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Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.

Title: Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
Authors: Soranzo, N
Sanna, S
Wheeler, E
Gieger, C
Radke, D
Dupuis, J
Bouatia-Naji, N
Langenberg, C
Prokopenko, I
Stolerman, E
Sandhu, MS
Heeney, MM
Devaney, JM
Reilly, MP
Ricketts, SL
Stewart, AF
Voight, BF
Willenborg, C
Wright, B
Altshuler, D
Arking, D
Balkau, B
Barnes, D
Boerwinkle, E
Böhm, B
Bonnefond, A
Bonnycastle, LL
Boomsma, DI
Bornstein, SR
Böttcher, Y
Bumpstead, S
Burnett-Miller, MS
Campbell, H
Cao, A
Chambers, J
Clark, R
Collins, FS
Coresh, J
De Geus, EJ
Dei, M
Deloukas, P
Döring, A
Egan, JM
Elosua, R
Ferrucci, L
Forouhi, N
Fox, CS
Franklin, C
Franzosi, MG
Gallina, S
Goel, A
Graessler, J
Grallert, H
Greinacher, A
Hadley, D
Hall, A
Hamsten, A
Hayward, C
Heath, S
Herder, C
Homuth, G
Hottenga, JJ
Hunter-Merrill, R
Illig, T
Jackson, AU
Jula, A
Kleber, M
Knouff, CW
Kong, A
Kooner, J
Köttgen, A
Kovacs, P
Krohn, K
Kühnel, B
Kuusisto, J
Laakso, M
Lathrop, M
Lecoeur, C
Li, M
Li, M
Loos, RJ
Luan, J
Lyssenko, V
Mägi, R
Magnusson, PK
Mälarstig, A
Mangino, M
Martínez-Larrad, MT
März, W
McArdle, WL
McPherson, R
Meisinger, C
Meitinger, T
Melander, O
Mohlke, KL
Mooser, VE
Morken, MA
Narisu, N
Nathan, DM
Nauck, M
O'Donnell, C
Oexle, K
Olla, N
Pankow, JS
Payne, F
Peden, JF
Pedersen, NL
Peltonen, L
Perola, M
Polasek, O
Porcu, E
Rader, DJ
Rathmann, W
Ripatti, S
Rocheleau, G
Roden, M
Rudan, I
Salomaa, V
Saxena, R
Schlessinger, D
Schunkert, H
Schwarz, P
Seedorf, U
Selvin, E
Serrano-Ríos, M
Shrader, P
Silveira, A
Siscovick, D
Song, K
Spector, TD
Stefansson, K
Steinthorsdottir, V
Strachan, DP
Strawbridge, R
Stumvoll, M
Surakka, I
Swift, AJ
Tanaka, T
Teumer, A
Thorleifsson, G
Thorsteinsdottir, U
Tönjes, A
Usala, G
Vitart, V
Völzke, H
Wallaschofski, H
Waterworth, DM
Watkins, H
Wichmann, HE
Wild, SH
Willemsen, G
Williams, GH
Wilson, JF
Winkelmann, J
Wright, AF
Zabena, C
Zhao, JH
Epstein, SE
Erdmann, J
Hakonarson, HH
Kathiresan, S
Khaw, KT
Roberts, R
Samani, NJ
Fleming, MD
Sladek, R
Abecasis, G
Boehnke, M
Froguel, P
Groop, L
McCarthy, MI
Kao, WH
Florez, JC
Uda, M
Wareham, NJ
Barroso, I
Meigs, JB
Item Type: Journal Article
Abstract: OBJECTIVE - Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA 1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS - We studied associations with HbA 1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS - Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10-26), HFE (rs1800562/P = 2.6 × 10-20), TMPRSS6 (rs855791/P = 2.7 x 10-14), ANK1 (rs4737009/P = 6.1 × 10-12), SPTA1 (rs2779116/P = 2.8 × 10-9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10 -9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10-54), MTNR1B (rs1387153/P = 4.0 × 10-11), GCK (rs1799884/P = 1.5 × 10-20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10-18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA 1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS - GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c. © 2010 by the American Diabetes Association.
Issue Date: 1-Dec-2010
Date of Acceptance: 5-Sep-2010
URI: http://hdl.handle.net/10044/1/28756
DOI: https://dx.doi.org/10.2337/db10-0502
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 3229
End Page: 3239
Journal / Book Title: Diabetes
Volume: 59
Issue: 12
Copyright Statement: © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
Keywords: Adult
Blood Glucose
Body Mass Index
Chromosome Mapping
Cohort Studies
European Continental Ancestry Group
Genetic Variation
Genome-Wide Association Study
Hemoglobin A, Glycosylated
Meta-Analysis as Topic
Middle Aged
Polymorphism, Single Nucleotide
Endocrinology & Metabolism
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute