Genetic and epidemiological studies of infantile hypertrophic pyloric stenosis

Abstract: Infantile Hypertrophic Pyloric Stenosis (IHPS) is a condition of early infancy characterized by thickening of the pyloric muscle resulting in obstruction of gastric outflow. It affects 1-3/1000 live births and is one of the most common causes of gastrointestinal obstruction in infants. IHPS is developed under influence of both genetic and environmental factors, but the exact pathogenesis is unknown. The aim of this thesis was to elucidate genetic and environmental factors contributing to development of IHPS. In study I and II we used a candidate gene approach to study association of two different genes with potential involvement in pathogenesis of IHPS. Since treatment with the motilin agonist erythromycin gives an increased risk for IHPS, we proposed the GI-hormon motilin as an IHPS candidate gene (study I). Sequencing of the MLN coding exons revealed three previously not reported sequence variants occurring in both cases and controls, though without obvious association to the disease. In addition, no significant association was found between the rs2281820 (p.Val15Ala) polymorphism and IHPS. Neuronal nitric oxide synthase encoded of NOS1 is key player in the pathway mediating pyloric relaxation, and is suggested as a IHPS susceptibility gene. A functional NOS1C promoter polymorphism (c.-84G>A; rs41279104) regulating expression of the gene was genotyped in cases and controls (study II). We could not confirm a previously reported association of the A-allele with IHPS in our material. In study III we used an unbiased strategy, genome wide linkage analysis, to search for chromosomal regions harboring candidate genes. 37 Swedish IHPS families were analysed in an initial genome wide scan revealing seven regions of interest for fine mapping. Fine mapping using a statistical model with equal weight to all families identified significant linkage to 2q24.3, and suggestive linkage to 7p22.2 and 12q24.23. The statistical model using a weighting scheme to compensate for different pedigree structures identified significant linkage to 2q24.3 and 7p21.3, and suggestive linkage to 6p21.31. Interestingly, these candidate regions harbor the previously suggested candidate genes MLN and NOS1. Two novel proposed candidate genes, NPY and GCG, were sequenced without obvious pathological findings. Extending the material with additional 31 British IHPS families in the fine mapped regions did not enhance the NPL score. In study IV we performed a nationwide register study based on all IHPS cases in Sweden 1973- 2008, yielding a study cohort of 3608 cases and 17588 matched controls. Incidence fell from 2.25 to 0.43/1000 between years 1988-1998 with a relatively constant sex ratio of 5:1 boys to girls. Study variables associated with an increased risk for IHPS in our material were caesarian delivery, prematurity, neonatal jaundice and being first born. Maternal smoking, low maternal age and Nordic ethnicity were also associated with increased IHPS risk. Maternal smoking and low birth rank were stronger risk factors during period with low incidence. Prematurity was a stronger risk factor when analysis was stratified for late onset of disease. In summary we have identified candidate gene regions on chromosome 2, 6, 7 and 12 and identified several epidemiological risk factors for IHPS