title: Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families.
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.
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Manju
authors.initials: M
authors.lastname: Mamtani
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Hemant
authors.initials: H
authors.lastname: Kulkarni
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Neary
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT USA ; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, CT USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Mahaney
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520 USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005190:Family; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055105:Waist Circumference / Q000235:genetics*
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D005819:Genetic Markers; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase