Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population

Abstract

PURPOSE-A recent genome-wide association study reported the novel finding that variants in diacylglycerol kinase kappa (DGKK) were associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially-ethnically diverse study population of California births and to provide a more comprehensive investigation of variants. METHODS-We examined the association of 27 DGKK SNPs with hypospadias, relative to population-based non-malformed controls born in selected California counties from 1990-2003. Analyses included a maximum of 928 controls and 665 cases (91 mild, 336 moderate, 221 severe, 17 undetermined). Results for mild and moderate cases were similar so they were grouped together.RESULTS-For mild and moderate cases, odds ratios (OR) for 15 of the 27 SNPs had p-values <0.05; two were <1, and the others ranged from 1.3 to 1.8. Among severe cases, ORs tended to be closer to one and none of the p-values were <0.05. Due to high LD across the SNPs, haplotype analyses were conducted, and two blocks were generated. These analyses identified a set of eight variants that was associated with a three-to four-fold increased risk, relative to the most common haplotype, regardless of severity of the phenotype (the OR was 4.1, p<10 -4 for mild to moderate cases and 3.3, p=0.001 for severe cases).CONCLUSIONS-This study confirms that DGKK variants are associated with hypospadias. Further studies are needed to enable a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.

The Genetic and Environmental Factors Underlying Hypospadias

“…In mice, Dgkk is expressed in the differentiating squamous epithelial cells of the urethral plate/groove and the epidermis during development [Shen et al, 2015]. While little is known about the function of this gene during this time, in humans there is a strong association between DGKK and hypospadias risk [van der Zanden et al, 2011; Carmichael et al, 2013b]. Individual genotyping of 2 SNPs in DGKK showed strong association in various European groups [van der Zanden et al, 2011] (table 2), and expression of DGKK in preputial tissues is significantly lower in carriers of the risk allele [van der Zanden et al, 2011].…”

In vitrofunctional characterization of the novelDHHmutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis

“…Additional VUS in MAMLD1 and DGKK were identified in patient 2. Both genes are located on chromosome X and mutations in MAMLD1 or SNPs in DGKK are associated with hypospadias (Carmichael et al., ; Fukami et al., ; Ogata, Sano, Nagata, Kato, & Fukami, ; Ogata, Wada, & Fukami, ; van der Zanden et al., ; van der Zanden et al., ; Xie et al., ). However, their contribution to the hypospadias phenotype of patient 2 is unclear.…”

This Month in Pediatric Urology

“…Carmichael et al (page 305) from California continue to study possible clues as to what causes hypospadias using genome-wide association studies. 3 The strategy behind genome-wide association studies is to examine common genetic variants, such as single nucleotide polymorphism, in individual patients to see if these variants are associated with a specific disease. The objective of this study was to replicate a prior large homogeneous, genomewide study of the association between diacylglycerol kinase kappa (DGKK) and hypospadias in a racially ethnic diverse population of children born in California.…”