title: GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence.
abstract: OBJECTIVE
  Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts.
  
  
  METHODS
  Cohort 1 included 1,082 participants, 35-67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18-90 years.
  
  
  RESULTS
  rs1495741 was significantly associated with SF in Cohort 1 (p < 6 × 10(-10)), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p = 8.3 × 10(-42)) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r (2) = 1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2-SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017).
  
  
  CONCLUSIONS
  We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.
authors.affiliation: Program in Genetics and Genomic Biology, Hospital for Sick Children, 686 Bay Street, Room 12.9830, Toronto, ON, M5G 0A4, Canada.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Eny
authors.forename: Helen L
authors.initials: HL
authors.lastname: Lutgers
authors.forename: John
authors.initials: J
authors.lastname: Maynard
authors.forename: Barbara E K
authors.initials: BE
authors.lastname: Klein
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Lee
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
authors.forename: Jana V
authors.initials: JV
authors.lastname: van Vliet-Ostaptchouk
authors.forename: Reindert
authors.initials: R
authors.lastname: Graaff
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: Melanie M
authors.initials: MM
authors.lastname: van der Klauw
authors.forename: David R
authors.initials: DR
authors.lastname: Sell
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cleary
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Braffett
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Orchard
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lyons
authors.forename: Kerri
authors.initials: K
authors.lastname: Howard
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Jill P
authors.initials: JP
authors.lastname: Crandall
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Sofiya
authors.initials: S
authors.lastname: Milman
authors.forename: Danny
authors.initials: D
authors.lastname: Ben-Avraham
authors.forename: Bruce H R
authors.initials: BH
authors.lastname: Wolffenbuttel
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D005260:Female; D005453:Fluorescence; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human