Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis.
Susceptibility to autoimmune hepatitis in white patients is associated with the human leukocyte antigen class II antigens DR3 and DR4. To analyze the molecular basis of these associations, we used oligonucleotide probes to determine the DRB, DQA and DQB hypervariable nucleotide sequences in 119 patients with autoimmune hepatitis and 177 matched controls. DRB3*0101, which encodes DR52a, predisposed patients most strongly to the disease. It was present in 58% of patients and 25% of controls (corrected P < 0.000005), whereas DQA1*0101 and 0102 conferred protection in males only. The DR4 subtype, DRB1*0401, was raised in the DRB3*0101-negative patients; 81% possessed either DRB3*0101 or DRB1*0401, compared with 42% of controls (corrected P < 0.0000001). These alleles encode the amino acid sequence Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DR beta polypeptide, which was present in 94% of patients and 64% of controls (corrected P < 0.000001) and in all patients who tested positive for autoantibodies to the hepatic asialoglycoprotein receptor. The patients with DRB1*0401 had less severe disease, relapsed less frequently and were first seen significantly later in life than those patients with DRB3*0101; and whereas a single copy of DRB1*0401 predisposed to autoimmune hepatitis, DRB3*0101-associated susceptibility had a dose-related effect. These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.
Doherty
D G
DG
Department of Child Health, King's College Hospital and School of Medicine and Dentistry, London, United Kingdom.
Donaldson
P T
PT
Underhill
J A
JA
Farrant
J M
JM
Duthie
A
A
Mieli-Vergani
G
G
McFarlane
I G
IG
Johnson
P J
PJ
Eddleston
A L
AL
Mowat
A P
AP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D014644:Genetic Variation; D006505:Hepatitis / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008968:Molecular Conformation; D008969:Molecular Sequence Data
D000949:Histocompatibility Antigens Class II