Integrating genetics with newborn metabolomics in infantile hypertrophic pyloric stenosis

Abstract

ABSTRACTBackgroundInfantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter smooth muscle. Building on a previously reported association between IHPS and lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-centric targeted metabolites in newborns, and (2) address causality of the associations by integrating genetic data.MethodsDried blood spots were taken from 267 pairs of IHPS cases and controls matched by sex and day of birth. A mixed effects linear regression model was used to evaluate associations between Biocrates p400 Kit selected 148 metabolites and IHPS in a matched case-control design.ResultsSeven metabolites showed significantly lower levels in IHPS cases. Levels of the top associated metabolite, phosphatidylcholine PC(38:4), were significantly correlated with levels of the remaining six metabolites (P<2.30 ⨯ 10−12). Associations were driven by case-control pairs with older age at sampling. IHPS cases had more diagnoses for neonatal difficulty in feeding at breast (P = 6.15 ⨯ 10−3). Genetic variants explaining a large proportion of variance in the levels of PC(38:4) did not associate with IHPS.ConclusionsWe detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.Key points–Our previous GWAS of IHPS identified genetic associations between lipid metabolism and IHPS.–Building on that finding, this study investigated associations between a wide array of lipid-centric metabolites in newborns and IHPS.–Newborns who later developed IHPS had lower levels of certain metabolites. The associations were driven by individuals born at a later age at sampling, suggesting different feeding patterns after birth.