5,242 Chinese women. Impact: These findings suggest that breast and ovarian cancer may not share common susceptibility variants among Chinese women.
Cancer Epidemiology Biomarkers & Prevention 01/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age at natural menopause (ANM) is a complex trait with high heritability and is associated with several major hormonal-related diseases. Recently, several genome-wide association studies (GWAS), conducted exclusively among women of European ancestry, have discovered dozens of genetic loci influencing ANM. No study has been conducted to evaluate whether these findings can be generalized to Chinese women.
We evaluated the index single nucleotide polymorphisms (SNPs) in 19 GWAS-identified genetic susceptibility loci for ANM among 3,533 Chinese women who had natural menopause. We also investigated 3 additional SNPs which were in LD with the index SNP in European-ancestry but not in Asian-ancestry populations. Two genetic risk scores (GRS) were calculated to summarize SNPs across multiple loci one for all SNPs tested (GRSall), and one for SNPs which showed association in our study (GRSsel). All 22 SNPs showed the same association direction as previously reported. Eight SNPs were nominally statistically significant with P≤0.05: rs4246511 (RHBDL2), rs12461110 (NLRP11), rs2307449 (POLG), rs12611091 (BRSK1), rs1172822 (BRSK1), rs365132 (UIMC1), rs2720044 (ASH2L), and rs7246479 (TMEM150B). Especially, SNPs rs4246511, rs365132, rs1172822, and rs7246479 remained significant even after Bonferroni correction. Significant associations were observed for GRS. Women in the highest quartile began menopause 0.7 years (P = 3.24×10(-9)) and 0.9 years (P = 4.61×10(-11)) later than those in the lowest quartile for GRSsel and GRSall, respectively.
Among the 22 investigated SNPs, eight showed associations with ANM (P<0.05) in our Chinese population. Results from this study extend some recent GWAS findings to the Asian-ancestry population and may guide future efforts to identify genetic determination of menopause.
PLoS ONE 01/2013; 8(3):e58766. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS: To investigate this hypothesis, a two-stage study was carried out to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P<0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage 2, which consisted of ten additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS: Five of the 21 SNPs had significant allelic odds ratios and 95% confidence intervals as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 12/2012; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer.
We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb).
SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03-1.16] for the A/G genotype and 1.17 (95% CI, 1.05-1.30) for the G/G genotype (P = 1.6 × 10(-4) in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04-1.18) and 1.21 (1.08-1.35), respectively (P = 2.4 × 10(-5)).
Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.
This study identified a potential genetic locus for endometrial cancer risk.
[Show abstract][Hide abstract] ABSTRACT: Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor-node-metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 associations were evaluated in an independent replication stage of 4,160 Shanghai patients with breast cancer. A consistent and highly significant association with total mortality was documented for SNPs rs3784099 and rs9934948. SNP rs3784099, located in the RAD51L1 gene, was associated with total morality in both the discovery stage (P = 1.44 × 10(-8)) and replication stage (P = 0.06; P-combined = 1.17 × 10(-7)). Adjusted HRs for total mortality were 1.41 [95% confidence interval (CI), 1.18-1.68] for the AG genotype and 2.64 (95% CI, 1.74-4.03) for the AA genotype, when compared with the GG genotype. The variant C allele of rs9934948, located on chromosome 16, was associated with a similarly elevated risk of total mortality (P-combined = 5.75 × 10(-6)). We also observed this association among 1,145 patients with breast cancer of European ancestry from the Nurses' Health Study (NHS; P = 0.006); the association was highly significant in a combined analysis of NHS and Chinese data (P = 1.39 × 10(-7)). Similar associations were observed for these two SNPs with breast cancer-specific mortality. This study provides strong evidence suggesting that the RAD51L1 gene and a chromosome 16 locus influence breast cancer prognosis.
Cancer Research 03/2012; 72(5):1182-9. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.
[Show abstract][Hide abstract] ABSTRACT: Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.
[Show abstract][Hide abstract] ABSTRACT: More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) was 1.08 (95% CI: 1.06-1.09) for GRS1 and 1.15 (95% CI: 1.13-1.18) for GRS2. The OR for quintiles were 1.00, 1.26, 1.69, 1.95 and 2.18 (P<0.0001) for GRS1 and 1.00, 1.33, 1.60, 2.03 and 2.80 (P<0.001) for GRS2. Participants in the higher tertile of GRS1 and the higher BMI category had a higher risk of T2D compared to those on the lower tertiles of the GRS1 and of BMI (OR = 11.08; 95% CI: 7.39-16.62). We found similar results when we investigated joint effects between GRS1 and WHR terciles and exercise participation. We finally investigated the joint effect between tertiles of GRSs and a composite high risk score (no exercise participation and high BMI and WHR) on T2D risk. We found that compared to participants with low GRS1 and no high risk factors for T2D, those with high GRS1 and three high risk factors had a higher risk of T2D (OR = 13.06; 95% CI: 8.65-19.72) but the interaction factor was of marginal significance. The association was accentuated when we repeated analysis with the GRS2. In conclusion we found an association between GRS and lifestyle factors, alone and in combination, contributed to the risk of and T2D among middle age Chinese.
