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

Soranzo, N.; Sanna, S.; Wheeler, E.; Gieger, C.; Radke, D.; Dupuis, J.; Bouatia-Naji, N.; Langenberg, C.; Prokopenko, I.; Stolerman, E.; Sandhu, M.S.; Heeney, M.M.; Devaney, J.M.; Reilly, M.P.; Ricketts, S.L.; Stewart, A.F.; Voight, B.F.; Willenborg, C.; Wright, B.; Altshuler, D.; Arking, D.; Balkau, B.; Barnes, D.; Boerwinkle, E.; Böhm, B.; Bonnefond, A.; Bonnycastle, L.L.; Boomsma, D.I.; Bornstein, S.R.; Böttcher, Y.; Bumpstead, S.; Burnett-Miller, M.S.; Campbell, H.; Cao, A.; Chambers, J.; Clark, R.; Collins, F.S.; Coresh, J.; de Geus, E.J.; Dei, M.; Deloukas, P.; Döring, A.; Egan, J.M.; Elosua, R.; Ferrucci, L.; Forouhi, N.; Fox, C.S.; Franklin, C.; Franzosi, M.G.; 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, J.J.; Hunter-Merrill, R.; Illig, T.; Jackson, A.U.; Jula, A.; Kleber, M.; Knouff, C.W.; 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, R.J.; Luan, J.; Lyssenko, V.; Mägi, R.; Magnusson, P.K.; Mälarstig, A.; Mangino, M.; Martínez-Larrad, M.T.; März, W.; McArdle, W.L.; McPherson, R.; Meisinger, C.; Meitinger, T.; Melander, O.; Mohlke, K.L.; Mooser, V.E.; Morken, M.A.; Narisu, N.; Nathan, D.M.; Nauck, M.; O'Donnell, C.; Oexle, K.; Olla, N.; Pankow, J.S.; Payne, F.; Peden, J.F.; Pedersen, N.L.; Peltonen, L.; Perola, M.; Polasek, O.; Porcu, E.; Rader, D.J.; 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, T.D.; Stefansson, K.; Steinthorsdottir, V.; Strachan, D.P.; Strawbridge, R.; Stumvoll, M.; Surakka, I.; Swift, A.J.; Tanaka, T.; Teumer, A.; Thorleifsson, G.; Thorsteinsdottir, U.; Tönjes, A.; Usala, G.; Vitart, V.; Völzke, H.; Wallaschofski, H.; Waterworth, D.M.; Watkins, H.; Wichmann, H.E.; Wild, S.H.; Willemsen, G.; Williams, G.H.; Wilson, J.F.; Winkelmann, J.; Wright, A.F.; WTCCC,; Zabena, C.; Zabena, C.; Zhao, J.H.; Epstein, S.E.; Erdmann, J.; Hakonarson, H.H.; Kathiresan, S.; Khaw, K.T.; Roberts, R.; Samani, N.J.; Fleming, M.D.; Sladek, R.; Abecasis, G.; Boehnke, M.; Froguel, P.; Groop, L.; McCarthy, M.I.; Kao, W.H.; Florez, J.C.; Uda, M.; Wareham, N.J.; Barroso, I.; Meigs, J.B.

doi:10.2337/db10-0502

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

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serval:BIB_B1ECF26752EF

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Article: article from journal or magazin.

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Title

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

Journal

Diabetes

Author(s)

Soranzo N., Sanna S., Wheeler E., Gieger C., Radke D., Dupuis J., Bouatia-Naji N., Langenberg C., Prokopenko I., Stolerman E., Sandhu M.S., Heeney M.M., Devaney J.M., Reilly M.P., Ricketts S.L., Stewart A.F., Voight B.F., Willenborg C., Wright B., Altshuler D., Arking D., Balkau B., Barnes D., Boerwinkle E., Böhm B., Bonnefond A., Bonnycastle L.L., Boomsma D.I., Bornstein S.R., Böttcher Y., Bumpstead S., Burnett-Miller M.S., Campbell H., Cao A., Chambers J., Clark R., Collins F.S., Coresh J., de Geus E.J., Dei M., Deloukas P., Döring A., Egan J.M., Elosua R., Ferrucci L., Forouhi N., Fox C.S., Franklin C., Franzosi M.G., 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 J.J., Hunter-Merrill R., Illig T., Jackson A.U., Jula A., Kleber M., Knouff C.W., 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 R.J., Luan J., Lyssenko V., Mägi R., Magnusson P.K., Mälarstig A., Mangino M., Martínez-Larrad M.T., März W., McArdle W.L., McPherson R., Meisinger C., Meitinger T., Melander O., Mohlke K.L., Mooser V.E., Morken M.A., Narisu N., Nathan D.M., Nauck M., O'Donnell C., Oexle K., Olla N., Pankow J.S., Payne F., Peden J.F., Pedersen N.L., Peltonen L., Perola M., Polasek O., Porcu E., Rader D.J., 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 T.D., Stefansson K., Steinthorsdottir V., Strachan D.P., Strawbridge R., Stumvoll M., Surakka I., Swift A.J., Tanaka T., Teumer A., Thorleifsson G., Thorsteinsdottir U., Tönjes A., Usala G., Vitart V., Völzke H., Wallaschofski H., Waterworth D.M., Watkins H., Wichmann H.E., Wild S.H., Willemsen G., Williams G.H., Wilson J.F., Winkelmann J., Wright A.F., WTCCC , Zabena C., Zabena C., Zhao J.H., Epstein S.E., Erdmann J., Hakonarson H.H., Kathiresan S., Khaw K.T., Roberts R., Samani N.J., Fleming M.D., Sladek R., Abecasis G., Boehnke M., Froguel P., Groop L., McCarthy M.I., Kao W.H., Florez J.C., Uda M., Wareham N.J., Barroso I., Meigs J.B.

Contributor(s)

WTCCC

ISSN

1939-327X (Electronic)

ISSN-L

0012-1797

Publication state

Published

Issued date

2010

Volume

Number

Pages

3229-3239

Language

english

Notes

Publication types: Journal ArticlePublication Status: ppublish

Abstract

OBJECTIVE: Glycated hemoglobin (HbA₁(c)), 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 HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels.
RESEARCH DESIGN AND METHODS: We studied associations with HbA₁(c) 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 HbA₁(c) 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 HbA(1c), 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 × 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 HbA₁(c) 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 HbA₁(c) 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 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c).
CONCLUSIONS: GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). 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 HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c).

Keywords

Adult, Blood Glucose/metabolism, Body Mass Index, Chromosome Mapping, Cohort Studies, European Continental Ancestry Group/genetics, Female, Genetic Variation, Genome-Wide Association Study, Hemoglobin A, Glycosylated/genetics, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide

DOI

10.2337/db10-0502

Pubmed

20858683

Web of science

000285988200032

Open Access

Yes

Create date

21/01/2013 10:56

Last modification date

18/01/2021 21:51

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

Details