Wellcome Sanger Institute, Cambridge, U.K.
Department of Public Health and Primary Care, The National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, U.K.
Diabetes. 2022 Feb 1;71(2):359-364. doi: 10.2337/db21-0320.
Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus.
果糖胺是衡量短期血糖控制的指标，它被认为是糖化血红蛋白（HbA1c）在诊断和监测糖尿病方面的有用补充。迄今为止，已经发表了一项包括 8951 名美国白人和 2712 名美国黑人且无糖尿病诊断的全基因组关联研究（GWAS）。在白人和黑人中的结果分别在 RCN3 和 CNTN5 附近产生了不同的关联位点。在这项研究中，我们对 20731 名欧洲血统的献血者进行了 GWAS，并与来自美国白人参与者的先前数据进行了荟萃分析，这些数据来自动脉粥样硬化风险社区（ARIC）研究（Nmeta = 29685）。我们在 GCK 附近发现了一个新的关联（rs3757840，βmeta = 0.0062；次要等位基因频率[MAF] = 0.49；Pmeta = 3.66×10-8），并确认了 RCN3 附近的关联（rs113886122，βmeta = 0.0134；MAF = 0.17；Pmeta = 5.71×10-18）。与全血表达数量性状基因座数据的共定位分析表明，FCGRT 是 RCN3 基因座的效应转录本。我们进一步表明，果糖胺的遗传力较低（h2 = 7.7%），在无糖尿病诊断的个体中与 HbA1c 和其他血糖特征没有显著的遗传相关性（P>0.05），但与一些人体测量特征有共享的遗传病因学证据（Bonferroni 校正后 P < 0.0012）。我们的研究结果拓宽了果糖胺遗传结构的知识，并将 FCGRT 列为在既定的 RCN3 基因座进行下游功能研究的优先事项。
