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    Keywords: RECEPTOR ; CANCER ; POPULATION ; RISK ; SITE ; DISTINCT ; GENE ; GENES ; GENOME ; RESOLUTION ; BINDING ; SEQUENCE ; ASSOCIATION ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; genetics ; SNP ; POPULATIONS ; PROJECT ; ESTROGEN-RECEPTOR ; HETEROGENEITY ; ORIGIN ; TAMOXIFEN ; ASSOCIATIONS ; SNPs ; SCIENCE ; ESTROGEN ; HAPLOTYPE ; LOCUS ; TRAITS ; estrogen receptor ; BINDING-SITE ; CHINESE POPULATION ; GENOME-WIDE ASSOCIATION ; AFRICAN-AMERICAN ; ESTROGEN-RECEPTOR-ALPHA ; CONFER SUSCEPTIBILITY ; BINDING SITE ; Genetic ; COMMON VARIANTS ; ANCESTRY ; PANEL ; CAUSAL VARIANTS
    Abstract: We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case: control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2x10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9x10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9x10(-7)), was without significant heterogeneity between ancestries (P-het = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[ T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping
    Type of Publication: Journal article published
    PubMed ID: 20661439
    Signatur Availability
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