Plasma Lipids, Genetic Variants Near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis | Congenital Defects | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Mitchell  LE, Risch  N.  The genetics of infantile hypertrophic pyloric stenosis: a reanalysis.  Am J Dis Child. 1993;147(11):1203-1211.PubMedGoogle Scholar
Krogh  C, Fischer  TK, Skotte  L,  et al.  Familial aggregation and heritability of pyloric stenosis.  JAMA. 2010;303(23):2393-2399.PubMedGoogle ScholarCrossref
Schechter  R, Torfs  CP, Bateson  TF.  The epidemiology of infantile hypertrophic pyloric stenosis.  Paediatr Perinat Epidemiol. 1997;11(4):407-427.PubMedGoogle ScholarCrossref
Ranells  JD, Carver  JD, Kirby  RS.  Infantile hypertrophic pyloric stenosis: epidemiology, genetics, and clinical update.  Adv Pediatr. 2011;58(1):195-206.PubMedGoogle ScholarCrossref
Honein  MA, Paulozzi  LJ, Himelright  IM,  et al.  Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin: a case review and cohort study.  Lancet. 1999;354(9196):2101-2105.PubMedGoogle ScholarCrossref
Pisacane  A, de Luca  U, Criscuolo  L,  et al.  Breast feeding and hypertrophic pyloric stenosis: population based case-control study.  BMJ. 1996;312(7033):745-746.PubMedGoogle ScholarCrossref
Krogh  C, Biggar  RJ, Fischer  TK, Lindholm  M, Wohlfahrt  J, Melbye  M.  Bottle-feeding and the risk of pyloric stenosis.  Pediatrics. 2012;130(4):e943-e949.PubMedGoogle ScholarCrossref
Pedersen  RN, Garne  E, Loane  M, Korsholm  L, Husby  S; EUROCAT Working Group.  Infantile hypertrophic pyloric stenosis: a comparative study of incidence and other epidemiological characteristics in seven European regions.  J Matern Fetal Neonatal Med. 2008;21(9):599-604.PubMedGoogle ScholarCrossref
Peeters  B, Benninga  MA, Hennekam  RC.  Infantile hypertrophic pyloric stenosis: genetics and syndromes.  Nat Rev Gastroenterol Hepatol. 2012;9(11):646-660.PubMedGoogle ScholarCrossref
Kelley  RI, Hennekam  RC.  The Smith-Lemli-Opitz syndrome.  J Med Genet. 2000;37(5):321-335.PubMedGoogle ScholarCrossref
Svenningsson  A, Lagerstedt  K, Omrani  MD, Nordenskjöld  A.  Absence of motilin gene mutations in infantile hypertrophic pyloric stenosis.  J Pediatr Surg. 2008;43(3):443-446.PubMedGoogle ScholarCrossref
Lagerstedt-Robinson  K, Svenningsson  A, Nordenskjöld  A.  No association between a promoter NOS1 polymorphism (rs41279104) and infantile hypertrophic pyloric stenosis.  J Hum Genet. 2009;54(12):706-708.PubMedGoogle ScholarCrossref
Saur  D, Vanderwinden  JM, Seidler  B, Schmid  RM, De Laet  MH, Allescher  HD.  Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis.  Proc Natl Acad Sci U S A. 2004;101(6):1662-1667.PubMedGoogle ScholarCrossref
Feenstra  B, Geller  F, Krogh  C,  et al.  Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis.  Nat Genet. 2012;44(3):334-337.PubMedGoogle ScholarCrossref
Olsen  J, Melbye  M, Olsen  SF,  et al.  The Danish National Birth Cohort: its background, structure and aim.  Scand J Public Health. 2001;29(4):300-307.PubMedGoogle ScholarCrossref
Abecasis  GR, Altshuler  D, Auton  A,  et al; 1000 Genomes Project Consortium.  A map of human genome variation from population-scale sequencing.  Nature. 2010;467(7319):1061-1073.PubMedGoogle ScholarCrossref
Devlin  B, Roeder  K.  Genomic control for association studies.  Biometrics. 1999;55(4):997-1004.PubMedGoogle ScholarCrossref
Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis.  Stat Med. 2002;21(11):1539-1558.PubMedGoogle ScholarCrossref
Magi  R, Lindgren  CM, Morris  AP.  Meta-analysis of sex-specific genome-wide association studies.  Genet Epidemiol. 2010;34(8):846-853.PubMedGoogle ScholarCrossref
Purcell  S, Neale  B, Todd-Brown  K,  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses.  Am J Hum Genet. 2007;81(3):559-575.PubMedGoogle ScholarCrossref
Delaneau  O, Marchini  J, Zagury  JF.  A linear complexity phasing method for thousands of genomes.  Nat Methods. 2012;9(2):179-181.PubMedGoogle ScholarCrossref
Howie  BN, Donnelly  P, Marchini  J.  A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.  PLoS Genet. 2009;5(6):e1000529.PubMedGoogle ScholarCrossref
Marchini  J, Howie  B.  Genotype imputation for genome-wide association studies.  Nat Rev Genet. 2010;11(7):499-511.PubMedGoogle ScholarCrossref
Willer  CJ, Li  Y, Abecasis  GR.  METAL: fast and efficient meta-analysis of genomewide association scans.  Bioinformatics. 2010;26(17):2190-2191.PubMedGoogle ScholarCrossref
