Approved research

The Genetics of Digestive Function - correlating genotypes from a locus encoding a pancreatic protease with gastrointestinal phenotypes

Lay summary

The pancreas produces vital digestive enzymes; when produced in inadequate amounts patients suffer gastrointestinal distress and malabsorption called 'exocrine pancreatic insufficiency.' We have studied a family with variants in a gene encoding a pancreatic enzyme; two siblings have pancreatic insufficiency. We have determined that one of these variants is present in ~4% of the population (1000 genomes data), and therefore 1/2500 people may have unrecognised pancreatic insufficiency. We aim to identify individuals with these genetic variants in the UK Biobank and assess their health status to correlate these gene variants to features of pancreatic insufficiency. Our research aims to identify individuals with pancreatic insufficiency caused by a variant within this chromosomal region. The relationship of this genetic region and its role in the pancreas has not previously been demonstrated, but could be of health significance to the wider population. By understanding this relationship, we may define a new previously unrecognised health condition, which could then lead to enhanced diagnosis and institution of appropriate treatment. We will extract genetic information from the UK Biobank to identify individuals with a genetic variant that we know is related to the pathogenic gene variant we have found in our study. We will then request baseline health information from these individuals on their medical history, gastrointestinal symptomatology , medication history (including pancreatic enzyme treatments), and growth parameters. We will also request available blood test data which may be affected by our gene: cholesterol, lipid profile and vitamin status, and if available, pancreatic MRI results and bone density scores as these can be affected by long-term poor absorption of vitamins. From the UK Biobank we predict that we would identify ~145 individuals who are positive for this hypothesised at-risk-genotype. Because the gastrointestinal phenotype may be variable, we would also request the health information of individuals with a single-dose of the gene variant, and predict that there are ~8500 of such individuals in the cohort. To understand how the genetic change affects the presentation of individuals with the genetic variants we would require a comparison group. We would request 1:5 matching of the homozygous individuals (~700 controls) and 1:1 matching for the heterozygous individuals (~8500 controls). A total of ~17,500 individuals.