Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians.
Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians.
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作者：
Rong R;Hanson RL;Ortiz D;Wiedrich C;Kobes S;Knowler WC;Bogardus C;Baier LJ
在最近的全基因组关联研究中，CDKAL 1、SLC 30 A8、HHEX、EXT 2、IGF 2BP 2、CDKN 2B、LOC 387761和FTO的变异与高加索人2型糖尿病的风险相关。我们调查了这些单核苷酸多态性（SNPs）和一些额外的标签SNPs与2型糖尿病和相关的数量性状在皮马印第安人的关联。研究设计和方法-在3,501名皮马印第安人中对47个SNPs进行基因分型，为2型糖尿病和BMI提供信息，其中370人有数量性状的测量。SNP-FTO为重复性提供了最强有力的证据，其中SNP与2型糖尿病（风险等位基因的比值比= 1.20，P = 0.03）和BMI（P = 0.002）相关。没有其他先前报道的SNP与2型糖尿病相关;然而，CDKAL 1和HHEX变异体与急性胰岛素反应（AIR）之间存在关联，其中2型糖尿病的高加索风险等位基因与血糖正常的皮马印第安人胰岛素分泌减少相关。多基因携带风险等位基因的多等位基因分析显示，在血糖正常的受试者中，风险等位基因的数量与2型糖尿病和胰岛素分泌受损之间存在相关性（2型糖尿病和AIR的P值分别为0.006和0.0001），这支持了许多这些基因通过影响胰岛素分泌来影响糖尿病风险的假设。结论：FTO的变异影响BMI，但其他基因中的常见变异并没有赋予皮马印第安人患2型糖尿病的显著风险。然而，他们估计的影响的置信区间是一致的，在高加索人中报告的小的影响，和多等位基因的“遗传风险概况”在高加索人中确定与减少早期胰岛素分泌在皮马印第安人。
OBJECTIVE—In recent genome-wide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians. RESEARCH DESIGN AND METHODS—Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits. RESULTS—FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI (P = 0.002). None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects (P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion. CONCLUSIONS—Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic “genetic risk profile” identified in Caucasians is associated with diminished early insulin secretion in Pima Indians.
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影响因子：
7.7
作者：
Marvelle, Amanda F.;Lange, Leslie A.;Qin, Li;Adair, Linda S.;Mohlke, Karen L.
通讯作者：
Mohlke, Karen L.
影响因子：
9.8
作者：
Abecasis, GR;Cardon, LR;Cookson, WOC
通讯作者：
Cookson, WOC
DOI：
10.1126/science.1151710
发表时间：
2007-11-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
3.5
作者：
Ohashi, Jun;Naka, Izumi;Ohtsuka, Ryutaro
通讯作者：
Ohtsuka, Ryutaro