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GWAS Risk Locus Suggests Low Cholesterol May Influence Infant Gut Condition

NEW YORK (GenomeWeb News) – A new study suggests that a set of genetic variants associated with slightly lower cholesterol levels may bump up an infant's propensity for developing a gastrointestinal blockage condition called infantile hypertrophic pyloric stenosis, or IHPS.

Members of an international research team did a multi-stage genome-wide association study based on dried blood spot samples from thousands of affected and unaffected infants from Denmark, Sweden, and the US in their effort to better understand IHPS. The gastrointestinal condition affects between one and three infants for every 1,000 born in the West, they noted, and is far more common in boys than girls.

As the team reported online today in the Journal of the American Medical Association, the search verified three risk loci identified previously. It also led to a new IHPS-associated locus containing SNPs in and around a cluster of apolipoprotein genes, prompting follow-up experiments that revealed somewhat lower blood cholesterol levels in individuals who carried the apparent chromosome 11 risk variants.

"Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk," corresponding author Bjarke Feenstra, with Copenhagen's Statens Serum Institut, and his colleagues wrote. Even so, they cautioned that additional work is needed to delve into the nature of this apparent relationship and the functional reasons for it.

Anatomically, IHPS occurs when the band of muscle that contracts and relaxes to control the movement of material from the stomach to the top of the small intestine becomes larger-than-usual and blocks the opening leading out of the stomach. That, in turn, can lead to symptoms such as vomiting, dehydration, and weight loss.

But while the condition tends to be heritable, the genetic roots are poorly understood — particularly for forms of the condition that are not part of a broader genetic syndrome.

For the current genetic study, Feenstra and his colleagues began by looking at SNP profiles in blood spot samples collected from 1,001 Danish infants with IHPS over more than two decades. In these samples — and in samples from 2,371 unaffected controls — they directly genotyped variants using Illumina's Human 660W-Quad bead arrays and imputed additional SNPs with the help of data from the 1000 Genomes Project.

By comparing SNP patterns in the cases and controls, the group identified suspicious variants at four loci: two sites on chromosomes 3 and 5 that had been implicated in IHPS risk in past studies and two more previously undetected loci on chromosomes 11 and 19.

The researchers took variants from all four loci, along with another known risk locus on chromosome 3, forward for further testing in 1,663 cases and 2,315 controls from cohorts in Denmark, Sweden, and the US. Following that validation step, all three loci from prior studies still showed significant ties to IHPS risk, they reported, as did the new chromosome 11 locus.

The locus contains a cluster of apolipoprotein genes. Among them: an APOA1 gene that codes for a constituent of high-density lipoprotein, or HDL, cholesterol itself. Moreover, within a large set of SNPs found in linkage disequilibrium at the new IHPS-linked locus were dozens of variants that reportedly influenced HDL cholesterol levels in past studies.

To explore potential ties between the IHPS risk site and cholesterol profiles further, the investigators went on to compare total cholesterol, HDL, low-density lipoprotein, and triglyceride levels in umbilical chord blood samples from dozens of infants who were eventually diagnosed with IHPS and 189 who were not.

Even at birth, they found, those who went on to develop the gastrointestinal condition had significantly lower levels of total cholesterol in their blood than did their unaffected counterparts.

More research is needed to rule out the possibility that other, non-apolipoprotein genes at the chromosome 11 locus contribute to IHPS, too, according to those involved in the study. But based on their findings so far, there are hints that IHPS risk may rise as levels of some forms of cholesterol dip in the blood.

If so, that may partly explain why IHPS occurs more often in infant boys than in infant girls, who typically have higher cholesterol levels, study authors noted. Moreover, they said, it could offer clues about why IHPS is somewhat more common in bottle-fed babies, who also tend towards lower cholesterol levels.