Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease

Abstract

Twin concordance studies indicate that genetic factors influence the individual susceptibility for alcoholic liver disease (ALD). Both clinical and experimental data suggest that Kupffer cell activation by gut-derived endotoxins and other bacterial products is an important pathogenic factor. Activated Kupffer cells release proinflammatory cytokines, a process that is regulated by the CD14 endotoxin receptor (CD14). Recently, a C→ T (- 159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression. In the present study, the association of CD 14 promoter polymorphism with different forms of ALD was examined in 3 separate autopsy series. Among 442 men with valid alcohol-consumption data, 381 men had been moderate or heavy alcohol consumers. The allele frequency of the CD14 promoter genotype, determined by a modified cycle minisequencing technique, was 0.34 (CC), 0.51 (CT), and 0.16 (TT). The T allele was found to be associated with advanced ALD, i.e., with alcoholic hepatitis (odds ratio [OR]: 2.48; P = .018), and especially with cirrhosis (OR: 3.45; P = .004), but not with fatty liver, periportal fibrosis, or bridging fibrosis. The overall age-adjusted risk for cirrhosis was 3.08 (P = .01) for the carriers of the CT genotype, and 4.17 (P = .005) for the homozygous TT genotype. These results suggest that in the relatively isolated Finnish population, the T allele confers increased risk of alcoholic liver damage. In particular, TT homozygotes are at a high risk to develop cirrhosis.