Low serum lipids are a risk factor for infantile hypertrophic pyloric stenosis (IHPS), according to a genetics study published in the August 20 issue of JAMA.
A Multifactorial Condition
Heritability exceeds 80% for IHPS, but little is known about specific genetic contributions to risk. Bjarke Feenstra, PhD, from the Statens Serum Institute in Copenhagen, Denmark, and colleagues scrutinized 4 independent sets of samples to identify genetic loci associated with increased risk for IHPS.
"[IHPS] is thought to result from both genetic and environmental factors. There is well-known increased risk in families of affected infants," Barbara Kaplan, MD, a pediatric gastroenterologist at the Cleveland Clinic in Ohio, told Medscape Medical News.
IHPS is 150 times more prevalent among children with Smith-Lemli-Opitz syndrome, who have low serum cholesterol from birth. The apparent protective effect of female sex and lower risk in breast-fed infants also support etiology in cholesterol metabolism.
Identifying Single Nucleotide Polymorphisms (SNPs)
In the current study, Dr. Feenstra and colleagues examined genetic risks in nonsyndromic IHPS. In the first step of the study, a discovery phase, the researchers analyzed 1001 blood spot samples from the Danish National Biobank from infants with IHPS but no other anomalies and from blood spots or buffy coats from 2371 control infants, using haplotype and SNP data gleaned from the 1000 Genomes Project.
In the second step of the project, the validation phase, the investigators retested the 5 most significant SNPs identified in the discovery phase in 3 independent case-control sample sets from Denmark, Sweden, and the United States, totaling 1663 cases and 2315 controls.
The US cases came from blood spots stored at the New York State Department of Health. The Swedish cases came from pediatric surgery clinics, and the control participants were healthy, middle-aged anonymous blood donors; healthy infants; and unaffected relatives of patients with IHPS.
A Marker of APOA1
The most strongly associated SNP was rs12721025 (odds ratio, 1.59; 95% confidence interval [CI], 1.38-1.83; P = 1.9 × 10−10) on the long arm of chromosome 11. The SNP is 301 bases downstream of the apolipoprotein A-I (APOA1) gene. APOA1 protein is the primary component of high-density lipoprotein.
The finding is consistent with previously identified SNPs, including 3 from this research group, associated with lowered levels of circulating cholesterol. However, they account for a very small proportion of the variability seen among nonfamilial cases of IHPS.
To begin to assess the biological importance of the lipid metabolism in IHPS, the researchers performed a follow-up study in which they compared the levels of total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides in plasma obtained prospectively from 46 IHPS cases and 189 control patients from the Danish National Birth Cohort from umbilical cord blood. Case patients and control patients were matched for sex and gestational age at birth.
They found that mean total cholesterol levels for 46 cases and 189 matching controls were 65.2 mg/dL (95% CI, 58.7 - 71.8) and 75.2 mg/dL (95% CI, 72.0 - 78.5), respectively. The risk for IHPS was inversely and significantly associated with total cholesterol level, with an odds ratio of 0.77 per 10 mg/dL (95% CI, 0.64 - 0.92; P = .005).
The researchers hypothesize that patients have poor innervation in the muscle tissue of the pyloric sphincter that perhaps reflects a requirement of cholesterol for neurological development. Further research is required to evaluate the role of inherited factors among possible nongenetic causes of IHPS, including reaction to erythromycin and feeding practices.
A limitation of the study is that the predominant SNP is closely linked to APOA1 but also to other genes. In addition, the study does not establish causality and measured lipids at an age before pyloric stenosis would produce initial symptoms.
"This exciting finding at the genome-wide level and its phenotypic confirmation with a prospective case-control study hints at a novel inverse relationship between levels of circulating cholesterol in neonates and this significant infant gastric morbidity, IHPS. If future studies confirm this inverse relationship, prenatal screening may heighten vigilance in children who harbor this SNP and potentially translate to more timely surgical attention," Rohit Kohli, MD, a gastroenterologist at Cincinnati Children's Hospital in Ohio, told Medscape Medical News. He added that establishing biologic causality may reveal targets for nonsurgical interventions.
"This study may be helpful in broadening our understanding of potential pathogenic pathways in the development of infantile pyloric stenosis. However, these findings are preliminary, and clinical relevance and application requires further investigation," added Dr. Kaplan.
Dr. Feenstra and 2 coauthors have filed a patent for developing a diagnostic based on the work reported here. The other authors and commentators have disclosed no relevant financial relationships.
JAMA. 2013;310:714-721. Abstract
Medscape Medical News © 2013 WebMD, LLC
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Cite this: Pyloric Stenosis Linked to Low Serum Lipids in Infants - Medscape - Aug 20, 2013.