Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

Obesity, genomic ancestry, and socioeconomic variables in Latin American mestizos.

OBJECTIVES: This article aims to assess the contribution of genomic ancestry and socioeconomic status to obesity in a sample of admixed Latin Americans. METHODS: The study comprised 6776 adult volunteers from Brazil, Chile, Colombia, Mexico, and Peru. Each volunteer completed a questionnaire about socioeconomic variables. Anthropometric variables such as weight, height, waist, and hip circumference were measured to calculate body indices: body mass index, waist-to-hip ratio and waist-to-height ratio (WHtR). Genetic data were extracted from blood samples, and ancestry was estimated using chip genotypes. Multiple linear regression was used to evaluate the relationship between the indices and ancestry, educational level, and economic well-being. The body indices were dichotomized to obesity indices by using appropriate thresholds. Odds ratios were calculated for each obesity index. RESULTS: The sample showed high percentages of obesity by all measurements. However, indices did not overlap consistently when classifying obesity. WHtR resulted in the highest prevalence of obesity. Overall, women with low education level and men with high economic wellness were more likely to be obese. American ancestry was statistically associated with obesity indices, although to a lesser extent than socioeconomic variables. CONCLUSIONS: The proportion of obesity was heavily dependent on the index and the population. Genomic ancestry has a significant influence on the anthropometric measurements, especially on central adiposity. As a whole, we detected a large interpopulation variation that suggests that better approaches to overweight and obesity phenotypes are needed in order to obtain more precise reference values.

Ancient remains and the first peopling of the Americas: Reassessing the Hoyo Negro skull.

OBJECTIVE: A noticeably well-preserved ∼12.500 years-old skeleton from the Hoyo Negro cave, Yucatán, México, was recently reported, along with its archaeological, genetic and skeletal characteristics. Based exclusively on an anatomical description of the skull (HN5/48), Chatters and colleagues stated that this specimen can be assigned to a set of ancient remains that differ from modern Native Americans, the so called "Paleoamericans". Here, we aim to further explore the morphological affinities of this specimen with a set of comparative cranial samples covering ancient and modern periods from Asia and the Americas. METHODS: Images published in the original article were analyzed using geometric morphometrics methods. Shape variables were used to perform Principal Component and Discriminant analysis against the reference samples. RESULTS: Even thought the Principal Component Analysis suggests that the Hoyo Negro skull falls in a subregion of the morphospace occupied by both "Paleoamericans" and some modern Native Americans, the Discriminant analyses suggest greater affinity with a modern Native American sample. DISCUSSION: These results reinforce the idea that the original population that first occupied the New World carried high levels of within-group variation, which we have suggested previously on a synthetic model for the settlement of the Americas. Our results also highlight the importance of developing formal classificatory test before deriving settlement hypothesis purely based on macroscopic descriptions.

ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans.

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.

Amerindian Helicobacter pylori strains go extinct, as european strains expand their host range.

We studied the diversity of bacteria and host in the H. pylori-human model. The human indigenous bacterium H. pylori diverged along with humans, into African, European, Asian and Amerindian groups. Of these, Amerindians have the least genetic diversity. Since niche diversity widens the sets of resources for colonizing species, we predicted that the Amerindian H. pylori strains would be the least diverse. We analyzed the multilocus sequence (7 housekeeping genes) of 131 strains: 19 cultured from Africans, 36 from Spanish, 11 from Koreans, 43 from Amerindians and 22 from South American Mestizos. We found that all strains that had been cultured from Africans were African strains (hpAfrica1), all from Spanish were European (hpEurope) and all from Koreans were hspEAsia but that Amerindians and Mestizos carried mixed strains: hspAmerind and hpEurope strains had been cultured from Amerindians and hpEurope and hpAfrica1 were cultured from Mestizos. The least genetically diverse H. pylori strains were hspAmerind. Strains hpEurope were the most diverse and showed remarkable multilocus sequence mosaicism (indicating recombination). The lower genetic structure in hpEurope strains is consistent with colonization of a diversity of hosts. If diversity is important for the success of H. pylori, then the low diversity of Amerindian strains might be linked to their apparent tendency to disappear. This suggests that Amerindian strains may lack the needed diversity to survive the diversity brought by non-Amerindian hosts.

Demographic and evolutionary trajectories of the Guarani and Kaingang natives of Brazil.

A total of 278 individuals from two Brazilian Indian tribes (Guarani and Kaingang) living in five different localities had their mitochondrial DNA sequenced for the first hypervariable segment (HVS-I), and a fraction of them was also studied for seven biallelic Y-chromosome polymorphisms. Nineteen HVS-I lineages were detected, which showed distinct distributions in the two tribes. The G(ST) value obtained with the mtDNA data is about 5 times higher for the Guarani as compared to the Kaingang, suggesting a higher level of differentiation between the three Guarani partialities than between the two Kaingang villages. Non-Amerindian admixture varied with sex and in the Guarani was only observed through the paternal line. Using these data and those of other Tupian and Jêan tribes, it was possible to make inferences about past migratory movements and the genetic differentiation of these populations.

Beta s haplotype diversity in Afro-Americans, Africans, and Euro-Asiatics: an attempt at a synthesis

A review was made of the distribution of the five common betas haplotypes in eight Euro-Asian, 16 African and 12 American population (total: 3,701 chromosomes). Considering the most frequent haplotype in each population discloses a clearly discontinuous pattern, the Euro-Asian groups presenting higher than 50 percent of their specific (Arab-Asian) haplotype, Africans three distinct categories (respectively higher prevalences of the Bantu, Benin and Senegal haplotypes), and the Americas showing higher frequencies of Benin in the North and Caribbean area, and Bantu in Mexico and Brazil. A dendrogram confirms these results, with the American populations being placed in an intermediary position. Genetic diversity analysis did not clearly separate the African clusters. Total diversity was similar in Africa and the Americas (0.689 and 0.622, respectively), with a higher interpopulation diversity in the former (62 percent versus 12 percent). Total genetic diversity considering Brazil only, as opposed to all America, yielded equivalent results (0.435, 0.622) but the interpopulation variability within Brazil is lower (6 percent versus 12 percent). Generally, the results showed a remarkable similarity with what would be expected taking into consideration the historical sources concerning African migrations.