Three genetic variants found for common digestive system disorder in newborns

An enigmatic digestive system disorder in newborns

Infantile hypertrophic pyloric stenosis is a potentially fatal condition affecting seemingly healthy infants when they are 2 to 8 weeks old. The disease is characterized by hypertrophy of the pyloric sphincter muscle, which leads to obstruction of the gastric outlet. Symptoms include projectile vomiting, dehydration and weight loss. The mortality was around 50% before successful surgical treatment was developed in 1911. The condition affects between 2 and 3 children per 1,000 live births in individuals of European ancestry, and it is the most common condition requiring surgery in the first months of life. There is a pronounced male excess in the incidence of the disease, with affected boys outnumbering girls by 4 to 1.

High heritability

The research team has in a previous study published in JAMA found that pyloric stenosis shows strong familial aggregation. If, for instance, the sibling of a child has had the disease, the child will have an almost 20 fold increased risk of also getting the disease. For identical twins, there is a nearly 200-fold increase in risk. In spite of the high heritability and strong familial aggregation of the disease, there are no genetic variants for which findings of association have been replicated in previous studies.

First genome-wide association study

The study is the first genome-wide association study (GWAS) of pyloric stenosis. The researchers analyzed data for more than 500,000 SNPs spread across the entire genome in 1,001 Danish children with a history of pyloric stenosis together with data from 2,401 healthy control children. The most significant genetic variants were tested in an independent set of 796 additional pyloric stenosis cases and 876 controls.

In infants with pyloric stenosis, the pyloric sphincter muscle
tissue shows dramatic overgrowth obstructing the passage
between the stomach and the duodenum.

Alternative splicing and muscular dystrophy

Two of the identified SNPs are located on either side of the gene MBNL1, which is a key regulator of so-called alternative splicing. Alternative splicing is a common mechanism that allows a given gene to be translated into multiple different protein variants. Many proteins involved in the formation of muscle tissue show a dramatic transition shortly after birth. In fetal life, one protein isoform is present, whereas another isoform of the same protein is produced after birth. ”It is striking that infantile hypertrophic pyloric stenosis almost always occurs 2 – 8 weeks after birth, and the identified SNPs close to MBNL1 indicate that misregulation of alternative splicing could play an important role in the etiology of the disease” says senior research scientist Bjarke Feenstra, who together with colleagues Frank Geller and Mads Melbye has been leading the study. The importance of MBNL1 for normal development of muscle tissue is highlighted in myotonic muscular dystrophy, where loss of MBNL1 function and consequent aberrant splicing are pivotal in the pathogenesis of the disease.

Congenital heart defects and embryonic gut development

The third identified genetic variant is located close to the gene NKX2-5, which is important for normal heart development. Previous studies have identified a range of mutations in NKX2-5 causing various types of congenital heart defects. Although NKX2-5 is mainly known as a heart gene in humans, it also plays in important role in the embryonic development of the digestive system. Studies in the chicken and mouse have shown that NKX2-5 is expressed exactly at the junction between the stomach and the small intestine on specific days of embryonic development. The researchers hope that these findings will lead to further functional studies of the biological mechanisms whereby genetic variants in or near NKX2-5 can lead to overgrowth of muscle tissue in the intestine or in the heart.

Perspectives

The GWAS is the first study to identify and confirm genetic variants associated with infantile hypertrophic pyloric stenosis. However, the exact molecular mechanisms behind the associations still need to be discovered. “This is a big step forward in our understanding of the disease, and the study has provided us with a number of hypotheses regarding potential mechanisms that we are investigating further” says Bjarke Feenstra. In a longer time span, deeper knowledge of the genetics of pyloric stenosis can potentially be used to prevent the disease. “If we are able to perform a genetic test at birth that indicates with high accuracy if a child is likely to get the condition, preventive treatment could be given and surgery could potentially be avoided” says Mads Melbye.

Read the scientific article

Feenstra B, Geller F, Krogh C, Hollegaard MV, Gørtz S, Boyd HA, Murray JC, Hougaard DM, Melbye M. Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis
Nature Genetics, Published online: 05 February 2012 | doi:10.1038/ng.1067