An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript.

Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE

Publication: Alexandria, VA : American Diabetes Association
Original Publication: [New York, American Diabetes Association]

Calcium-Binding Proteins/*genetics ; Fructosamine/*blood ; Histocompatibility Antigens Class I/*genetics ; Receptors, Fc/*genetics; Adult ; Atherosclerosis/blood ; Atherosclerosis/epidemiology ; Atherosclerosis/genetics ; Cohort Studies ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/genetics ; Female ; Fructosamine/metabolism ; Gene Expression Regulation ; Gene Frequency ; Genetic Loci ; Genetic Variation ; Genome-Wide Association Study ; Glycated Hemoglobin/metabolism ; Humans ; Male ; Metabolic Networks and Pathways/genetics ; Polymorphism, Single Nucleotide ; United Kingdom/epidemiology ; United States/epidemiology

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.
(© 2022 by the American Diabetes Association.)

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MR/L003120/1 United Kingdom MRC_ Medical Research Council; BTRU-2014-10024 United Kingdom DH_ Department of Health; R01 HL086694 United States HL NHLBI NIH HHS; RG/18/13/33946 United Kingdom BHF_ British Heart Foundation; HHSN268201700002C United States HL NHLBI NIH HHS; HHSN268201700001I United States HL NHLBI NIH HHS; SP/09/002 United Kingdom BHF_ British Heart Foundation; UL1 RR025005 United States RR NCRR NIH HHS; K24 HL152440 United States HL NHLBI NIH HHS; 206194 United Kingdom WT_ Wellcome Trust; R01 DK089174 United States DK NIDDK NIH HHS; R01 HL059367 United States HL NHLBI NIH HHS; U01 HG004402 United States HG NHGRI NIH HHS; HHSN268201700004I United States HL NHLBI NIH HHS; HHSN268201700005C United States HL NHLBI NIH HHS; HHSN268201700001C United States HL NHLBI NIH HHS; HHSN268201700003C United States HL NHLBI NIH HHS; HHSN268201700004C United States HL NHLBI NIH HHS; United Kingdom WT_ Wellcome Trust; HHSN268201700002I United States HL NHLBI NIH HHS; HHSN268201700005I United States HL NHLBI NIH HHS; United Kingdom CSO_ Chief Scientist Office; R01 HL087641 United States HL NHLBI NIH HHS; HHSN268201700003I United States HL NHLBI NIH HHS; RG/13/13/30194 United Kingdom BHF_ British Heart Foundation

figshare 10.2337/figshare.16933561

0 (Calcium-Binding Proteins)
0 (Glycated Hemoglobin A)
0 (Histocompatibility Antigens Class I)
0 (RCN3 protein, human)
0 (Receptors, Fc)
4429-04-3 (Fructosamine)
TW3XAW0RCY (Fc receptor, neonatal)

Date Created: 20211110 Date Completed: 20220223 Latest Revision: 20240610

20240610

PMC8914280

10.2337/db21-0320

34753797