Elsevier

Journal of Hepatology

Volume 35, Issue 3, September 2001, Pages 324-328
Journal of Hepatology

Apolipoprotein E polymorphism, a marker of disease severity in primary biliary cirrhosis?

https://doi.org/10.1016/S0168-8278(01)00137-4Get rights and content

Abstract

Background/Aims: To determine whether the apolipoprotein E (apo-E) polymorphism is associated with the risk of primary biliary cirrhosis (PBC), the severity of the disease and its response to ursodeoxycholic acid (UDCA) therapy.

Methods: The apo-E genotype was determined in 72 PBC patients. Genotype and allele distributions were compared with those found in the French general population. Laboratory parameters obtained before and after 1- and 4-year UDCA treatment were compared according to the apo-E allele carrier status.

Results: Apo-E allele and genotype distributions were similar between PBC patients and the general population. At the time of diagnosis, the ε4 allele carriers were younger (P<0.05), had higher bilirubin (P<0.05) and IgG (P<0.001) levels and a lower prothrombin index (P<0.01) than ε2 (homozygous+heterozygous) or ε3 homozygous allele carriers. After 4-year UDCA therapy, the decrease in serum alkaline phosphatase and in alanine and aspartate aminotransferase activities was lower in percentage in the ε4 than in other ε allele carriers (P<0.01).

Conclusions: Although apo-E polymorphism does not appear to confer susceptibility to PBC, it probably influences PBC progression and response to UDCA. The ε4 allele may identify patients with high risk of severe disease and poor response to treatment.

Introduction

It is now well established that genetic factors play an important role in the onset, progression and severity of numerous diseases. Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterized by inflammatory destruction of small intrahepatic bile ducts and the presence of antimitochondrial antibodies. Familial clustering of PBC strongly supports the genetic basis for the disease [1], [2], [3]. However, to date, only weak (or controversial) associations have been found between PBC susceptibility and HLA, TNF-α or CTLA-4 gene polymorphisms [4], [5], [6]. The progression of PBC is highly variable, a finding which suggests that the severity of the disease might depend at least in part on individual vulnerability to cholestasis and to toxicity of endogenous bile acids. In the past decade, ursodeoxycholic acid (UDCA) has been shown to be a safe and effective treatment for PBC [7], [8], [9]. However, the degree of response to UDCA is variable from one patient to another. These observations suggest that genetic variations in lipid and/or bile acid metabolism might play a role in the development and severity of the disease. Vuoristo et al. [10] have found that apolipoprotein E (apo-E) polymorphism could modify disease expression in PBC. Apo-E is a protein constituent of plasma lipoproteins which plays an important role in their clearance. This occurs in the liver through several cellular receptors mediating lipoprotein endocytosis [11]. Apo-E is present in three major isoforms in humans, referred to as apo-E2, -E3, and -E4, which are products of three common alleles (ε2, ε3, ε4) at the apo-E gene locus. Apo-E3 is by far the most common allele in human populations, about three out of four individuals being carriers of this allele. In addition, the affinity of the three apo-E isoforms for the low-density lipoprotein (LDL) receptor in liver and peripheral cells increases from apo-E2 to apo-E4 [12], [13]. This was shown to increase liver cholesterol influx from E2 to E4. Finally, the apo-E gene polymorphism was shown to modulate levels of circulating cholesterol and bile acid metabolism [14], [15], [16], [17].

In the present study, we attempted to determine whether the apo-E gene polymorphism could contribute to the genetic predisposition for PBC, to the severity of the disease and its response to UDCA therapy.

Section snippets

Patients

We performed a retrospective, cross-sectional study of a cohort of 72 unrelated PBC patients (96% female, mean age: 50 years), in whom apo-E genotype was determined. All patients met the following criteria for the diagnosis of PBC: alkaline phosphatase (AP) activity more than 1.5 times the upper limit of normal, no evidence of extrahepatic biliary obstruction by ultrasonography or endoscopic cholangiography, positive for antimitochondrial antibody, and compatible liver histology. All patients

Apo-E allele and genotype frequencies

The distributions of apo-E genotypes and alleles in patients with PBC are shown in Table 1. Genotype distribution was in the Hardy–Weinberg equilibrium proportions. The most common allele was ε3, followed by ε4 and ε2 in decreasing order. Genotype and allele distributions did not differ between PBC patients and the French middle-aged population [21].

Baseline expression of the disease as a function of apo-E polymorphism

The relationships between the main characteristics of the disease and apo-E genotypic groups are shown in Table 2. Four parameters were

Discussion

Two main findings were drawn from the present study: (1) apo-E polymorphism is not associated with the risk of PBC in the French population; and (2) PBC patients carrying the ε4 allele have a more severe disease and a poorer response to UDCA therapy.

To date, only one study has investigated the influence of apo-E polymorphism in PBC [10]. This study showed that in Finland, the ε2 allele was two-fold more frequent in PBC patients than in the general population, suggesting that the apo-E genotype

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