Subtypes of Native American ancestry and leading causes of death: Mapuche ancestry-specific associations with gallbladder cancer risk in Chile

Abstract

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.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

“…Mapuche Native American ancestry has been strongly associated with the risk of GBC, and we found that the percentage of Mapuche Native American ancestry of the male donor of the primary tumor cells was 36%. For comparison, the first (third) quartiles of Mapuche ancestry reported in a recent study that included 1805 Chileans were 28% (43%) [6], confirming the representativeness of the established GBC cell lines for the Chilean population. The three new cell lines displayed an epithelial phenotype and showed abnormality in structure and number of chromosomes, with a tendency to triploidy.…”

“…Surrogates of African and European ancestry were 87 Yorubans in Ibadan, Nigeria, and 80 Utah residents with Northern and Western European ancestry from the 1000 Genome Project. Nine Mapuche and nine Aymara individuals were selected to represent the two largest indigenous peoples in Chile based on the three following criteria: four grandparental Mapuche or Aymara surnames, estimated Native American proportion of at least 74% for Mapuche and at least 99% for Aymara reference individuals, and mitochondrial DNA haplogroups consistent with Mapuche (haplogroup C or D) or Aymara (haplogroup B) descent [6]. The ADMIXTURE software was used for supervised estimation of the African, European, Mapuche Native American and Aymara Native American ancestry components relying on the above-mentioned identified common variants, reference individuals and genotype data from a recent study that included 1805 Chileans [6,97].…”

“…In Chile, GBC is one of the most common neoplasms and represents the second cause of cancer-related death in women, the mortality rate in 2015 was 10.2 deaths per 100 000 women [4]. The regional distribution of GBC in Chile is correlated with the prevalence of its main risk factor, gallstone disease, together with the regional proportions of Mapuche Native American ancestry and other socioeconomic factors [5,6].…”

Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico

“…Interestingly, the Hispanic populations of New Mexico also show an elevated incidence of GBC (compared to Caucasians in New Mexico), though not to the degree seen in Native Americans [ 4 ]. In Chile, for each 1% increase in Mapuche heritage, an indigenous people common in Chile, there is an associated 3.7% increase in risk for GBC [ 9 ]. These observations argue for specific predisposing genetic factors (direct or indirect) unique to certain indigenous populations.…”

The Genetic Population Structure of Robinson Crusoe Island, Chile

“…Studies into genetic conditions common to South American nations tend to be underrepresented in the literature which is historically European-centric ( Carvajal-Carmona et al, 2000 , 2003 ; Bedoya et al, 2006 ; Criollo-Rayo et al, 2018 ). Recently Lorenzo Bermejo et al (2017) showed that the percentage of indigenous ancestry in modern Chileans is correlated with an increased risk of developing gall bladder cancer ( Lorenzo Bermejo et al, 2017 ). Investigations into population structure form the basis of these studies, and several large recent studies have begun to shed light upon the genetic ancestry of modern South American populations.…”