A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis.

Genome scanning studies suggest an important role for genes outside the major histocompatibility complex in autoimmunity. Key candidates are those genes involved in immune regulation and preservation of immune homeostasis, including the genes involved in apoptosis. Our aim was to determine the association between the Fas gene polymorphism at position -670 and susceptibility, clinical expression, and outcome in type 1 autoimmune hepatitis (AIH). An adenosine to guanine single nucleotide polymorphism in the Fas gene (TNFRSF6) promoter was assessed in 149 well-characterized Caucasoid patients and 172 matched controls. Patients and normal subjects had the similar TNFRSF6-670 allele and genotype frequencies. Serum aspartate aminotransferase (510 +/- 77 vs 283 +/- 53 U/l), gamma-globulin (3.3 +/- 0.2 vs 2.6 +/- 0.2 g/dl), and immunoglobulin G (2976 +/- 223 vs 2324 +/- 203 mg/dl) levels were higher in patients with the guanine/guanine genotype than in those with the adenosine/adenosine genotype. Cirrhosis at presentation was more common in patients with the adenosine/adenosine or adenosine/guanine genotypes than in those with the guanine/guanine genotype (29% vs 6%). Polymorphism of the Fas gene at position -670 does not influence susceptibility to AIH, but may affect the early development of cirrhosis.