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.
Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In ...Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry.
After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice.
The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.
The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single ...nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5 × 10−4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10−3 to 3.77 × 10−8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent.
Gallstones (cholelithiasis) constitute a major health burden with high costs related to surgical removal of the gallbladder (cholecystectomy), generally indicated for symptomatic gallstones. The ...association between gallstones and cholecystectomy and kidney cancer is controversial. We comprehensively investigated this association, considering age at cholecystectomy and time from cholecystectomy to kidney cancer diagnosis, and assessed the causal effect of gallstones on kidney cancer risk by Mendelian randomization (MR).
We compared the risk of kidney cancer in cholecystectomized and noncholecystectomized patients (16.6 million in total) from the Swedish nationwide cancer, census, patient, and death registries using hazard ratios (HRs). For 2-sample and multivariable MR, we used summary statistics based on 408,567 UK Biobank participants.
During a median follow-up of 13 years, 2627 of 627,870 cholecystectomized Swedish patients developed kidney cancer (HR, 1.17; 95% CI, 1.12–1.22). Kidney cancer risk was particularly increased in the first 6 months after cholecystectomy (HR, 3.79; 95% CI, 3.18–4.52) and in patients cholecystectomized before age 40 years (HR, 1.55; 95% CI, 1.39–1.72). MR results based on 18,417 patients with gallstones and 1788 patients with kidney cancer from the United Kingdom revealed a causal effect of gallstones on kidney cancer risk (9.6% risk increase per doubling in gallstone prevalence; 95% CI, 1.2%–18.8%).
Both observational and causal MR estimates based on large prospective cohorts support an increased risk of kidney cancer in patients with gallstones. Our findings provide solid evidence for the compelling need to diagnostically rule out kidney cancer before and during gallbladder removal, to prioritize kidney cancer screening in patients undergoing cholecystectomy in their 30s, and to investigate the underlying mechanisms linking gallstones and kidney cancer in future studies.
The number of gallbladder operations to treat gallstones continues to rise. Patients with gallstone disease have an increased risk of kidney cancer shortly after and even many years after gallbladder surgery.
This paper summarizes the contributions from the Genome-wide Association Study group (GWAS group) of the GAW20. The GWAS group contributions focused on topics such as association tests, phenotype ...imputation, and application of empirical kinships. The goals of the GWAS group contributions were varied. A real or a simulated data set based on the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study was employed by different methods. Different outcomes and covariates were considered, and quality control procedures varied throughout the contributions.
The consideration of heritability and family structure played a major role in some contributions. The inclusion of family information and adaptive weights based on data were found to improve power in genome-wide association studies. It was proven that gene-level approaches are more powerful than single-marker analysis. Other contributions focused on the comparison between pedigree-based kinship and empirical kinship matrices, and investigated similar results in heritability estimation, association mapping, and genomic prediction. A new approach for linkage mapping of triglyceride levels was able to identify a novel linkage signal.
This summary paper reports on promising statistical approaches and findings of the members of the GWAS group applied on real and simulated data which encompass the current topics of epigenetic and pharmacogenomics.
Background and Aims
Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low‐income and middle‐income countries, and research into this ...disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide.
Approach and Results
To perform epigenome‐wide methylation profiling, genomic DNA extracted from sections of formalin‐fixed, paraffin‐embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality‐controlled data from 82 samples (gallstones n = 32, low‐grade dysplasia n = 13, high‐grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine–guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin‐dependent kinase inhibitor 2A, MDM2 proto‐oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb‐B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples.
Conclusions
Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low‐grade dysplasia), intermediate (high‐grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.
Gallstones are considered the main risk factor for gallbladder cancer (GBC) development. The prevalence of gallstones has a strong ethnic component – more than 40% of Chilean Native Americans are ...affected by gallstones, compared to 15–20% of Europeans. In a meta-analysis of genome-wide association studies, Joshi et al. identified six genetic variants associated to gallstone disease. In order to examine the possible pleiotropic, combined effect of identified variants in both gallstone disease and GBC risk, we examined genotype data from Chileans (295 GBC cases and 2267 controls) and Europeans (100 cases and 134 controls). We constructed weighted genetic risk scores for gallstone disease based on the reported log odds ratios for the six variants and individual genotypes. The association between the genetic risk of gallstone disease and GBC risk was assessed by logistic regression with the individual risk score as independent variable adjusting for potential confounders (e.g. age and gender). We found an association between the genetic risk of gallstone disease and GBC risk in both Chileans (1.20 per standard deviation in the genetic risk score, 95% CI 1.05–1.36) and Europeans (OR = 1.82, 95% CI 1.29–2.55). Two variants in the ABCG8 gene showed a strong GBC association in Europeans: rs11887534 (OR = 2.52, 95% CI 1.17–5.43) and rs4245791 (OR = 1.81, 95% CI 1.12–2.93). Among the six variants associated with gallstone disease, only rs11887534 was associated with GBC risk in Chileans (OR = 1.38, 95% 1.04–1.83). We are currently working on the validation of GBC findings from an Indian association study in Chileans and Europeans, and on Mendelian randomization analyses to evaluate the causal relationship between gallstones and GBC risk. Updated results will be presented at the meeting.
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