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Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer
Long, Jirong,Cai, Qiuyin,Sung, Hyuna,Shi, Jiajun,Zhang, Ben,Choi, Ji-Yeob,Wen, Wanqing,Delahanty, Ryan J.,Lu, Wei,Gao, Yu-Tang,Shen, Hongbing,Park, Sue K.,Chen, Kexin,Shen, Chen-Yang,Ren, Zefang,Haima Public Library of Science 2012 PLoS genetics Vol.8 No.2
<P>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 (<I>TAB2</I>) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a <I>P</I>-value of 3.8×10<SUP>−12</SUP> 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 (<I>P</I> = 1.9×10<SUP>−6</SUP> from the combined analysis of all samples), located in intron 5 of the <I>ESR1</I> gene, and SNP rs7107217 (<I>P</I> = 4.6×10<SUP>−7</SUP>), 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 <I>TAB2</I> gene (6q25.1), and identifies two possible susceptibility loci located in the <I>ESR1</I> gene and 11q24.3, respectively.</P><P><B>Author Summary</B></P> <P>Breast cancer is one of the most common malignancies among women worldwide. Genetic factors play an important role in the etiology of breast cancer. To identify common genetic susceptibility alleles for breast cancer, we performed a four-stage genome-wide association study in 19,091 cases and 20,606 controls among East-Asian women. Single nucleotide polymorphism (SNP) rs9485372, near the TGF-beta activated kinase 1 (<I>TAB2</I>) gene at chromosome 6q25.1, was associated with breast cancer risk (<I>P</I> = 3.8×10<SUP>−12</SUP>). SNPs rs9383951, located in intron 5 of the estrogen receptor 1 (<I>ESR1</I>) gene, and rs7107217, located at 11q24.3, were also consistently associated with breast cancer risk in all four stages with a combined <I>P</I> of 1.9×10<SUP>−6</SUP> and 4.6×10<SUP>−7</SUP>, respectively. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the <I>TAB2</I> gene (6q25.1), and identifies two possible susceptibility loci located in the <I>ESR1</I> gene and 11q24.3, respectively.</P>
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