Exome Sequencing Data Analysis and a Case-Control Study in Mexican Population Reveals Lipid Trait Associations of New and Known Genetic Variants in Dyslipidemia-Associated Loci.

Background: Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American populations have been underrepresented in these studies. Objective: To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia. Methods: We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r2 threshold of 0.1. Results: Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in BUD13 with hypertriglyceridemia, rs7252453 in CILP2 with decreased risk to hypercholesterolemia and rs11076176 in CETP with increased risk to low high density lipoprotein cholesterol. Conclusions: We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.

The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas.

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15-30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4-9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.

Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos.

Amerindian ancestry appears to be a risk factor for metabolic diseases (MetD), making Mexicans an ideal population to better understand the genetic architecture of metabolic health. In this study, we determine the association of genetic variants previously reported with metabolic entities, in two Mexican populations, including the largest sample of Amerindians reported to date. We investigated the association of eigth single-nucleotide polymorphisms (SNPs) in AKT1, GCKR, and SOCS3 genes with different metabolic traits in 1923 Mexican Amerindians (MAs) belonging to 57 ethnic groups, and 855 Mestizos (MEZs). The allele frequency of 7/8 SNPs showed significant differences between MAs and MEZs. Interestingly, some alleles were monomorphic in particular ethnic groups, and highly frequent in other ones. With the exception of GCKR rs1260326T, as expected, all SNP frequencies in the MEZ population had intermediate values between its two main ancestral populations (MAs and Iberian populations in Spain [IBS]). We detected ethnic differences in linkage disequilibrium patterns and haplotype structure between MAs and MEZs, possibly due to the high genetic heterogeneity in these populations. Remarkably, AKT1 was associated with hypertension in MEZs, but not in MAs. GCKR was associated with protection against type 2 diabetes (T2D) in MAs, and with hypertriglyceridemia and protection against low HDL Cholesterol (HDL-C) levels in MEZs. The CAT haplotype in SOCS3 was associated with metabolic syndrome (MetS) in MEZs, and correlated with protection against high blood pressure (HBP) and risk for high waist circumference and T2D in MAs. Our results show differential genetic associations with metabolic traits between MAs and MEZs, possibly due to the differences in genetic structure between these Mexican populations.

[Systemic lupus erythematosus: genomics of the disease]. / Lupus eritematoso sistémico (LES): genómica de la enfermedad.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases with multiple autoantigens as targets,resulting in damage to many organs of the body. The disease is more common in females (> 90%) and around 15% of the cases present during childhood.Systemic lupus erythematosus is a complex disease in which both genetic (susceptibility/protection alleles) and environmental factors (infections, drugs, stress, etc.) contribute to its development.The current knowledge on genetic factors involved in SLE is based on the results of linkage analyses in multi-case families as well as from case-control or family-based genetic association studies. These types of genetic analyses have contributed to identifying susceptibility genes and constitute the first step towards understanding the molecular mechanisms underlying SLE.The aim of this review is to provide a current picture of the genes identified as susceptibility factors for SLE, and to highlight the ones described in the Mexican population.