Eny Karen M, Lutgers Helen L, Maynard John, Klein Barbara E K, Lee Kristine E, Atzmon Gil, Monnier Vincent M, van Vliet-Ostaptchouk Jana V, Graaff Reindert, van der Harst Pim, Snieder Harold, van der Klauw Melanie M, Sell David R, Hosseini S Mohsen, Cleary Patricia A, Braffett Barbara H, Orchard Trevor J, Lyons Timothy J, Howard Kerri, Klein Ronald, Crandall Jill P, Barzilai Nir, Milman Sofiya, Ben-Avraham Danny, Wolffenbuttel Bruce H R, Paterson Andrew D
Program in Genetics and Genomic Biology, Hospital for Sick Children, 686 Bay Street, Room 12.9830, Toronto, ON, M5G 0A4, Canada.
Diabetologia. 2014 Aug;57(8):1623-34. doi: 10.1007/s00125-014-3286-9. Epub 2014 Jun 17.
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.
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.
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.
目的/假设：皮肤荧光（SF）是晚期糖基化终末产物（AGEs）的一种非侵入性标志物，与糖尿病的长期并发症相关。SF随年龄增长而增加，在糖尿病患者中也更高。SF的家族相关性表明遗传因素可能起作用。因此，我们在两个队列中对SF进行了平行的全基因组关联研究。
队列1包括1082名年龄在35 - 67岁的1型糖尿病患者。队列2包括8721名年龄在18 - 90岁的非糖尿病患者。
rs1495741在队列1中与SF显著相关（p < 6 × 10⁻¹⁰），已知其可标记NAT2乙酰化酶表型。快速乙酰化酶基因型与较低的SF相关，可解释高达15%的变异。在队列2中，与SF相关的最强信号（p = 8.3 × 10⁻⁴²）是rs4921914，同样位于NAT2基因中，在rs1495741上游440个碱基处（rs4921914与rs1495741的连锁不平衡r² = 1.0）。我们在另外两个队列中重复了这些结果，一个有1型糖尿病，一个没有。最后，为了解哪些化合物导致了NAT2 - SF信号，我们检测了从皮肤活检样本（n = 198）中分析的11种化合物：快速乙酰化酶基因型与乙二醛的AGEs水解咪唑啉酮水平较低相关（p = 0.017）。
结论/解读：我们在糖尿病患者和非糖尿病患者中均发现了NAT2与SF之间的紧密关联。我们的研究结果提供了原理证明，即基因变异导致个体间SF存在差异，且NAT2乙酰化状态起主要作用。
