The role of apolipoprotein E and glucose intolerance in gallstone disease in middle aged subjects

Abstract

Background-The polymorphism of apolipoprotein E has been suggested to be associated with the cholesterol content of gallstones, the crystallisation rate of gall bladder bile, and the prevalence of gallstone disease (GSD). Aims-To investigate whether apolipoprotein E polymorphism modulates the susceptibility to GSD at the population level and to study the possible associations between impaired glucose tolerance, diabetes, and GSD. Methods-Apolipoprotein E phenotypes were determined in a middle aged cohort of 261 randomly selected hypertensive men, 259 control men, 257 hypertensive women, and 267 control women. All subjects without a documented history of diabetes were submitted to a two hour oral glucose tolerance test (OGTT). GSD was verified by ultrasonography. Results-In women with apolipoprotein E2 (phenotypes E2/2, 2/3, and 2/4) compared with women without E2 (E3/3, 4/3, and 4/4), the odds ratio for GSD was 0.28 (95% confidence interval 0.08-0.92). There was no protective eVect in men. The relative risk for GSD was 1.2 (0.8-1.7) for hypertensive women and 1.8 (1.0-2.7) for hypertensive men. In a stepwise multiple logistic regression model, E2 protected against GSD in women, whereas two hour blood glucose in the OGTT, serum insulin, and plasma triglycerides were risk factors. Elevated blood glucose during the OGTT was also a significant risk factor for GSD in men. Conclusions-The data suggest that apolipoprotein E2 is a genetic factor providing protection against GSD in women. In contrast, impaired glucose tolerance and frank diabetes are associated with the risk of GSD. (Gut 1999;44:557-562)

Genetic evidence that apolipoprotein E4 is not a relevant susceptibility factor for cholelithiasis in two high-risk populations

“…Different ethnicities with lower gallstone prevalence and the inclusion of younger control probands might contribute to these discrepancies, because apoE4 allele frequencies are low in Asian populations (31,32,63) and decrease with age as a result of increased serum LDL cholesterol levels and increased risk for cardiovascular mortality (26). In our study, the apoE allele distributions in Chile and Germany were in accordance with the distributions expected for populations with Spanish-Amerindian admixture or primary Caucasian origin, respectively (63): intermediate between the Asian studies (31-33) and the higher apoE4 frequencies (28-33%) in the Finnish studies (28,30). Furthermore, in agreement with other studies (65), apoE4 genotypes of German patients were associated with higher LDL cholesterol levels in serum, whereas no such association was detected in the Chilean population.…”

“…Our results contrast with the increased risk of GD in apoE4 carriers reported in Finland (28,30) and Spain (29). How can we explain these apparently contradictory findings?…”

“…The apoE2 isoform, by contrast, was found less frequently in Finnish women with gallstones than in controls (30). However, other studies have not yielded consistent association findings (31)(32)(33)(34)(35).…”

Pathogenesis of gallstones: a genetic perspective

“…The ApoE2 isoform, by contrast, was found less frequently in women with gallstones than in controls. 75 In line with these findings, Apoe knockout mice show a markedly lower frequency of gallstones than wild-type controls upon challenge with a high-cholesterol diet. 76 The association between gallstones and APOE could be due to increased hepatic cholesterol uptake via chylomicrons in patients carrying the isoform ApoE4; alternatively, biliary ApoE might have a role in the destabilization of bile.…”

Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy

“…For example, it is possible that apoE2 is associated with a lower risk of incident gallbladder sludge or stones, analogous to its association with a lower risk of Alzheimer' s disease. 29 In this case, the apoE2/4 genotype would not necessarily increase the risk of gallbladder sludge or stones, and inclusion of this genotype with the other apoE4-containing genotypes in the analysis could mask a true effect of apoE4. To assess this possibility, we examined genotypes separately, with apoE3/3 as the referent group.…”