Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families

Abstract

BackgroundThere is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively.ResultsData for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26 % of these individuals had HTGW. This phenotype was significantly heritable (h2r = 0.52, p = 1.1 × 10−5) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism.ConclusionsOur results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0173-x) contains supplementary material, which is available to authorized users.

The Epigenomic Analysis of Human Obesity

“…This clearly shows the power of EWAS to identify more precise biochemical phenotypes and the benefit of closely examining the distinct biological changes associated with broad epidemiological measures, such as BMI. A number of these exact CpGs also are supported by additional studies in or related to BMI, including analyses involving Arabs , metabolic syndrome , and hypertriglyceridemic waist in Mexican Americans . Of interest is that one of the CpGs, cg06192883, in MYO5C was recently identified in an EWAS for the inflammatory marker C‐reactive protein .…”

Epigenetics of Lipid Phenotypes

“…Methylation at the top CPT1A locus explained 12% of TG variation in the discovery cohort (Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), CD4+ lymphocytes, n=991) and 6% in the replication cohort (Framingham Heart Study, whole blood, n=1261) [12]. Subsequent studies have replicated the observed association with lipids [7, 15, 16] and lipoprotein subfraction profiles [17], as well as linked CPT1A methylation with obesity traits [18, 19], metabolic syndrome [20], and hypertriglyceridemic waist [21] in diverse populations. Interestingly, CPT1A loci were also shown to be differentially methylated in Dutch Hunger Winter survivors exposed to famine in utero , associating with both birth weight and serum LDL cholesterol levels later in life [22] and providing a possible mechanism for the well-known adverse metabolic sequelae of prenatal malnutrition.…”

Associations of LEP, CRH, ICAM-1, and LINE-1 methylation, measured in saliva, with waist circumference, body mass index, and percent body fat in mid-childhood

“…The prevalence differed by race/ethnicity, with evidence of highest prevalence in the Hispanic/Latino population [5, 6]. Since genetic variation explains only a small proportion of the variation in BMI [7, 8], a growing number of studies have investigated the role of epigenetic factors.…”