title: Genetic analysis of advanced glycation end products in the DHS MIND study.
abstract: Advanced glycation end-products (AGEs) are a diverse group of molecules produced by the non-enzymatic addition of glucose to proteins, lipids, and nucleic acids. AGE levels have been associated with hyperglycemia and diabetic complications, especially in animal models, but less clearly in human studies. We measured total serum AGEs using an enzyme linked immunosorbant assay (ELISA) in 506 subjects from 246 families in the Diabetes Heart Study (DHS)/DHS MIND Study (n=399 type 2 diabetes (T2D)-affected). Single nucleotide polymorphisms (SNPs) in several candidate genes, including known AGE receptors, were tested for their influence on circulating AGE levels. The genetic analysis was expanded to include an exploratory genome-wide association study (GWAS) and exome chip analysis of AGEs (≈440,000 SNPs). AGEs were found to be highly heritable (h(2)=0.628, p=8.96 × 10(-10)). While no SNPs from candidate genes were significantly associated after Bonferroni correction, rs1035798 in the gene AGER was the most significantly associated (p=0.007). Additionally, rs7198427, in MT1A, showed a nominally significant p-value (p=0.0099). No SNPs from the GWAS or exome studies were identified after correction for multiple comparisons; however, rs17054480 in the PALLD2 gene on chromosome 4 showed the strongest association (p=7.77 × 10(-7)). Five SNPs at two loci (ISCA2/NPC2 and FBXO33) had p-values of less than 2.0 × 10(-5) and three additional SNPs (rs716326 in MACROD2, and rs6795197 and rs6765857 in ZBTB38) showed a nominal association with p-values of less than 1.0 × 10(-5).These findings provide a foundation for further investigation into the genetic component of circulating AGEs.
authors.affiliation: Program in Molecular Genetics and Genomics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Adams
authors.affiliation: Program in Molecular Genetics and Genomics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Raffield
authors.affiliation: Integrative Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Martelle
authors.affiliation: Department of Internal Medicine - Nephrology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Radiologic Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: J Jeffrey
authors.initials: JJ
authors.lastname: Carr
authors.affiliation: Molecular Basis of Disease, Griffith University, Southport, QLD, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Cox
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address: dbowden@wakehealth.edu.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000368:Aged; D005260:Female; D055106:Genome-Wide Association Study; D017127:Glycation End Products, Advanced / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D017127:Glycation End Products, Advanced
keywords: AGE receptor; Genome-wide association study; Type 2 diabetes