PLoS ONE 01/2012; 7(11):e49464. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin D deficiency has been consistently associated with obesity. However, it is unclear whether vitamin D deficiency is the cause or consequence of obesity. We investigated this question by evaluating the association between genetic variants in vitamin D metabolism pathway genes and obesity-related traits. Using directly genotyped and imputed data from a genome-wide association study of 6922 women aged 25-70 years, we examined the association of 198 single-nucleotide polymorphisms (SNPs) in vitamin D pathway genes (CYP27A1, CYP27B1, CYP24A1, CYP2R1, group-specific component (GC) and vitamin D nuclear receptor (VDR)) with body mass index (BMI) and body weight. Per allele beta (β) estimates were calculated for this association using linear regression models, controlling for age, square of age, menopausal status and sample sets. Overall, only two SNPs (rs2248359 in CYP24A1 and rs10832313 in CYP2R1) had a nominally significant association with BMI and weight (P<0.05 for all), with no variation observed by menopausal status, physical activity or dietary energy intake. None of the SNPs examined in the VDR gene were associated with BMI or weight. Our findings suggest that common genetic variants in vitamin D pathway genes do not have a major role in obesity among Chinese women. This comprehensive evaluation of genetic polymorphisms in vitamin D metabolism-related genes and obesity-related traits did not provide strong evidence to support low vitamin D levels as a cause of obesity.
International journal of obesity (2005) 12/2011; 36(9):1252-5. · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is a well-established risk factor for endometrial cancer, the most common gynecologic malignancy. Recent genome-wide association studies (GWAS) have identified multiple genetic markers for obesity. The authors evaluated the association of obesity-related single nucleotide polymorphisms (SNPs) with endometrial cancer using GWAS data from their recently completed study, the Shanghai Endometrial Cancer Genetics Study, which comprised 832 endometrial cancer cases and 2,049 controls (1996-2005). Thirty-five SNPs previously associated with obesity or body mass index (BMI; weight (kg)/height (m)(2)) at a minimum significance level of ≤5 × 10(-7) in the US National Human Genome Research Institute's GWAS catalog (http://genome.gov/gwastudies) and representing 26 unique loci were evaluated by either direct genotyping or imputation. The authors found that for 22 of the 26 unique loci tested (84.6%), the BMI-associated risk variants were present at a higher frequency in cases than in population controls (P = 0.0003). Multiple regression analysis showed that 9 of 35 BMI-associated variants, representing 7 loci, were significantly associated (P ≤ 0.05) with the risk of endometrial cancer; for all but 1 SNP, the direction of association was consistent with that found for BMI. For consistent SNPs, the allelic odds ratios ranged from 1.15 to 1.29. These 7 loci are in the SEC16B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes. The associations persisted after adjustment for BMI, suggesting that genetic markers of obesity provide value in addition to BMI in predicting endometrial cancer risk.
American journal of epidemiology 11/2011; 174(10):1115-26. · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.
Human Molecular Genetics 09/2011; 20(24):4991-9. · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies evaluating the association of vitamin D-related genetic variants with breast cancer risk have produced inconsistent results.
We evaluated the association between breast cancer risk and 559 single-nucleotide polymorphisms (SNP) in 12 vitamin D-related genes, including 6 genes associated with circulating 25-hydroxyvitamin D [25(OH)D] level identified by recent genome-wide association studies (GWAS), using directly observed and imputed GWAS genotyping data from 2,919 breast cancer cases and 2,323 controls recruited in the Shanghai Breast Cancer Study.
Of the SNPs studied, only rs12570116 in the ACADSB gene, rs4760658 in the VDR gene and rs6091822, rs8124792, and rs6097809 in the CYP24A1 gene, and rs10902845 in C10orf88 had a nominal association with breast cancer risk (P < 0.05 for all). None of these associations persisted after adjustment for multiple comparisons. The most extensively studied SNPs including rs10735810, also known as rs2228570 (Fok1, VDR), rs1544410 (Bsm1, VDR), and rs2296241 (CYP24A1), were not associated with breast cancer risk. GWAS-identified genetic variants that were associated with 25(OH)D were also not related to breast cancer risk.
Our data suggest that genetic polymorphisms in vitamin D-related genes do not play a major role in breast cancer risk in Chinese women.
Although our study confirms previously documented breast cancer risk factor associations, our null results suggest that common genetic variants in vitamin D genes and loci associated with control of vitamin D levels are not risk factors for breast cancer in Chinese women. Our data contribute to filling the gap in this field of research.