Wake Forest School of Medicine, Winston-Salem, NC, USA.
Am J Kidney Dis. 2012 Feb;59(2):210-21. doi: 10.1053/j.ajkd.2011.09.020. Epub 2011 Nov 25.
African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.
Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.
SETTING & PARTICIPANTS: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls.
Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes.
APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1.
The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001).
Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy.
This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.
与欧洲裔美国人相比，非裔美国人易患非糖尿病性肾病。
对非裔美国透析患者中非糖尿病性肾病的全基因组关联研究（GWAS）进行随访；新的基因-基因相互作用分析。
维克森林样本：962 名非裔美国非糖尿病性肾病病例，931 名非肾病对照。复制样本：668 个家族性肾病和糖尿病研究（FIND）非裔美国非糖尿病性肾病病例，804 名非肾病对照。
对前 1420 个全基因组关联研究相关的单核苷酸多态性（SNP）和 6 个肾病易感性基因中的 54 个 SNP 进行个体基因分型。
APOL1 遗传关联和与 APOL1 相互作用或独立作用的其他候选易感性基因座。
最强的 GWAS 关联包括 2 个非编码 APOL1 SNP，rs2239785（OR，0.33；显性；P = 5.9×10(-24)）和 rs136148（OR，0.54；加性；P = 1.1×10(-7)），在 FIND 中有复制（P = 5.0×10(-21)和 1.9×10(-05)）。rs2239785 在控制 APOL1 G1 和 G2 编码变体后仍显著相关。其他顶级命中包括 CFH SNP（meta 分析中 3367 名非裔美国病例和对照的 OR，0.81；加性；P = 6.8×10(-4)）。对 1420 个 SNP 进行了与 APOL1 G1 和 G2 变体的相互作用测试。检测到几个具有交互作用的 SNP，最显著的是足细胞基因（NPHS2）中的 rs16854341（P = 0.0001）。
非裔美国非糖尿病性肾病患者未进行非聚合 GWAS。
本研究对全基因组关联研究的随访提供了额外的独立证据，表明 APOL1 变体与非裔美国人的非糖尿病性肾病有关，并确定了其他相关和相互作用的非糖尿病性肾病易感性基因。
