Methylation at CPT1A locus is associated with lipoprotein subfraction profiles.
Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4(+) T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10(-7) in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10(-12) in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.
USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Alexis C
AC
Frazier-Wood
Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
Stella
S
Aslibekyan
Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, Birmingham, AL HudsonAlpha Institute for Biotechnology, Huntsville, AL.
Devin M
DM
Absher
Department of Internal Medicine, University of Utah, Salt Lake City, UT.
Paul N
PN
Hopkins
Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
Jin
J
Sha
Department of Laboratory Medicine and Pathology, University of Minnesota, MN.
Michael Y
MY
Tsai
Section on Statistical Genetics, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
Hemant K
HK
Tiwari
HudsonAlpha Institute for Biotechnology, Huntsville, AL Section on Statistical Genetics, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
Lindsay L
LL
Waite
Section on Statistical Genetics, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
Degui
D
Zhi
Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
Donna K
DK
Arnett
D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000235:genetics; D008297:Male
D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase
Genetics of Lipid Lowering Drugs and Diet Network; carnitine palmitoyltransferase-1A; epigenome-wide association study; high density lipoprotein size; lipoprotein diameter; lipoprotein particle number; low density lipoprotein size; nuclear magnetic resonance data; very low density lipoprotein size