Primary sclerosing cholangitis is associated with extended HLA-DR3 and HLA-DR6 haplotypes.
Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.
Wiencke
K
K
Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway. kristine.wiencke@medisin.uio.no
Karlsen
T H
TH
Boberg
K M
KM
Thorsby
E
E
Schrumpf
E
E
Lie
B A
BA
Spurkland
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000276:immunology*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015803:HLA-DR3 Antigen / Q000235:genetics*; D015808:HLA-DR6 Antigen / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D008875:Middle Aged
D005819:Genetic Markers; D015803:HLA-DR3 Antigen; D015808:HLA-DR6 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II