Author(s): Eny KM, Lutgers HL, Maynard J, Klein BE, Lee KE, Atzmon G, Monnier VM, van Vliet-Ostaptchouk JV, Graaff R, van der Harst P, Snieder H, van der Klauw MM, Sell DR, Hosseini SM, Cleary PA, Braffett BH, Orchard TJ, Lyons TJ, Howard K, Klein R, Crandall JP, Barzilai N, Milman S, Ben-Avraham D; LifeLines Cohort Study Group; DCCT/EDIC Research Group, Wolffenbuttel BH, Paterson AD. GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. Diabetologia. 2014 Aug;57(8):1623-34. doi: 10.1007/s00125-014-3286-9. Epub 2014 Jun 17. PMID 24934506
Journal: Diabetologia, Volume 57, Issue 8, Aug 2014
AIMS/HYPOTHESIS 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/INTERPRETATION 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.