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Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis
Journal article   Open access   Peer reviewed

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

Bjarke Feenstra, Frank Geller, Lisbeth Carstensen, Paul A Romitti, Izabella Baranowska Körberg, Bruce Bedell, Camilla Krogh, Ruzong Fan, Anna Svenningsson, Michele Caggana, …
JAMA : the journal of the American Medical Association, Vol.310(7), pp.714-721
08/21/2013
DOI: 10.1001/jama.2013.242978
PMCID: PMC4031654
PMID: 23989729
url
https://doi.org/10.1001/jama.2013.242978View
Published (Version of record) Open Access

Abstract

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. To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. 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. Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis. 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. 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.
 Genome-Wide Association Study Pyloric Stenosis, Hypertrophic - genetics Cholesterol - blood Humans Genotype Infant Male Risk Sweden - epidemiology Case-Control Studies Apolipoprotein A-I - genetics Pyloric Stenosis, Hypertrophic - blood Denmark - epidemiology Female Infant, Newborn, Diseases - genetics Pyloric Stenosis, Hypertrophic - epidemiology Polymorphism, Single Nucleotide Odds Ratio Infant, Newborn

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