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Plasma Lipids, Genetic Variants near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis
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Aug 21 2013
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Source: JAMA. 310(7):714-721.
[PDF-455.54 KB]
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Alternative Title:JAMA
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Description:Importance
Infantile Hypertrophic Pyloric Stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. IHPS 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 three independent sample sets.
Design, Setting, and Participants
In stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide dataset of 1001 Danish surgery-confirmed cases (diagnosed between 1987–2008) and 2371 disease-free controls. In stage 2, the five most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed between 1983–2010), Sweden (cases diagnosed between 1958–2011), and the United States (cases diagnosed between 1998–2005) with a total of 1663 cases and 2315 controls.
Main Outcome Measure
Presence of Infantile Hypertrophic Pyloric Stenosis
Results
We found a new genomewide significant locus for IHPS at chromosome 11q23.3. The most significant SNP at the locus, rs12721025 (odds ratio [OR], 1.59; 95% confidence interval [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 conferred increased risk of IHPS.
Conclusions and Relevance
We have identified a new genomewide 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.
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Pubmed ID:23989729
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Pubmed Central ID:PMC4031654
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