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. 2013 Aug 21;310(7):714-21.
doi: 10.1001/jama.2013.242978.

Plasma Lipids, Genetic Variants Near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis

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Plasma Lipids, Genetic Variants Near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis

Bjarke Feenstra et al. JAMA. .
Free PMC article


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.

Conflict of interest statement

Conflict of Interest Disclosures: Statens Serum Institut has filed a priority patent application at the Danish Patent and Trademark Office on the use of genetic profiling to identify newborns at risk of IHPS, which contains subject matter drawn from the work also published here. Dr Feenstra, Mr Geller, and Dr Melbye are listed on the patent application. No other potential conflict of interest relevant to this article was reported.


Figure 1
Figure 1. Forest plot
Discovery stage, validation stage, and combined results for the most significant SNP at each of the four genomewide significant IHPS loci.
Figure 2
Figure 2. Regional association plot showing imputed SNP results for the novel IHPS locus on chromosome 11q23.3
SNPs are plotted by chromosomal location (x axis) and association with IHPS (−log10 P value; y axis). The colours reflect the linkage disequilibrium of each SNP with rs12721025 (based on pairwise r2 values from the 1000 genomes project; red, r2>0.8; orange, 0.6<r2<0.8; green, 0.4<r2<0.6; light blue, 0.2<r2<0.4; purple, r2<0.2; grey, r2 data not available). Estimated recombination rates (from HapMap) are plotted to reflect the local LD structure. Genes are indicated in the lower panel of the plot. The figure was generated using LocusZoom (

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