title: Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis.
abstract: OBJECTIVE
  Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited.
  
  
  OBJECTIVE
  To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets.
  
  
  METHODS
  During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls.
  
  
  METHODS
  Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis.
  
  
  RESULTS
  We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 × 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS.
  
  
  CONCLUSIONS
  This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation.
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. fee@ssi.dk
authors.forename: Bjarke
authors.initials: B
authors.lastname: Feenstra
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Carstensen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
authors.forename: Izabella Baranowska
authors.initials: IB
authors.lastname: Körberg
authors.forename: Bruce
authors.initials: B
authors.lastname: Bedell
authors.forename: Camilla
authors.initials: C
authors.lastname: Krogh
authors.forename: Ruzong
authors.initials: R
authors.lastname: Fan
authors.forename: Anna
authors.initials: A
authors.lastname: Svenningsson
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
mesh_terms: D016632:Apolipoprotein A-I / Q000235:genetics; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood*; D003718:Denmark / Q000453:epidemiology; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D046248:Pyloric Stenosis, Hypertrophic / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D012306:Risk; D013548:Sweden / Q000453:epidemiology
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D002784:Cholesterol