Analysis of the common vasoactive intestinal peptide receptor 1 polymorphism in gallstone patients

Cholesterol gallstone disease is caused by both genetic and environmental factors (e.g., deranged motility of the gallbladder wall). Recently, a single nucleotide polymorphism (SNP) of the vasoactive intestinal peptide receptor 1 (VIPR1) gene has been linked to late onset of achalasia, a lower esophagus dysmotility disorder. As VIPR1 is expressed in the gallbladder wall as well, and patients with achalasia exhibit extraesophageal motility disorders, the influence of VIPR1 SNP on cholelithiasis was investigated.

We analyzed 254 gallstone-free controls (confirmed by ultrasound, age 21-78 years, 88% women, BMI 16-43 kg/m²) and 226 individuals from 107 families with gallstones (age 24-80 years, 87% women, BMI 17-55 kg/m²). All individuals were genotyped for the VIPR1 rs437876 SNP (intron 4) with PCR-based 5'-nuclease and fluorescence detection assays (TaqMan). We performed nonparametric linkage (NPL) analysis in affected sib-pairs (ASP), association tests, and regression analyses.

Controls were significantly younger (P < 0.01) and leaner than ASP and cases (P < 0.01), and both age as well as BMI significantly increased the risk of developing gallstones (P < 0.001). Allele frequencies were in line with database entries and no deviation from Hardy-Weinberg equilibrium was detected. Neither allele and genotype distributions nor NPL scores or the restriction of analysis to individuals older than 50 years provided evidence for association or linkage of the VIPR1 SNP and cholelithiasis.

The VIPR1 polymorphism, previously linked to gastrointestinal dysmotility disorders, does not represent a common risk factor for gallstones in the general or in an elderly population.