Leak Tennille S, Mychaleckyj Josyf C, Smith Shelly G, Keene Keith L, Gordon Candace J, Hicks Pamela J, Freedman Barry I, Bowden Donald W, Sale Michèle M
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Hum Genet. 2008 Aug;124(1):63-71. doi: 10.1007/s00439-008-0523-7. Epub 2008 Jun 17.
Previously, we performed a genome scan for type 2 diabetes (T2DM) using 638 African-American (AA) affected sibling pairs from 247 families; non-parametric linkage analysis suggested evidence of linkage at 6q24-27 (LOD 2.26). To comprehensively evaluate this region, we performed a two-stage association study by first constructing a SNP map of 754 SNPs selected from HapMap on the basis of linkage disequilibrium (LD) in 300 AAT2DM end-stage renal disease (ESRD) subjects, 311 AA controls, 43 European American controls and 45 Yoruba Nigerian samples (Set 1). Replication analyses were conducted in an independent population of 283 AA T2DM-ESRD subjects and 282 AA controls (Set 2). In addition, we adjusted for the impact of admixture on association results by using ancestry informative markers (AIMs). In Stage 1, 137 (18.2%) SNPs showed nominal evidence of association (P < 0.05) in one or more of tests of association: allelic (n = 33), dominant (n = 36), additive (n = 29), or recessive (n = 34) genotypic models, and 2- (n = 47) and 3-SNP (n = 43) haplotypic analyses. These SNPs were selected for follow-up genotyping. Stage 2 analyses confirmed association with a predicted 2-SNP "risk" haplotype in the PARK2 gene. Also, two intergenic SNPs showed consistent genotypic association with T2DM-ESRD: rs12197043 and rs4897081. Combined analysis of all subjects from both stages revealed nominal associations with 17 SNPs within genes, including suggestive associations in ESR1 and PARK2. This study confirms known diabetic nephropathy loci and identifies potentially novel susceptibility variants located within 6q24-27 in AA.
此前，我们利用来自247个家庭的638对非裔美国（AA）患病同胞对进行了2型糖尿病（T2DM）的全基因组扫描；非参数连锁分析表明在6q24 - 27存在连锁证据（LOD 2.26）。为全面评估该区域，我们进行了一项两阶段关联研究，首先在300例AA T2DM终末期肾病（ESRD）患者、311例AA对照、43例欧美对照和45例约鲁巴尼日利亚样本（数据集1）中，基于连锁不平衡（LD）构建了从HapMap中选取的754个单核苷酸多态性（SNP）的图谱。在一个由283例AA T2DM - ESRD患者和282例AA对照组成的独立人群（数据集2）中进行了重复分析。此外，我们通过使用祖先信息标记（AIMs）来调整混合血统对关联结果的影响。在第一阶段，137个（18.2%）SNP在一项或多项关联测试中显示出名义上的关联证据（P < 0.05）：等位基因（n = 33）、显性（n = 36）、加性（n = 29）或隐性（n = 34）基因型模型，以及双SNP（n = 47）和三SNP（n = 43）单倍型分析。这些SNP被选作后续基因分型。第二阶段分析证实与PARK2基因中一个预测的双SNP“风险”单倍型相关联。此外，两个基因间SNP显示出与T2DM - ESRD一致的基因型关联：rs12197043和rs4897081。对两个阶段所有受试者的联合分析揭示了与基因内17个SNP的名义关联，包括在ESR1和PARK2中的提示性关联。本研究证实了已知的糖尿病肾病位点，并鉴定出AA人群中位于6q24 - 27内潜在的新型易感变异。
