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Complement factor H gene associations with end-stage kidney disease in African Americans
发布于：2014年3月3日 文字：【大】【中】【小】
Nephrol. Dial. Transplant.first published online February 28, 2014
doi:10.1093/ndt/gfu036
Complement factor H gene associations with end-stage kidney disease in African Americans
Jason A. Bonomo, Nicholette D. Palmer, Pamela J. Hicks, Janice P. Lea, Mark D. Okusa, Carl D. Langefeld, Donald W. Bowden, and Barry I. Freedman
Background Mutations in the complement factor H gene (CFH) region associate with renal-limited mesangial proliferative forms of glomerulonephritis including IgA nephropathy (IgAN), dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Lack of kidney biopsies could lead to under diagnosis of CFH-associated end-stage kidney disease (ESKD) in African Americans (AAs), with incorrect attribution to other causes. A prior genome-wide association study in AAs with non-diabetic ESKD implicated an intronic CFH single nucleotide polymorphism (SNP).
Methods Thirteen CFH SNPs (8 exonic, 2 synonymous, 2 3′UTR, and the previously associated intronic variant rs379489) were tested for association with common forms of non-diabetic and type 2 diabetes-associated (T2D) ESKD in 3770 AAs (1705 with non-diabetic ESKD, 1305 with T2D-ESKD, 760 controls). Most cases lacked kidney biopsies; those with known IgAN, DDD or C3GN were excluded.
Results Adjusting for age, gender, ancestry and apolipoprotein L1 gene risk variants, single SNP analyses detected 6 CFH SNPs (5 exonic and the intronic variant) as significantly associated with non-diabetic ESKD (P = 0.002–0.01), three of these SNPs were also associated with T2D-ESKD. Weighted CFH locus-wide Sequence Kernel Association Testing (SKAT) in non-diabetic ESKD (P = 0.00053) and T2D-ESKD (P = 0.047) confirmed significant evidence of association.
Conclusions CFH was associated with commonly reported etiologies of ESKD in the AA population. These results suggest that a subset of cases with ESKD clinically ascribed to the effects of hypertension or glomerulosclerosis actually have CFH-related forms of mesangial proliferative glomerulonephritis. Genetic testing may prove useful to identify the causes of renal-limited kidney disease in patients with ESKD who lack renal biopsies.
补体H因子基因与非洲裔美国人终末期肾脏病的关联研究
背景：补体H因子（CFH）基因突变与肾脏局限的系膜增生型肾小球肾炎，如IgA肾病、致密物沉积病及C3肾小球肾炎相关。肾穿刺活检的缺乏可导致非洲裔美国人群（AAs）中CFH相关的终末期肾脏病（ESKD）误诊为其他种类疾病。前期在AAs中的全基因组关联研究显示，非糖尿病导致的ESKD的发生与CFH基因内含子区的一个单核苷酸多态性位点（SNP）相关。
方法：分别在非糖尿病导致的ESKD及2型糖尿病导致的ESKD 共3770AAs人群中（1705人为非糖尿病导致的ESKD，1305人为2型糖尿病导致的ESKD，760个正常对照）检测了13个CFH基因的SNP位点（8个位于外显子切、2个为同义突变、2个3′UTR突变及之前内含子区阳性SNP位点rs379489）。大多数患者缺少肾穿刺活检诊断结果，已知诊断为IgA肾病、致密物沉积病及C3肾小球肾炎的患者均被排除。
结果：进行年龄、性别、种族及载脂蛋白LI危险基因的校正后，6个SNP位点（5个位于外显子区，1个位于内含子区）与非糖尿病导致的ESKD发生显著相关（P = 0.002–0.01），其中3个SNP 位点与2型糖尿病导致的ESKD的发生相关。SKAT进一步验证在非糖尿病导致的ESKD (P = 0.00053)与2型糖尿病导致的ESKD (P = 0.047)中均具有显著的相关性。
结论：H因子基因与AA人群中已报道的常见种类的ESKD发生相关。这些结果提示ESKD中临床归因于高血压或者肾小球肾炎的亚类实际上可能是CFH相关的系膜增生性肾小球肾炎。基因检测可能对于鉴定无肾穿刺结果的肾脏局限的ESKD患者的病因具有重要作用。