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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 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, WTCCCZabena 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 - Diabetes (2010)

Bottom Line: We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B).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.

View Article: PubMed Central - PubMed

Affiliation: Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.

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).

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Related in: MedlinePlus

Regional association plots at the HbA1c loci. Each panel spans ± 250 kb around the most significant associated SNP in the region, which is highlighted with a blue square (panel C spans ± 300 kb). At the top of each panel, comb diagrams indicate the location of SNPs in the Illumina HumanHap 550K and Affymetrix 500K chips, and of SNPs imputed. The SNPs are colored according to their linkage disequilibrium with the top variant based on the CEU HapMap population (http://www.hapmap.org). Gene transcripts are annotated in the lower box, with the most likely biologic candidate highlighted in blue; ± indicates the direction of transcription. In panel C, a few gene names were omitted for clarity. Here, genes are, from left to right, SCGN, HIST1H2AA, HIST1H2BA, SLC17A4, SLC17A1, SLC17A3, SLC17A2, TRIM38, HIST1H1A, HIST1H3A, HIST1H4A, HIST1H4B, HIST1H3B, HIST1H2AB, HIST1H2BB, HIST1H3C, HIST1H1C, HFE, HIST1H4C, HIST1H1T, HIST1H2BC, HIST1H2AC, HIST1H1E, HIST1H2BD, HIST1H2BD, HIST1H2BE, HIST1H4D, HIST1H3D, HIST1H2AD, HIST1H2BF, HIST1H4E, HIST1H2BG, HIST1H2AE, HIST1H3E, HIST1H1D, HIST1H4F, HIST1H4G, HIST1H3F, HIST1H2BH, HIST1H3G, HIST1H2BI, and HIST1H4H. In panel D, the names of the first two genes, UBE2D4 and WBSCR19, were also omitted for clarity. (A high-quality color representation of this figure is available in the online issue.)
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Figure 2: Regional association plots at the HbA1c loci. Each panel spans ± 250 kb around the most significant associated SNP in the region, which is highlighted with a blue square (panel C spans ± 300 kb). At the top of each panel, comb diagrams indicate the location of SNPs in the Illumina HumanHap 550K and Affymetrix 500K chips, and of SNPs imputed. The SNPs are colored according to their linkage disequilibrium with the top variant based on the CEU HapMap population (http://www.hapmap.org). Gene transcripts are annotated in the lower box, with the most likely biologic candidate highlighted in blue; ± indicates the direction of transcription. In panel C, a few gene names were omitted for clarity. Here, genes are, from left to right, SCGN, HIST1H2AA, HIST1H2BA, SLC17A4, SLC17A1, SLC17A3, SLC17A2, TRIM38, HIST1H1A, HIST1H3A, HIST1H4A, HIST1H4B, HIST1H3B, HIST1H2AB, HIST1H2BB, HIST1H3C, HIST1H1C, HFE, HIST1H4C, HIST1H1T, HIST1H2BC, HIST1H2AC, HIST1H1E, HIST1H2BD, HIST1H2BD, HIST1H2BE, HIST1H4D, HIST1H3D, HIST1H2AD, HIST1H2BF, HIST1H4E, HIST1H2BG, HIST1H2AE, HIST1H3E, HIST1H1D, HIST1H4F, HIST1H4G, HIST1H3F, HIST1H2BH, HIST1H3G, HIST1H2BI, and HIST1H4H. In panel D, the names of the first two genes, UBE2D4 and WBSCR19, were also omitted for clarity. (A high-quality color representation of this figure is available in the online issue.)

Mentions: We carried out a meta-analysis of SNP associations with HbA1c levels in up to 46,368 participants of European ancestry from 31 cohorts. We identified 10 genomic regions associated with HbA1c levels (Table 2, Figs. 1 and 2). Six associated regions were new, including FN3K (rs1046896, P = 1.57 × 10−26), HFE (rs1800562, P = 2.59 × 10−20), TMPRSS6 (rs855791, P = 2.74 × 10−4), ANK1 (rs4737009, P = 6.11 × 10−12), SPTA1 (rs2779116, P = 2.75 × 10−9), and ATP11A/TUBGCP3 (rs7998202, P = 5.24 × 10−9). A second, independent SNP near ANK1 was also associated with HbA1c (rs6474359, P = 1.18 × 10−8; r2 with rs4737009 = 0.0001; see also supplementary methods). In addition, SNPs in or near HK1 (rs16926246, P = 3.11 × 10−54), MTNR1B (rs1387153, P = 3.96 × 10−11), GCK (rs1799884, P = 1.45 × 10−20), and G6PC2/ABCB11 (rs552976, P = 8.16 × 10−18) were associated with HbA1c levels. These loci had previously been associated with HbA1c (15,16), FG (9–12,14,15) and/or type 2 diabetes risk (9–12,15,16,19). Associations were generally similar across cohorts, showing no significant heterogeneity (Table 2). This lack of heterogeneity suggests that there is good consistency in trait measurement across different cohorts.


