Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
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作者：
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;WTCCC;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
糖化血红蛋白（HbA1c）用于监测和诊断糖尿病，受2- 3个月期间平均血糖的影响。影响血红蛋白表达、转换和异常糖化的遗传因素也可能与HbA1c水平升高有关。我们的目的是确定这些遗传因素，并研究它们在多大程度上影响基于HbA1c水平的糖尿病分类。我们研究了来自23项全基因组关联研究（GWAS）和8个从头基因型单核苷酸多态性（SNPs）队列的46,368名欧洲血统非糖尿病成年人与HbA1c的相关性。我们使用反方差荟萃分析合并研究，并使用条件分析测试血糖的中介作用。我们使用多位点风险评分来估计HbA1c基因座的整体影响，并使用净重分类来估计遗传对糖尿病筛查的影响。10个位点与HbA1c全基因组显著相关，包括FN3K附近的6个新位点（SNP/P值，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）和ATP11A/TUBGCP3 （rs7998202/P = 5.2 × 10−9）和4个已知的HbA1c位点。HK1 （rs16926246/P = 3.1 × 10−54）、MTNR1B （rs1387153/P = 4.0 × 10−11）、GCK （rs1799884/P = 1.5 × 10−20）和G6PC2/ABCB11 （rs552976/P = 8.2 × 10−18）。我们发现，与HbA1c相关的部分功能与10个基因座中的3个（GCK， G6PC2和MTNR1B）相关的高血糖有关。7个非糖化基因座在危险评分的极端10%尾部之间的差异为0.19 (% HbA1c)，并且将对筛查糖尿病合并HbA1c的普通白人人群进行重新分类~ 2%。GWAS鉴定出10个与HbA1c可重复相关的遗传位点。其中6个是新发现的，7个定位于导致遗传性贫血和铁储存障碍的罕见变异位点。这些基因座的常见变异可能通过红细胞生物学影响HbA1c水平，并通过HbA1c对糖尿病诊断进行微小但可检测的重新分类。
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 HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. We studied associations with HbA1c 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. 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 × 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 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. 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.
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影响因子：
7.7
作者：
Bonnefond A;Vaxillaire M;Labrune Y;Lecoeur C;Chèvre JC;Bouatia-Naji N;Cauchi S;Balkau B;Marre M;Tichet J;Riveline JP;Hadjadj S;Gallois Y;Czernichow S;Hercberg S;Kaakinen M;Wiesner S;Charpentier G;Lévy-Marchal C;Elliott P;Jarvelin MR;Horber F;Dina C;Pedersen O;Sladek R;Meyre D;Froguel P
通讯作者：
Froguel P
影响因子：
4.2
作者：
McCarthy, Mark I.;Zeggini, Eleftheria
通讯作者：
Zeggini, Eleftheria
影响因子：
3.7
作者：
Ioannidis JP;Patsopoulos NA;Evangelou E
通讯作者：
Evangelou E
新的遗传基因座涉及禁食葡萄糖稳态及其对2型糖尿病风险的影响。
影响因子：
30.8
作者：
通讯作者：
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HK1与糖化血红蛋白在非糖尿病人群中的新型关联：对女性基因组健康研究中14,618名参与者的全基因组评估。
影响因子：
4.5
作者：
Paré G;Chasman DI;Parker AN;Nathan DM;Miletich JP;Zee RY;Ridker PM
通讯作者：
Ridker PM