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

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

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    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.

    Original languageEnglish (US)
    JournalClinical Epigenetics
    DOIs
    StateAccepted/In press - Jan 20 2016

    Fingerprint

    Hypertriglyceridemic Waist
    Genome-Wide Association Study
    Type 2 Diabetes Mellitus
    Phenotype
    Epigenomics
    Triglycerides
    Single Nucleotide Polymorphism
    Fatty Acids
    Genome
    Waist Circumference
    DNA Methylation
    Population
    Insulin Resistance
    Fasting
    Cardiovascular Diseases
    Glucose

    ASJC Scopus subject areas

    • Genetics
    • Molecular Biology
    • Developmental Biology
    • Genetics(clinical)

    Cite this

    Mamtani, M., Kulkarni, H., Dyer, T. D., Göring, H. H. H., Neary, J. L., Cole, S. A., ... Carless, M. A. (Accepted/In press). Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families. Clinical Epigenetics. https://doi.org/10.1186/s13148-016-0173-x

    Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families. / Mamtani, Manju; Kulkarni, Hemant; Dyer, Thomas D.; Göring, Harald H.H.; Neary, Jennifer L.; Cole, Shelley A.; Kent, Jack W.; Kumar, Satish; Glahn, David C.; Mahaney, Michael C.; Comuzzie, Anthony G.; Almasy, Laura; Curran, Joanne E.; Duggirala, Ravindranath; Blangero, John; Carless, Melanie A.

    In: Clinical Epigenetics, 20.01.2016.

    Research output: Contribution to journalArticle

    Mamtani, M, Kulkarni, H, Dyer, TD, Göring, HHH, Neary, JL, Cole, SA, Kent, JW, Kumar, S, Glahn, DC, Mahaney, MC, Comuzzie, AG, Almasy, L, Curran, JE, Duggirala, R, Blangero, J & Carless, MA 2016, 'Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families', Clinical Epigenetics. https://doi.org/10.1186/s13148-016-0173-x
    Mamtani, Manju ; Kulkarni, Hemant ; Dyer, Thomas D. ; Göring, Harald H.H. ; Neary, Jennifer L. ; Cole, Shelley A. ; Kent, Jack W. ; Kumar, Satish ; Glahn, David C. ; Mahaney, Michael C. ; Comuzzie, Anthony G. ; Almasy, Laura ; Curran, Joanne E. ; Duggirala, Ravindranath ; Blangero, John ; Carless, Melanie A. / Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families. In: Clinical Epigenetics. 2016.
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    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.",
    author = "Manju Mamtani and Hemant Kulkarni and Dyer, {Thomas D.} and G{\"o}ring, {Harald H.H.} and Neary, {Jennifer L.} and Cole, {Shelley A.} and Kent, {Jack W.} and Satish Kumar and Glahn, {David C.} and Mahaney, {Michael C.} and Comuzzie, {Anthony G.} and Laura Almasy and Curran, {Joanne E.} and Ravindranath Duggirala and John Blangero and Carless, {Melanie A.}",
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    AU - Mamtani, Manju

    AU - Kulkarni, Hemant

    AU - Dyer, Thomas D.

    AU - Göring, Harald H.H.

    AU - Neary, Jennifer L.

    AU - Cole, Shelley A.

    AU - Kent, Jack W.

    AU - Kumar, Satish

    AU - Glahn, David C.

    AU - Mahaney, Michael C.

    AU - Comuzzie, Anthony G.

    AU - Almasy, Laura

    AU - Curran, Joanne E.

    AU - Duggirala, Ravindranath

    AU - Blangero, John

    AU - Carless, Melanie A.

    PY - 2016/1/20

    Y1 - 2016/1/20

    N2 - 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.

    AB - 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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