GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence

Abstract

Aims/hypothesisSkin 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.MethodsCohort 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.Resultsrs1495741 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 r2 = 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/interpretationWe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3286-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

“…*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, relative to basal pCMV controls or the indicated comparison bar, ANOVA. (rs1495741), which has modest linkage disequilibrium with rs1208 (r 2 = 0.23) but tags the NAT2 acetylator phenotype, has been associated with skin fluorescence, a noninvasive marker of advanced glycation endproducts (44). Interestingly, the rapid acetylator genotype was associated with lower skin fluorescence but higher fasting glucose and HbA1C values.…”

Association of anti-inflammatory cytokine IL10 polymorphisms with motoric cognitive risk syndrome in an Ashkenazi Jewish population

“…The strengths of our study include the systematic cognitive and clinical assessments, longitudinal design and well-characterized homogenous population (Eny et al, 2014; Roshandel et al, 2016). Limitations include absence of IL10 gene expression data to correlate with associated genotype and cohort characteristics.…”

“…Hence, we hypothesized that inflammatory gene variants would increase the risk of developing MCR in older adults. To examine the role of inflammatory pathways in the pathogenesis of MCR, we conducted a prospective cohort study in 530 community-residing Ashkenazi Jewish (AJ) seniors participating in the LonGenity Study (Eny et al, 2014; Roshandel et al, 2016). Establishing biological underpinnings of the MCR syndrome may provide new insights into preventive strategies to reduce the burden of dementia.…”

A bőr-autofluoreszcencia és a konvencionális glykaemiás markerek kapcsolata diabeteses betegekben

“…A NAT2-acetilátor genetikai fenotípus összefügg a SAF-szintekkel, a gyors acetilátor status alacsonyabb SAF-szintekkel, hidroimidazolon-és glioxálkoncentráci-óval társult bőrbiopsziás mintákban [37]. A microalbuminuria és a lassú acetilátor állapot társulását magyar szerzők már korábban megfi gyelték [38].…”