Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)

Gao, Chuan; Tabb, Keri L.; Dimitrov, Latchezar; Taylor, Kent D.; Wang, Nan; Guo, Xiuqing; Long, Jirong; Rotter, Jerome I.; Watanabe, Richard M.; Curran, Joanne E.; Blangero, John; Langefeld, Carl D.; Bowden, Donald W.; Palmer, Nicholette D.

doi:10.1038/s41598-018-23727-2

Cited by 10 publications

(8 citation statements)

References 57 publications

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“…effects sizes for associations with HDL and TG. A majority of our significant CpG-lipid associations do not implicate genes previously identified through GWAS of lipids [7][8][9][10]27,28 , but many of our associations overlap with those identified in EWAS to date of related cardiometabolic traits especially for TG and HDL [14][15][16][17][18][19]33 . Thirty CpG-lipid trait associations were significant in at least 2 racial/ethnic groups with~1/3 of these being novel.…”

Section: Discussionmentioning

confidence: 57%

“…A bnormal blood lipid levels are important risk factors for various diseases including cardiovascular disease 1 , diabetes 2 , renal disease 3 , Alzheimer's disease 4 , and cancers 5,6 . Several large-scale genome-wide 7,8 and exome-wide association studies of lipids 9,10 have identified single nucleotide polymorphisms (SNPs) involved in lipid metabolism. However, the biological mechanisms behind abnormalities in lipid metabolism are not fully understood.…”

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confidence: 99%

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A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

et al. 2021

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Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

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Section: Discussionmentioning

confidence: 57%

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confidence: 99%

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

et al. 2021

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“…Data were imputed via IMPUTE2 [ 15 ] using two reference panels: 1) 1000 Genomes phase 3 and 2) WGS data from 623 IRASFS Mexican American samples. Whole exome sequencing was performed on 1205 IRASFS Mexican American samples as described previously [ 16 ]. Whole genome sequencing was performed on 623 IRASFS Mexican American samples using the Illumina HiSeq X Ten instrument by Macrogen, targeting a mean depth of 30X (paired-end, 150 bp reads).…”

Section: Methodsmentioning

confidence: 99%

Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease

Das

Ainsworth

Dimitrov

et al. 2021

Molecular Metabolism

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Objective Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. Methods Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort ( n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data. Results A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans ( P MA <2.02 × 10 −27 ). Trait associations were replicated in IRASFS African Americans ( P AA < 1.12 × 10 −07 ). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (S I ), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable ( h 2 > 0.47), and a significant genetic signal at the ZSCAN25 / CYP3A5 locus ( P MA = 9.00 × 10 −41 , P AA = 2.31 × 10 −10 ) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels ( P FDR = 6.64 × 10 −07 ). Conclusions Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5 , which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health.

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“…On the other hand, this strategy requires considerable recruitment and funding efforts, which are out of reach for many Latin American countries. It is more achievable in Hispanic/Latinos living in the US, and there are numerous published examples (e.g., [22,23]).…”

Section: Generating New Information Locally: Genome-wide Association and Sequencing Studies In Latin American Populationsmentioning

confidence: 99%

Genetic Epidemiology in Latin America: Identifying Strong Genetic Proxies for Complex Disease Risk Factors

Bonilla

Baccarini

2020

Genes

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Epidemiology seeks to determine the causal effects of exposures on outcomes related to the health and wellbeing of populations. Observational studies, one of the most commonly used designs in epidemiology, can be biased due to confounding and reverse causation, which makes it difficult to establish causal relationships. In recent times, genetically informed methods, like Mendelian randomization (MR), have been developed in an attempt to overcome these disadvantages. MR relies on the association of genetic variants with outcomes of interest, where the genetic variants are proxies or instruments for modifiable exposures. Because genotypes are sorted independently and at random at the time of conception, they are less prone to confounding and reverse causation. Implementation of MR depends on, among other things, a strong association of the genetic variants with the exposure, which has usually been defined via genome-wide association studies (GWAS). Because GWAS have been most often carried out in European populations, the limited identification of strong instruments in other populations poses a major problem for the application of MR in Latin America. We suggest potential solutions that can be realized with the resources at hand and others that will have to wait for increased funding and access to technology.

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Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)

Cited by 10 publications

References 57 publications

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease

Genetic Epidemiology in Latin America: Identifying Strong Genetic Proxies for Complex Disease Risk Factors

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