An Ping, Freedman Barry I, Hanis Craig L, Chen Yii-Der I, Weder Alan B, Schork Nicholas J, Boerwinkle Eric, Province Michael A, Hsiung Chao Agnes, Wu Xiaodong, Quertermous Thomas, Rao D C
Division of Biostatistics (Campus Box 8067), Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110-1093, USA.
Diabetes. 2005 Mar;54(3):909-14. doi: 10.2337/diabetes.54.3.909.
Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting <8 h, those with a history of type 2 diabetes, or those on antidiabetic medications were excluded from the current investigation. These three phenotypes were suitably transformed to approximate normal distributions. Each phenotype was adjusted for the effects of age, BMI, and field center separately by sex within each of the eight network ethnicity groups before genetic analysis. A total of 8,664 subjects comprising 5,923 sibpairs from 4,043 families with 365 markers were available for conducting a meta-analysis using a modified Fisher's method of combining the P values from each of the eight scans. Evidence of linkages was found on chromosome 7q36 at 163 cM, with a logarithm of odds (LOD) score of 3.21 for HOMA-IR, and on chromosome 19q13 at 88 cM, with a LOD score of 3.33 for fasting glucose. We also found suggestive linkages (LOD score >/=2.2) on chromosome 7q36 at 163 cM, with LOD scores of 2.31 for fasting glucose and 2.26 for fasting insulin (versus the LOD score of 3.21 for HOMA-IR at this locus). In conclusion, QTLs were identified on chromosomes 7q36 and 19q13 for fasting glucose, insulin, and insulin resistance in large and multiple-ethnicity populations in the FBPP with good replications across several other independent studies for relevant traits. Follow-up dense mapping and association studies are warranted.
使用多点方差分量法对来自四个多中心网络的八个研究组（GenNet中的白人和黑人；GENOA中的白人、黑人和墨西哥裔美国人；HyperGEN中的白人和黑人；以及SAPPHIRe中的亚洲人）进行全基因组连锁分析，这些研究组构成了美国国立心肺血液研究所家族血压项目（FBPP），目的是确定影响空腹血糖、胰岛素和胰岛素抵抗稳态模型评估（HOMA-IR）的数量性状基因座（QTL）。这些研究人群中血压升高的受试者较多。空腹不足8小时的参与者、有2型糖尿病病史的参与者或正在服用抗糖尿病药物的参与者被排除在本次研究之外。对这三种表型进行了适当转换，以使其近似正态分布。在进行基因分析之前，在八个网络种族组中的每个组内，按性别分别对每种表型进行年龄、体重指数和研究中心效应的校正。共有8664名受试者，包括来自4043个家庭的5923对同胞对，使用改良的Fisher方法对来自八项扫描的P值进行合并，从而进行荟萃分析，这些受试者共有3,65个标记。在163厘摩（cM）的7号染色体q36区域发现了连锁证据，HOMA-IR的对数优势（LOD）得分为3.21；在88厘摩的19号染色体q13区域也发现了连锁证据，空腹血糖的LOD得分为3.33。我们还在163厘摩的7号染色体q36区域发现了提示性连锁（LOD得分≥2.2），空腹血糖的LOD得分为{2.31}，空腹胰岛素的LOD得分为2.26（相比之下，该位点HOMA-IR的LOD得分为3.21）。总之，在FBPP的大型多民族人群中，在7号染色体q36和19号染色体q13上鉴定出了与空腹血糖、胰岛素和胰岛素抵抗相关的QTL，并且在其他几项针对相关性状的独立研究中得到了很好的重复验证。后续进行密集图谱绘制和关联研究是必要的。
