title: Diacylglycerol kinase K variants impact hypospadias in a California study population.
abstract: OBJECTIVE
  A recent genome wide association study demonstrated the novel finding that variants in DGKK are 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 single nucleotide polymorphisms with hypospadias relative to population based nonmalformed controls born in selected California counties from 1990 to 2003. Analyses included a maximum of 928 controls and 665 cases (mild in 91, moderate in 336, severe in 221 and undetermined in 17). Results for mild and moderate cases were similar, so they were grouped together.
  
  
  RESULTS
  For mild and moderate cases OR for 15 of the 27 single nucleotide polymorphisms had p values less than 0.05, with 2 less than 1 and the others ranging from 1.3 to 1.8. Among severe cases ORs tended to be closer to 1, and none of the p values were less than 0.05. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and 2 blocks were generated. These analyses identified a set of 8 variants associated with a threefold to fourfold increased risk relative to the most common haplotype, regardless of severity of the phenotype (OR 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. Additional studies are needed to allow a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California 94305-5415, USA. scarmichael@stanford.edu
authors.forename: Suzan L
authors.initials: SL
authors.lastname: Carmichael
authors.forename: Nebil
authors.initials: N
authors.lastname: Mohammed
authors.forename: Chen
authors.initials: C
authors.lastname: Ma
authors.forename: Dave
authors.initials: D
authors.lastname: Iovannisci
authors.forename: Shweta
authors.initials: S
authors.lastname: Choudhry
authors.forename: Larry S
authors.initials: LS
authors.lastname: Baskin
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
mesh_terms: D002140:California; D016022:Case-Control Studies; D019852:Diacylglycerol Kinase / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D019852:Diacylglycerol Kinase