RESUMO
Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Receptor alfa de Estrogênio/genética , Loci Gênicos , Predisposição Genética para Doença , Hispânico ou Latino/genética , Neoplasias da Mama/classificação , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genéticaRESUMO
Microsatellite variation (CAG and GGC repeats) of the androgen receptor (AR) gene shows remarkable differences among African and non-African populations. In vitro studies have demonstrated an inverse relationship between the length of both microsatellites and AR activity. This fact may explain the observed association of the AR gene with prostate cancer and the strong ethnic differences in the incidence of this cancer. CAG and GGC genetic variation has been tested in a large set of populations from the Ivory Coast as well as 12 Mediterranean samples whose variation is described for the first time. The pattern of frequencies observed in the Ivory Coast agrees with data previously reported for other Sub-Saharan populations. Concerning the Mediterranean variation, Sardinian samples are characterised by low genetic diversities, and Egyptian Siwa Berbers by a particular pattern of GGC frequencies. High and Middle Atlas Moroccan Berbers are the most closely related to the Sub-Saharan variation. For both the CAG and GGC repeats, the Ivory Coast and some Moroccan samples exhibit high frequencies of low size alleles (CAG under 18 repeats, and GGC under 15 repeats) that have been associated with prostate cancer.