Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5) -: A sex-specific effect
Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5) -: A sex-specific effect
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DOI：
10.2337/diabetes.54.11.3331
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发表时间：
2005-11-01
期刊：
影响因子：
7.7
通讯作者：
Krolewski, AS
中科院分区：
文献类型：
--
作者：
Mlynarski, WM;Placha, GP;Krolewski, AS
趋化因子及其受体与糖尿病肾病的发展有关。为了确定糖尿病肾病的风险是否受到正常t细胞表达和分泌受体（RANTES）基因（CCR5）的两种功能多态性的影响，我们招募了1型糖尿病患者，包括496例明显蛋白尿或终末期肾病患者和298例正常蛋白尿对照患者。携带59029G等位基因的男性患糖尿病肾病的风险明显高于非携带者（OR [95% CI] 1.9[1.2-3.0]）。59029G等位基因与免疫功能细胞表面CCR5的表达减少有关。同样，32-bp缺失导致该蛋白截断的男性携带者患糖尿病肾病的风险明显高于非携带者（2.3[1.3-4.2]）。结合这两种多态性，分离出3种单倍型：1种携带59029A等位基因且插入32bp的无风险单倍型和2种携带59029A等位基因且缺失32bp的携带59029G等位基因且插入32bp的风险单倍型。这些单倍型在男性糖尿病肾病患者和非糖尿病肾病患者中的分布差异显著（P < 0.00001），但与女性糖尿病肾病患者无关。综上所述，CCR5的两种功能多态性降低了免疫活性细胞上RANTES受体的表达，与1型糖尿病患者糖尿病肾病的风险增加有关，但仅在男性中存在。
Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2-3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3-4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.