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

Abstract

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.

Genetic Determinants of Atherogenic Indexes

“…Several studies confirm a variety of loci, not always in LD, mapping on the APOC1, APOC3, and APOA5 clusters and its relation to blood lipids [38][39][40]. Variant APOC3 rs147210663 has been reported over 40 times associated to dyslipidemia, cholesterol, and BMI, it is in LD with APOC3 rs5128 here identified, and whose association with triglyceride levels in Pima Amerindians has been reported as a founder mutation [41]. Also, a recent multi-ancestry analysis on 170,000 exomes including 16,440 individuals of "Hispanic" origin reported that APOC3 is a relevant gene for HDL-C and the TG/HDL-C ratio [11].…”

“…Also, a recent multi-ancestry analysis on 170,000 exomes including 16,440 individuals of "Hispanic" origin reported that APOC3 is a relevant gene for HDL-C and the TG/HDL-C ratio [11]. To further delve into the relevance of the APOC3 and chromosome 11 loci, Jurado-Camacho et al described the APOA1/C3/A5-ZPR1-BUD13 cluster and its impact on several lipid traits including, HDL-C and TG [41]. These observations agree with our results of the intron variant APOC3 rs5128 as significantly associated to the AIP index in Mexican adults highlighting that the connection of APOC3 and blood triglycerides is likely population independent [42].…”

Genetic Determinants of Atherogenic Indexes

“…Variant APOC3 rs147210663 has been reported to be associated with dyslipidemia, cholesterol, and BMI over 40 times. It is in LD with APOC3 rs5128 identified here, and its association with triglycerides in Pima Amerindians has been reported as a founder mutation [ 28 ]. Additionally, a recent multi-ancestry analysis on 170,000 exomes, including 16,440 individuals of “Hispanic” origin, reported that APOC3 is a relevant gene for HDL-C and the TG/HDL-C ratio [ 11 ].…”

“…Additionally, a recent multi-ancestry analysis on 170,000 exomes, including 16,440 individuals of “Hispanic” origin, reported that APOC3 is a relevant gene for HDL-C and the TG/HDL-C ratio [ 11 ]. To further delve into the relevance of the APOC3 and chromosome 11 loci, Jurado-Camacho et al described the APOA1/C3/A5-ZPR1-BUD13 cluster and its impact on several lipid traits, including HDL-C and TG [ 28 ]. These observations agree with our results of the intron variant APOC3 rs5128 as significantly associated with the AIP index in Mexican adults, highlighting that the connection of APOC3 and blood triglycerides is likely population independent [ 28 ].…”

“…To test for an association between AIP or CI2 as continuous variables and 330 K genetic variants, we developed linear regression models based on classical GWA strategies [ 26 , 27 , 28 ] using PLINK. These models, one for AIP and another for CI2, assumed additive effects for each SNV tested.…”