@article{b3a1e559c98647c9a88fb01f01814ac2,
title = "GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence",
abstract = "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 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/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.",
keywords = "Acetylation, Genome-wide association study, NAT2, Skin autofluorescence, Skin fluorescence, Skin intrinsic fluorescence",
author = "Eny, {Karen M.} and Lutgers, {Helen L.} and John Maynard and Klein, {Barbara E.K.} and Lee, {Kristine E.} and Gil Atzmon and Monnier, {Vincent M.} and {Van Vliet-Ostaptchouk}, {Jana V.} and Reindert Graaff and {Van Der Harst}, Pim and Harold Snieder and {Van Der Klauw}, {Melanie M.} and Sell, {David R.} and Hosseini, {S. Mohsen} and Cleary, {Patricia A.} and Braffett, {Barbara H.} and Orchard, {Trevor J.} and Lyons, {Timothy J.} and Kerri Howard and Ronald Klein and Crandall, {Jill P.} and Nir Barzilai and Sofiya Milman and Danny Ben-Avraham and Wolffenbuttel, {Bruce H.R.} and Paterson, {Andrew D.}",
note = "Funding Information: The LifeLines Cohort Study is supported by the: Netherlands Organization for Scientific Research (NWO) (grant 175.010.2007.006); Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University Medical Center Groningen; University of Groningen; Dutch Kidney Foundation; and Dutch Diabetes Research Foundation. Funding Information: Duality of interest JM is a former employee of VeraLight, Inc., the manufacturer of SCOUT, which was used in the present study. TJO has in the past received grant support from VeraLight, Inc and serves as a consultant to Lilly Inc. RG is founder and stockholder of the spin-off DiagnOptics B.V. (Groningen, the Netherlands), the producer of the AGE Reader, which has been used in the present study. Funding Information: The skin biopsy ancillary substudy in DCCT/EDIC was funded by the Juvenile Diabetes Research Foundation International (grant no. 17-2010-318 to VMM) and the NIDDK (DK-79432 to DRS). Funding Information: LonGenity is supported by the: National Institutes of Health (NIH) (P01 AG027734 Barzilai); Glenn Foundation for the Biology of Aging; Nathan Shock Center (P30 AG038072); Einstein Institute for Clinical and Translational Research (CTSA Grant 8UL1 TR000086 from the National Center for Advancing Translational Sciences); Diabetes Research Center (NIH-5P60 DK20541); and NIH (RO1 1R01AG042188 Atzmon). Results for association of rs1495741 with lipids were made available by Teslovich et al [36] and were downloaded from: http://www.sph.umich. edu/csg/abecasis/public/lipids2010/. Data on glycaemic traits have been contributed by MAGIC investigators [37, 38] and have been downloaded from www.magicinvestigators.org. Funding Information: Participation in this work was in part also supported by the National Consortium for Healthy Ageing and the BioSHaRE-EU consortium (KP7, project reference 261433). LifeLines (BRIF4568) is engaged in a Bioresource research impact factor (BRIF) policy pilot study, details of which can be found at www.bioshare.eu/content/ bioresource-impact-factor. Funding Information: Funding The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982–93, 2011–2016) and contracts (1982–2011) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support from the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993–2007) and Clinical Translational Science Center Program (2006–present), Bethesda, MD, USA. Trial Registration: clinicaltrials.gov NCT00360815 and NCT00360893. Funding Information: Additional support for this DCCT/EDIC collaborative study was provided by grants from the National Institute of Diabetes and Digestive and Kidney Diseases contract N01-DK-6-2204, National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-077510, R01-DK077489 and P60-DK20595, and support from Genome Canada through the Ontario Genomics Institute. ADP holds a Canada Research Chair in the Genetics of Complex Diseases. KME is a recipient of the Gibney Family Scholar Award of the Heart and Stroke Foundation. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Funding Information: WESDR is supported by the National Institutes of Health, Bethesda, MD, USA (no. EY016379, to RK and BEKK) and by an unrestricted grant from Research to Prevent Blindness, New York, NY, USA. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Eye Institute or the National Institutes of Health.",
year = "2014",
month = aug,
doi = "10.1007/s00125-014-3286-9",
language = "English (US)",
volume = "57",
pages = "1623--1634",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "8",
}
