RESUMO
BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Chile/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Estudos de Associação Genética , Humanos , Indígenas Sul-Americanos/genética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , População Branca/genéticaRESUMO
Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1022 Colombian BC cases and 1023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC) = 0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC = 0.58) or the combined effect of all 13 associated risk variants (AUC = 0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Colômbia/epidemiologia , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , RiscoRESUMO
Latin Americans are highly heterogeneous regarding the type of Native American ancestry. Consideration of specific associations with common diseases may lead to substantial advances in unraveling of disease etiology and disease prevention. Here we investigate possible associations between the type of Native American ancestry and leading causes of death. After an aggregate-data study based on genome-wide genotype data from 1805 admixed Chileans and 639,789 deaths, we validate an identified association with gallbladder cancer relying on individual data from 64 gallbladder cancer patients, with and without a family history, and 170 healthy controls. Native American proportions were markedly underestimated when the two main types of Native American ancestry in Chile, originated from the Mapuche and Aymara indigenous peoples, were combined together. Consideration of the type of Native American ancestry was crucial to identify disease associations. Native American ancestry showed no association with gallbladder cancer mortality (P = 0.26). By contrast, each 1% increase in the Mapuche proportion represented a 3.7% increased mortality risk by gallbladder cancer (95%CI 3.1-4.3%, P = 6×10-27). Individual-data results and extensive sensitivity analyses confirmed the association between Mapuche ancestry and gallbladder cancer. Increasing Mapuche proportions were also associated with an increased mortality due to asthma and, interestingly, with a decreased mortality by diabetes. The mortality due to skin, bladder, larynx, bronchus and lung cancers increased with increasing Aymara proportions. Described methods should be considered in future studies on human population genetics and human health. Complementary individual-based studies are needed to apportion the genetic and non-genetic components of associations identified relying on aggregate-data.