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 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, WTCCCZabena 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 - Diabetes (2010)

Regional association plots at the HbA1c loci. Each panel spans ± 250 kb around the most significant associated SNP in the region, which is highlighted with a blue square (panel C spans ± 300 kb). At the top of each panel, comb diagrams indicate the location of SNPs in the Illumina HumanHap 550K and Affymetrix 500K chips, and of SNPs imputed. The SNPs are colored according to their linkage disequilibrium with the top variant based on the CEU HapMap population (http://www.hapmap.org). Gene transcripts are annotated in the lower box, with the most likely biologic candidate highlighted in blue; ± indicates the direction of transcription. In panel C, a few gene names were omitted for clarity. Here, genes are, from left to right, SCGN, HIST1H2AA, HIST1H2BA, SLC17A4, SLC17A1, SLC17A3, SLC17A2, TRIM38, HIST1H1A, HIST1H3A, HIST1H4A, HIST1H4B, HIST1H3B, HIST1H2AB, HIST1H2BB, HIST1H3C, HIST1H1C, HFE, HIST1H4C, HIST1H1T, HIST1H2BC, HIST1H2AC, HIST1H1E, HIST1H2BD, HIST1H2BD, HIST1H2BE, HIST1H4D, HIST1H3D, HIST1H2AD, HIST1H2BF, HIST1H4E, HIST1H2BG, HIST1H2AE, HIST1H3E, HIST1H1D, HIST1H4F, HIST1H4G, HIST1H3F, HIST1H2BH, HIST1H3G, HIST1H2BI, and HIST1H4H. In panel D, the names of the first two genes, UBE2D4 and WBSCR19, were also omitted for clarity. (A high-quality color representation of this figure is available in the online issue.)
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Figure 2: Regional association plots at the HbA1c loci. Each panel spans ± 250 kb around the most significant associated SNP in the region, which is highlighted with a blue square (panel C spans ± 300 kb). At the top of each panel, comb diagrams indicate the location of SNPs in the Illumina HumanHap 550K and Affymetrix 500K chips, and of SNPs imputed. The SNPs are colored according to their linkage disequilibrium with the top variant based on the CEU HapMap population (http://www.hapmap.org). Gene transcripts are annotated in the lower box, with the most likely biologic candidate highlighted in blue; ± indicates the direction of transcription. In panel C, a few gene names were omitted for clarity. Here, genes are, from left to right, SCGN, HIST1H2AA, HIST1H2BA, SLC17A4, SLC17A1, SLC17A3, SLC17A2, TRIM38, HIST1H1A, HIST1H3A, HIST1H4A, HIST1H4B, HIST1H3B, HIST1H2AB, HIST1H2BB, HIST1H3C, HIST1H1C, HFE, HIST1H4C, HIST1H1T, HIST1H2BC, HIST1H2AC, HIST1H1E, HIST1H2BD, HIST1H2BD, HIST1H2BE, HIST1H4D, HIST1H3D, HIST1H2AD, HIST1H2BF, HIST1H4E, HIST1H2BG, HIST1H2AE, HIST1H3E, HIST1H1D, HIST1H4F, HIST1H4G, HIST1H3F, HIST1H2BH, HIST1H3G, HIST1H2BI, and HIST1H4H. In panel D, the names of the first two genes, UBE2D4 and WBSCR19, were also omitted for clarity. (A high-quality color representation of this figure is available in the online issue.)
Mentions: We carried out a meta-analysis of SNP associations with HbA1c levels in up to 46,368 participants of European ancestry from 31 cohorts. We identified 10 genomic regions associated with HbA1c levels (Table 2, Figs. 1 and 2). Six associated regions were new, including FN3K (rs1046896, P = 1.57 × 10−26), HFE (rs1800562, P = 2.59 × 10−20), TMPRSS6 (rs855791, P = 2.74 × 10−4), ANK1 (rs4737009, P = 6.11 × 10−12), SPTA1 (rs2779116, P = 2.75 × 10−9), and ATP11A/TUBGCP3 (rs7998202, P = 5.24 × 10−9). A second, independent SNP near ANK1 was also associated with HbA1c (rs6474359, P = 1.18 × 10−8; r2 with rs4737009 = 0.0001; see also supplementary methods). In addition, SNPs in or near HK1 (rs16926246, P = 3.11 × 10−54), MTNR1B (rs1387153, P = 3.96 × 10−11), GCK (rs1799884, P = 1.45 × 10−20), and G6PC2/ABCB11 (rs552976, P = 8.16 × 10−18) were associated with HbA1c levels. These loci had previously been associated with HbA1c (15,16), FG (9–12,14,15) and/or type 2 diabetes risk (9–12,15,16,19). Associations were generally similar across cohorts, showing no significant heterogeneity (Table 2). This lack of heterogeneity suggests that there is good consistency in trait measurement across different cohorts.

Bottom Line: We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B).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.

View Article: PubMed Central - PubMed

Affiliation: Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.

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).

Show MeSH
Related in: MedlinePlus