背景:皮肤自发荧光(SAF)是一种非侵入性措施,反映了皮肤中晚期糖基化终产物(AGEs)的积累。较高的SAF水平与患2型糖尿病和心血管疾病的风险增加有关。较早的全基因组关联研究(GWAS)揭示了NAT2变体与SAF之间的强关联。这项研究的目的是计算SAF的遗传力,并通过全基因组关联研究(GWAS)鉴定与SAF相关的其他遗传变异。
结果:在27,534名没有糖尿病的参与者中,在校正了协变量的模型中,lnSAF的遗传度估计值为33%±2.0%(SE)。在lnSAF五个SNP的meta-GWAS中,在染色体8、11、15和16上与lnSAF相关(P<5×10-8):1。rs2846707(Chr11:102,576,358,C>T),其导致MMP27外显子1(NM_022122.3)中的Met30Val错义变体;2.rs2470893(Chr15:75,019,449,C>T),在CYP1A1和CYP1A2之间的基因间区域;当咖啡消费作为协变量时,SNP效应减弱;3.rs12931267(Chr16:89,818,732,C>G)在FANCA内含子30和MC1R附近;以及以下条件分析4.rs3764257(Chr16:89,800,887,C>G)是ZNF276中的内含子变体,位于rs12931267上游的17.8kb;最后,30kb下游NAT25。rs576201050(Chr8:18,288,053,G>A)。
结论:该大型meta-GWAS揭示了非糖尿病人群中与SAF相关的4个位点的5个SNP。进一步阐明SAF的遗传结构将有助于提高其作为筛查和早期发现疾病和疾病并发症的工具的效用。
BACKGROUND: Skin autofluorescence (SAF) is a non-invasive measure reflecting accumulation of advanced glycation endproducts (AGEs) in the skin. Higher SAF levels are associated with an increased risk of developing type 2 diabetes and cardiovascular disease. An earlier genome-wide association
study (GWAS) revealed a strong association between NAT2 variants and SAF. The aim of this
study was to calculate SAF heritability and to identify additional genetic variants associated with SAF through genome-wide association studies (GWAS).
RESULTS: In 27,534 participants without diabetes the heritability estimate of lnSAF was 33% ± 2.0% (SE) in a model adjusted for covariates. In meta-GWAS for lnSAF five SNPs, on chromosomes 8, 11, 15 and 16 were associated with lnSAF (P < 5 × 10-8): 1. rs2846707 (Chr11:102,576,358,C > T), which results in a Met30Val missense variant in MMP27 exon 1 (NM_022122.3); 2. rs2470893 (Chr15:75,019,449,C > T), in intergenic region between CYP1A1 and CYP1A2; with attenuation of the SNP-effect when coffee consumption was included as a covariate; 3. rs12931267 (Chr16:89,818,732,C > G) in intron 30 of FANCA and near MC1R; and following conditional analysis 4. rs3764257 (Chr16:89,800,887,C > G) an intronic variant in ZNF276, 17.8 kb upstream from rs12931267; finally, 30 kb downstream from NAT2 5. rs576201050 (Chr8:18,288,053,G > A).
CONCLUSIONS: This large meta-GWAS revealed five SNPs at four loci associated with SAF in the non-diabetes population. Further unravelling of the genetic architecture of SAF will help in improving its utility as a tool for screening and early detection of diseases and disease complications.