Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to Type 1 diabetes
Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to Type 1 diabetes
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DOI：
10.1111/j.1464-5491.2009.02846.x
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
DiStefano, J. K.
中科院分区：
文献类型：
--
作者：
Craig, D. W.;Millis, M. P.;DiStefano, J. K.
目的遗传因素在糖尿病肾病的进展中起主要作用。为了鉴定对终末期肾病（ESRD）易感性具有潜在影响的候选单核苷酸多态性（SNP），我们使用来自高加索1型糖尿病个体的合并DNA进行全基因组关联扫描。方法我们利用Illumina Infinium II HumanHap 550微珠芯片平台对由547例ESRD患者和549例对照受试者组成的DNA库中的555352个SNP进行基因分型1型糖尿病病程> 20年，无ESRD。合并的探针强度用于预测每个位点的平均等位基因频率（MAF）。个体基因分型使用iPLEX测定结合MassARRAY平台（Sequenom）进行。ResultsWe鉴定了2870个标记物，这些标记物在库之间的MAF（5.0-10.7%）中显示出实质性差异。为了开始验证这些发现，我们从全基因组SNP基因分型研究样本中选择了462名ESRD患者和470名未受影响的对照受试者，对22个高级标记进行基因分型。我们观察到ESRD与位于ZMIZ 1基因的rs 1749824相关的最有力证据[OR = 1.47（1.21-1.78）/拷贝，P = 8.1 × 10 ~（-5）; rs 9298190位于musculin基因[OR = 1.56（1.28-1.91）/拷贝，P = 1.6 × 10 ~（-5）]。IRS 2、TMPO、BID、KLRA 1、ELMO 1和CNDP 1基因内或附近的标记物也存在名义相关性（P <0.0006.ConclusionsThese findings identified several novel loci that might contribute to ESRD susceptibility in individuals with Type 1 diabetes.
AimsGenetic factors play a major role in the progression of kidney disease in diabetes. To identify candidate single nucleotide polymorphisms (SNPs) with potential effects on susceptibility to end-stage renal disease (ESRD), we performed a whole genome association scan using pooled DNA from Caucasian individuals with Type 1 diabetes.MethodsWe utilized the Illumina Infinium II HumanHap 550 beadchip platform to genotype 555 352 SNPs in DNA pools comprised of 547 cases with ESRD and 549 control subjects with Type 1 diabetes duration > 20 years and no ESRD. Pooled probe intensity was used to predict mean allele frequency (MAF) for each locus. Individual genotyping was performed using the iPLEX assay in conjunction with the MassARRAY platform (Sequenom).ResultsWe identified 2870 markers showing substantial differences in MAF (5.0-10.7%) between pools. To initiate validation of these findings, we genotyped 22 high-ranking markers in 462 individuals with ESRD and 470 unaffected control subjects selected from the genome-wide SNP genotyping study sample. We observed the strongest evidence for association between ESRD and rs1749824, located in the ZMIZ1 gene [OR = 1.47 (1.21-1.78) per copy of T allele; P = 8.1 x 10-5] and rs9298190, located in the musculin gene [OR = 1.56 (1.28-1.91) per copy of C allele; P = 1.6 x 10-5]. Evidence for nominal association with markers in or near the IRS2, TMPO, BID, KLRA1, ELMO1 and CNDP1 genes was also observed (P < 0.0006).ConclusionsThese findings identify several novel loci which may contribute to ESRD susceptibility in individuals with Type 1 diabetes.