TY - JOUR

T1 - Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis

AU - Feenstra, Bjarke

AU - Geller, Frank

AU - Carstensen, Lisbeth

AU - Romitti, Paul A.

AU - Körberg, Izabella Baranowska

AU - Bedell, Bruce

AU - Krogh, Camilla

AU - Fan, Ruzong

AU - Svenningsson, Anna

AU - Caggana, Michele

AU - Nordenskjöld, Agneta

AU - Mills, James L.

AU - Murray, Jeffrey C.

AU - Melbye, Mads

PY - 2013/8/21

Y1 - 2013/8/21

N2 - IMPORTANCE: 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. OBJECTIVES: To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

AB - IMPORTANCE: 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. OBJECTIVES: To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

UR - http://www.scopus.com/inward/record.url?scp=84883003114&partnerID=8YFLogxK

U2 - 10.1001/jama.2013.242978

DO - 10.1001/jama.2013.242978

M3 - Journal article

C2 - 23989729

AN - SCOPUS:84883003114

VL - 310

SP - 714

EP - 721

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0098-7484

IS - 7

ER -