McKnight Amy Jayne, Savage David A, Patterson Chris C, Sadlier Denise, Maxwell A Peter
Nephrology Research Group, Queen's University of Belfast, Belfast, UK.
BMC Med Genet. 2007 Feb 23;8:5. doi: 10.1186/1471-2350-8-5.
Diabetic nephropathy is the leading cause of end stage renal failure in the western world. There is substantial epidemiological evidence supporting a genetic predisposition to diabetic nephropathy, however the exact molecular mechanisms remain unknown. Transforming growth factor (TGFbeta1) is a crucial mediator in the pathogenesis of diabetic nephropathy.
We investigated the role of five known single nucleotide polymorphisms (SNPs) in the TGFB1 gene for their association with diabetic nephropathy in an Irish, type 1 diabetic case (n = 272) control (n = 367) collection. The activity of TGFbeta1 is facilitated by the action of type 1 and type 2 receptors, with both receptor genes (TGFBR1 and TGFBR2) shown to be upregulated in diabetic kidney disease. We therefore screened TGFBR1 and TGFBR2 genes for genomic variants using WAVEtrade mark (dHPLC) technology and confirmed variants by direct capillary sequencing. Allele frequencies were determined in forty-eight healthy individuals. Data for all SNPs was assessed for Hardy Weinberg equilibrium, with genotypes and allele frequencies compared using the chi2 test for contingency tables. Patterns of linkage disequilibrium were established and common haplotypes estimated.
Fifteen variants were identified in these genes, seven of which are novel, and putatively functional SNPs were subsequently genotyped using TaqMantrade mark, Invadertrade mark or Pyrosequencing(R) technology. No significant differences (p > 0.1) were found in genotype or allele distributions between cases and controls for any of the SNPs assessed.
Our results suggest common variants in TGFB1, TGFBR1 and TGFBR2 genes do not strongly influence genetic susceptibility to diabetic nephropathy in an Irish Caucasian population.
在西方世界，糖尿病肾病是终末期肾衰竭的主要原因。有大量流行病学证据支持糖尿病肾病存在遗传易感性，但其确切分子机制仍不清楚。转化生长因子（TGFβ1）是糖尿病肾病发病机制中的关键介质。
我们在一组爱尔兰1型糖尿病病例（n = 272）对照（n = 367）样本中，研究了TGFB1基因中五个已知单核苷酸多态性（SNP）与糖尿病肾病的关联。TGFβ1的活性受1型和2型受体作用的促进，这两种受体基因（TGFBR1和TGFBR2）在糖尿病肾病中均显示上调。因此，我们使用WAVE商标（dHPLC）技术筛选TGFBR1和TGFBR2基因的基因组变异，并通过直接毛细管测序确认变异。在48名健康个体中确定等位基因频率。对所有SNP的数据进行哈迪-温伯格平衡评估，使用列联表的卡方检验比较基因型和等位基因频率。建立连锁不平衡模式并估计常见单倍型。
在这些基因中鉴定出15个变异，其中7个是新的，随后使用TaqMan商标、Invader商标或焦磷酸测序技术对推定具有功能的SNP进行基因分型。在所评估的任何SNP的病例和对照之间，基因型或等位基因分布均未发现显著差异（p > 0.1）。
我们的结果表明，TGFB1、TGFBR1和TGFBR2基因中的常见变异对爱尔兰白种人群中糖尿病肾病的遗传易感性没有强烈影响。
