Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Nat Genet. 2011 Jan;43(1):48-50. doi: 10.1038/ng.721. Epub 2010 Nov 28.
Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase κ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 × 10⁻¹¹ and OR = 2.3, P = 2.9 × 10⁻⁹, respectively) and in the Dutch (OR = 3.9, P = 2.4 × 10⁻⁵ and OR = 3.8, P = 3.4 × 10⁻⁵) and Swedish (OR = 2.5, P = 2.6 × 10⁻⁸ and OR = 2.2, P = 2.7 × 10⁻⁶) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias.
尿道下裂是男性外生殖器的一种常见先天畸形。我们使用来自 436 名尿道下裂（病例）和 494 名欧洲血统对照的合并 DNA 进行了全基因组关联研究，并在发现样本中对选择的最高排名 SNP 进行了个体基因分型，该发现样本包括 133 名病例及其父母的荷兰额外样本和 266 名病例和 402 名对照的瑞典系列。在编码二酰基甘油激酶 κ 的 DGKK 中的两个 SNP(rs1934179 和 rs7063116) 的个体基因分型，在发现样本中产生了与尿道下裂关联的令人信服的证据（等位基因特异性优势比 (OR) = 2.5，P = 2.5 × 10⁻¹¹ 和 OR = 2.3，P = 2.9 × 10⁻⁹，分别）和在荷兰（OR = 3.9，P = 2.4 × 10⁻⁵ 和 OR = 3.8，P = 3.4 × 10⁻⁵）和瑞典（OR = 2.5，P = 2.6 × 10⁻⁸ 和 OR = 2.2，P = 2.7 × 10⁻⁶）复制样本中。表达研究表明，DGKK 在病例和对照的包皮组织中有表达，携带 rs1934179 风险等位基因的携带者表达水平较低（P = 0.047）。我们提出 DGKK 是尿道下裂的主要风险基因。
