OBJECTIVETo investigate the role of single nucleotide polymorphisms of the gene of diacylglycerol kinase κ (DGKK) in hypospadias in Chinese children.

METHODSWe performed direct sequencing on 2 hypospadias-related candidate single nucleotide polymorphisms of the DGKK gene (rs1934179 and rs7063116, never previously reported in the Chinese population) from 300 children with sporadic hypospadias and 200 healthy controls, and compared the results between the two groups.

RESULTSThe mutation frequencies of rs1934179 and rs7063116 were 5.0% (15/300) and 5.67% (17/300) respectively in the hypospadias patients, significantly higher than 1.5% (3/200) and 2.0% (4/200) in the normal controls (P <0.05). The mutation frequencies of rs1934179 and rs7063116 in the cases of distal and middle hypospadias were also remarkably higher (6.5%, [13/200] and 7.5% [15/200], P <0.05), but those in the proximal cases (both 2.0% [2/100]) showed no statistically significant difference from the control (P >0.05).

CONCLUSIONThe polymorphisms of the DGKK gene may be associated with hypospadias, particularly distal and middle hypospadias, in Chinese children.

Asian Continental Ancestry Group ; Case-Control Studies ; Child ; China ; Diacylglycerol Kinase ; genetics ; Humans ; Hypospadias ; enzymology ; genetics ; Male ; Polymorphism, Single Nucleotide

Previous genome-wide association studies have identified variants in the diacylglycerol kinase kappa (DGKK) gene associated with hypospadias in populations of European descent. However, no variants of DGKK were confirmed to be associated with hypospadias in a recent Han Chinese study population, likely due to the limited number of single-nucleotide polymorphisms (SNPs) included in the analysis. In this study, we aimed to address the inconsistent results and evaluate the association between DGKK and hypospadias in the Han Chinese population through a more comprehensive analysis of DGKK variants. We conducted association analyses for 17 SNPs in or downstream of DGKK with hypospadias among 322 cases (58 mild, 113 moderate, 128 severe, and 23 unknown) and 1008 controls. Five SNPs (rs2211122, rs4554617, rs7058226, rs7063116, and rs5915254) in DGKK were significantly associated with hypospadias (P < 0.05), with odds ratios (ORs) of 1.64-1.76. When only mild and moderate cases were compared to controls, 10 SNPs in DGKK were significant (P < 0.05), with ORs of 1.56-2.13. No significant SNP was observed when only severe cases were compared to controls. This study successfully implicated DGKK variants in hypospadias risk among a Han Chinese population, especially for mild/moderate cases. Severe forms of hypospadias are likely due to other genetic factors.
Asian People ; Case-Control Studies ; Child ; China/epidemiology* ; Diacylglycerol Kinase/genetics* ; Genetic Predisposition to Disease/genetics* ; Genetic Variation/genetics* ; Genome-Wide Association Study ; Haplotypes ; Humans ; Hypospadias/genetics* ; Linkage Disequilibrium ; Male ; Polymorphism, Single Nucleotide/genetics* ; Risk Assessment