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. 2016 Jan 20:8:6.
doi: 10.1186/s13148-016-0173-x. eCollection 2016.

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

Manju Mamtani  1 , Hemant Kulkarni  1 , Thomas D Dyer  1 , Harald H H Göring  1 , Jennifer L Neary  2 , Shelley A Cole  2 , Jack W Kent  2 , Satish Kumar  1 , David C Glahn  3 , Michael C Mahaney  1 , Anthony G Comuzzie  2 , Laura Almasy  1 , Joanne E Curran  1 , Ravindranath Duggirala  1 , John Blangero  1 , Melanie A Carless  2
Affiliations

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

Manju Mamtani et al. Clin Epigenetics. .

Abstract

Background: There 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.

Results: Data 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 (h (2) r = 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.

Conclusions: Our 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.

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Figures

Fig. 1
Fig. 1
Manhattan plots showing the genome-wide association of DNA sequence variants and epigenome-wide association of DNA methylation with liability of HTGW. a Genome-wide association study. Genome-wide significance is indicated by the red horizontal line and chromosomal locations are color-coded. Results are from polygenic regression models that accounted for age, age2, sex, age × sex interaction, and age2 × sex interaction, the top four principal components quantifying ancestry-based population admixture, and use of anti-lipid, anti-hypertensive and anti-diabetic medications. b Epigenome-wide association study. Epigenome-wide significance is indicated by the red horizontal line. Significantly associated CpG sites are labeled and chromosomal locations are color-coded. Results are from polygenic regression models adjusted for age, age2, sex, age × sex interaction, and age2 × sex interaction, Illumina Sentrix® ID and Sentrix® position (to account for batch effects), estimated cell counts, and use of anti-lipid, anti-hypertensive and anti-diabetic medications. Q-Q plots corresponding to Panel A and B are shown in Additional file 2: Figures S1 and S2, respectively
Fig. 2
Fig. 2
Distribution of DNA methylation scores for the significantly associated CpG sites in the study participants. Panels a, c, and e show histograms based on all study participants while panels b, d, and f show box plots for the corresponding CpG site in those with (red boxes) or without (yellow boxes) HTGW
Fig. 3
Fig. 3
Agreement between the results of HumanMethylation450 BeadChip array and pyrosequencing for the cg00574958 CpG site. a Correlation scatter plot. b Bland-Altman plot of the difference in the measurements of the two methods (ordinate) versus the mean (abscissa). Limits of agreement (LAG) are shown pictorially using dashed horizontal lines. Samples that fall outside the LAG are colored red. c Distribution of the DNA methylation as measured by pyrosequencing in individuals with (red box) and without (yellow box) HTGW
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