title: Novel epigenetic determinants of type 2 diabetes in Mexican-American families.
abstract: Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and kulkarnih@uthscsa.edu.
authors.forename: Hemant
authors.initials: H
authors.lastname: Kulkarni
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: Mark Z
authors.initials: MZ
authors.lastname: Kos
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Neary
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Mahaney
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Sciences Center at San Antonio, Regional Academic Health Center, Harlingen, TX 78550, USA and.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002874:Chromosome Mapping; D018899:CpG Islands; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D012737:Sex Factors; D013781:Texas / Q000453:epidemiology / Q000208:ethnology; D055815:Young Adult