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Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

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-? 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.

SUBMITTER: Long J

PROVIDER: S-EPMC3285588 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

Long Jirong J Cai Qiuyin Q Sung Hyuna H Shi Jiajun J Zhang Ben B Choi Ji-Yeob JY Wen Wanqing W Delahanty Ryan J RJ Lu Wei W Gao Yu-Tang YT Shen Hongbing H Park Sue K SK Chen Kexin K Shen Chen-Yang CY Ren Zefang Z Haiman Christopher A CA Matsuo Keitaro K Kim Mi Kyung MK Khoo Ui Soon US Iwasaki Motoki M Zheng Ying Y Xiang Yong-Bing YB Gu Kai K Rothman Nathaniel N Wang Wenjing W Hu Zhibin Z Liu Yao Y Yoo Keun-Young KY Noh Dong-Young DY Han Bok-Ghee BG Lee Min Hyuk MH Zheng Hong H Zhang Lina L Wu Pei-Ei PE Shieh Ya-Lan YL Chan Sum Yin SY Wang Shenming S Xie Xiaoming X Kim Sung-Won SW Henderson Brian E BE Le Marchand Loic L Ito Hidemi H Kasuga Yoshio Y Ahn Sei-Hyun SH Kang Han Sung HS Chan Kelvin Y K KY Iwata Hiroji H Tsugane Shoichiro S Li Chun C Shu Xiao-Ou XO Kang Dae-Hee DH Zheng Wei W

PLoS genetics 20120223 2

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 we ...[more]

PMID: 22383897

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Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

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Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

Publications

Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

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