Genetic and environmental aspects of symptomatic gallstone disease

Abstract

Gallstone disease (GD) represents a major healthcare problem. Gallstones are likely to result from a complex interaction of the environment and the effects of multiple undetermined genes.

The aim of this study was: to evaluate the contribution of hereditary and environmental factors to the pathogenesis of gallstone disease by analyzing a large twin population; to examine the association between known environmental factors such as body mass index, alcohol and tobacco on symptomatic GD by analyzing parameter data from the Swedish Twin Registry; and to identify human candidate genes and polymorphisms for gallstone disease by selected sampling from the Swedish Twin Registry (STR).

In the first study we linked the STR with the Swedish inpatient-discharge and causes of death registries for symptomatic GD. Structural equation modelling techniques were used to estimate the contributions of genetic effects as well as shared and non-shared environmental factors to the development of symptomatic GD. In the second study we used the same screening procedure and evaluated those twins where weight, height, and data on use of alcohol and tobacco were provided by the STR and analyzed for possible associations by conditional logistic regression. In the third study we first identified the concordant monozygotic (MZ) and dizygotic (DZ) twins as well as discordant monozygotic (MZ) twins born between 1912 and 1958 alive in Stockholm County. We collected DNA, performed an abdominal ultrasound in case of undefined GD. For the ABCG8 D19H polymorphism association analysis, we collected additional DNA from the nationwide TwinGene project identifying 20 MZ and 54 DZ cases as well as 109 MZ and 126 DZ controls.

A total of 43,141 twin pairs were screened in the first study. We found that concordances and correlations were higher in MZ compared with DZ twins, both for males and females. Genetic effects accounted for 25% (95% CI, 9%-40%), shared environmental effects for 13% (95% CI, 1%-25%), and unique environmental effects for 62% (95% CI, 56%- 68%) of the phenotypic variance among twins. In the second study we found that overweight and obesity were associated with significantly higher risk for GD in the whole study population (OR 1.86 and OR 3.38; CI: 1.52 2.28 and 2.28 5.02 respectively). High alcohol consumption was associated with a lower risk for GD in the whole population (OR 0.62; CI: 0.51 0.74) with no difference between discordant MZ and DZ twins (OR 1.08 and OR 0.96; CI: 0.82 1.42 and 0.79 1.16). Smoking or smoke-free tobacco were not correlated with GD. Twenty-four (75%) out of 32 evaluable MZ twin pairs in Stockholm County were concordant for GD. Hetero- or homozygous 19H carriers were found in 5 concordant MZ twin pairs (20.8%), but only in 1 pair (12.5%) discordant for GD. Nationwide, we found 18.2% vs. 9.2% D19H carriers in MZ with and without GD, respectively, likewise 22.6% vs. 9.5% D19H in DZ. Overall D19H frequency was 20.8 % in cases compared to 9.4 % in controls. Association analysis showed that D19H allele significantly increased risk for GD (OR, 2.56; 95%CI, 1.28-5.15; p<0.01).

In conclusion, heritability is a major susceptibility factor for GD. There are positive associations between symptomatic GD and body mass index (BMI), and negative between GD and high alcohol consumption, whereas tobacco use has no impact. D91H was more common in cases than in controls and the association analysis found a significantly increased GD risk for twins carrying this ABCG8 allele.