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

Twin concordance studies indicate that genetic factors influence the indivi dual susceptibility for alcoholic liver disease (ALD). Both clinical and ex perimental data suggest that Kupffer cell activation by gut-derived endotox ins and other bacterial products is an important pathogenic factor. Activat ed Kupffer cells release proinflammatory cytokines, a process that is regul ated by the CD14 endotoxin receptor (CD14). Recently, a C -->T (-159) polym orphism in the promoter region of the CD14 gene was detected and found to c onfer increased CD14 expression. In the present study, the association of C D14 promoter polymorphism with different forms of ALD was examined in 3 sep arate autopsy series. Among 442 men with valid alcohol-consumption data, 38 1 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 ra tio [OR]: 2.48; P = .018), and especially with cirrhosis (OR: 3.45; P = .00 4), but not with fatty liver, periportal fibrosis, or bridging fibrosis. Th e overall age-adjusted risk for cirrhosis was 3.08 (P = .01) for the carrie rs of the CT genotype, and 4.17 (P = .005) for the homozygous TT genotype. These results suggest that in the relatively isolated Finnish population, t he T allele confers increased risk of alcoholic liver damage. In particular , TT homozygotes are at a high risk to develop cirrhosis.