David H. Murdoch Research Institute, Kannapolis, NC, USA.
Am J Nephrol. 2012;36(3):252-60. doi: 10.1159/000342205. Epub 2012 Sep 4.
African-Americans (AAs) are predisposed to non-diabetic (non-DM) end-stage renal disease (ESRD), and studies have shown a genetic component to this risk. Rare mutations in ACTN4 (α-actinin-4), an actin-binding protein expressed in podocytes, cause familial focal segmental glomerulosclerosis.
We assessed the contribution of coding variants in ACTN4 to non-DM ESRD risk in AAs. Nineteen exons, 2,800 bases of the promoter and 392 bases of the 3' untranslated region of ACTN4 were sequenced in 96 AA non-DM ESRD cases and 96 non-nephropathy controls (384 chromosomes). Sixty-seven single-nucleotide polymorphisms (SNPs) including 51 novel SNPs were identified. The SNPs comprised 33 intronic, 21 promoter, 12 exonic, and one 3' variant. Sixty-two of the SNPs were genotyped in 296 AA non-DM ESRD cases and 358 non-nephropathy controls.
One SNP, rs10404257, was associated with non-DM ESRD (p < 1.0E-4, odds ratio, OR = 0.76; confidence interval, CI = 0.59-0.98; additive model). Forty-seven SNPs had minor allele frequencies <5%. These SNPs were segregated into risk and protective SNPs, and each category was collapsed into a single marker, designated by the presence or absence of any rare allele. The presence of any rare allele at a risk SNP was significantly associated with non-DM ESRD (p = 0.001, dominant model). The SNPs with the strongest evidence for association (n = 20) were genotyped in an independent set of 467 non-DM ESRD cases and 279 controls. Although rs10404257 was not associated in this replication sample, when the samples were combined, rs10404257 was modestly associated (p = 0.032, OR = 0.78, CI = 0.63-0.98; dominant model). SNPs were tested for interaction with markers in the APOL1 gene, previously associated with non-DM ESRD in AAs, and rs10404257 was modestly associated (p = 0.0261, additive model).
This detailed evaluation of ACTN4 variation revealed limited evidence of association with non-DM ESRD in AAs.
非裔美国人（非裔美国人）易患非糖尿病（非 DM）终末期肾病（ESRD），研究表明这种风险与遗传因素有关。在足细胞中表达的肌动蛋白结合蛋白 ACTN4（α-肌动蛋白-4）的罕见突变导致家族性局灶节段性肾小球硬化症。
我们评估了 ACTN4 编码变异在非裔美国人中非 DM ESRD 风险中的作用。在 96 例非 DM ESRD 病例和 96 例非肾病对照（384 条染色体）中，对 ACTN4 的 19 个外显子、2800 个碱基的启动子和 392 个碱基的 3'非翻译区进行了测序。确定了 67 个单核苷酸多态性（SNP），包括 51 个新 SNP。SNP 包括 33 个内含子、21 个启动子、12 个外显子和 1 个 3'变体。在 296 例非 DM ESRD 病例和 358 例非肾病对照中，62 个 SNP 进行了基因分型。
一个 SNP，rs10404257，与非 DM ESRD 相关（p < 1.0E-4，优势比，OR = 0.76；置信区间，CI = 0.59-0.98；加性模型）。47 个 SNP 的次要等位基因频率<5%。这些 SNP 被分离成风险和保护 SNP，每个类别都被折叠成一个单一的标记，标记为是否存在稀有等位基因。在风险 SNP 中存在任何稀有等位基因与非 DM ESRD 显著相关（p = 0.001，显性模型）。与关联最强的证据（n = 20）的 SNP 在独立的 467 例非 DM ESRD 病例和 279 例对照中进行了基因分型。虽然在这个复制样本中 rs10404257 没有关联，但当样本合并时，rs10404257 与非 DM ESRD 呈中度关联（p = 0.032，OR = 0.78，CI = 0.63-0.98；显性模型）。对与 APOL1 基因中先前与非 DM ESRD 相关的标记的 SNP 进行了相互作用测试，rs10404257 呈中度关联（p = 0.0261，加性模型）。
这项对 ACTN4 变异的详细评估表明，ACTN4 变异与非 DM ESRD 在非裔美国人中关联的证据有限。