Teslovich  TM, Musunuru  K, Smith  AV,  et al.  Biological, clinical and population relevance of 95 loci for blood lipids.  Nature. 2010;466(7307):707-713.PubMedGoogle ScholarCrossref
WikiGWA: an open platform for collecting and using genome-wide association results. Accessed July 26, 2013.
Catalog of published genome-wide association studies. National Human Genome Research Institute. Accessed July 26, 2013.
eQTL resources at the Pritchard lab. Accessed July 26, 2013.
UCSC genome browser. Accessed July 26, 2013.
Ryan  AK, Bartlett  K, Clayton  P,  et al.  Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype.  J Med Genet. 1998;35(7):558-565.PubMedGoogle ScholarCrossref
Hennekam  RC, Waterham  HR, Wanders  RJ, Aronson  DC.  No cholesterol metabolism anomalies detectable in infants with hypertrophic pyloric stenosis.  Am J Med Genet. 2001;99(3):256-257.PubMedGoogle ScholarCrossref
Carlson  LA, Hardell  LI.  Sex differences in serum lipids and lipoproteins at birth.  Eur J Clin Invest. 1977;7(2):133-135.PubMedGoogle ScholarCrossref
Owen  CG, Whincup  PH, Odoki  K, Gilg  JA, Cook  DG.  Infant feeding and blood cholesterol: a study in adolescents and a systematic review.  Pediatrics. 2002;110(3):597-608.PubMedGoogle ScholarCrossref
Nielsen  JP, Haahr  P, Haahr  J.  Infantile hypertrophic pyloric stenosis: decreasing incidence.  Dan Med Bull. 2000;47(3):223-225.PubMedGoogle Scholar
Persson  S, Ekbom  A, Granath  F, Nordenskjöld  A.  Parallel incidences of sudden infant death syndrome and infantile hypertrophic pyloric stenosis: a common cause?  Pediatrics. 2001;108(4):E70.PubMedGoogle ScholarCrossref
Sommerfield  T, Chalmers  J, Youngson  G, Heeley  C, Fleming  M, Thomson  G.  The changing epidemiology of infantile hypertrophic pyloric stenosis in Scotland.  Arch Dis Child. 2008;93(12):1007-1011.PubMedGoogle ScholarCrossref
de Laffolie  J, Turial  S, Heckmann  M, Zimmer  KP, Schier  F.  Decline in infantile hypertrophic pyloric stenosis in Germany in 2000-2008.  Pediatrics. 2012;129(4):e901-e906.PubMedGoogle ScholarCrossref
Yngve  A, Sjöström  M.  Breastfeeding in countries of the European Union and EFTA: current and proposed recommendations, rationale, prevalence, duration and trends.  Public Health Nutr. 2001;4(2B):631-645.PubMedGoogle Scholar
Mauch  DH, Nägler  K, Schumacher  S,  et al.  CNS synaptogenesis promoted by glia-derived cholesterol.  Science. 2001;294(5545):1354-1357.PubMedGoogle ScholarCrossref
Fan  QW, Yu  W, Gong  JS,  et al.  Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons.  J Neurochem. 2002;80(1):178-190.PubMedGoogle ScholarCrossref
Fünfschilling  U, Jockusch  WJ, Sivakumar  N,  et al.  Critical time window of neuronal cholesterol synthesis during neurite outgrowth.  J Neurosci. 2012;32(22):7632-7645.PubMedGoogle ScholarCrossref
Langer  JC, Berezin  I, Daniel  EE.  Hypertrophic pyloric stenosis: ultrastructural abnormalities of enteric nerves and the interstitial cells of Cajal.  J Pediatr Surg. 1995;30(11):1535-1543.PubMedGoogle ScholarCrossref
Vanderwinden  JM, Liu  H, De Laet  MH, Vanderhaeghen  JJ.  Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis.  Gastroenterology. 1996;111(2):279-288.PubMedGoogle ScholarCrossref
Piotrowska  AP, Solari  V, Puri  P.  Distribution of heme oxygenase-2 in nerves and interstitial cells of Cajal in the normal pylorus and in infantile hypertrophic pyloric stenosis.  Arch Pathol Lab Med. 2003;127(9):1182-1186.PubMedGoogle Scholar
Cirulli  ET, Goldstein  DB.  Uncovering the roles of rare variants in common disease through whole-genome sequencing.  Nat Rev Genet. 2010;11(6):415-425.PubMedGoogle ScholarCrossref
Original Investigation
August 21, 2013

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

Author Affiliations
  • 1Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  • 2Department of Epidemiology, University of Iowa, Iowa City
  • 3Department of Women’s and Children’s Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  • 4Department of Pediatrics, University of Iowa, Iowa City
  • 5Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Heath, Bethesda, Maryland
  • 6Wadsworth Center, New York State Department of Health, Albany
JAMA. 2013;310(7):714-721. doi:10.1001/jama.2013.242978

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.