DRB1*15 and DRB1*03 extended haplotype interaction in primary Sjögren's syndrome genetic susceptibility.
OBJECTIVE
Sjögren's syndrome (SS) is a chronic autoimmune disease with a genetic component. Among the genetic factors, the role of HLA class II genes has been suggested and a positive association with DRB1*03 allele has been described. However, there is no consensus on a unique HLA locus for this disease nor on the role of the HLA gene product in the disease. The aim of this study was to analyse prospectively MHC region involvement in the genetic susceptibility to SS by studying DRB1, DQB1, DPB1, TAP1, TAP2 genes and TNF microsatellites in a population of 45 primary SS patients.


METHODS
All the polymorphisms studied were analysed at the genomic level using PCR-based methodologies.


RESULTS
Concerning HLA class II alleles, the highest relative risk to develop the disease was associated with the DRB1*15-DRB1*0301 heterozygous genotype (17.8% vs 3.5% in controls - pc < 0.005, OR = 5.96). Analysing other genes located on the same region allowed us to further determine the DRB1 haplotypes at risk. For instance, the DRB1*0301 haplotype involved in the genetic susceptibility to SS was more often associated with the DPB1* 0201 and TNF-a2 alleles in SS patients than in controls. Moreover, all the DRB1*15-DRB1*0301 SS patients were TAP1-0101, TAP2-0101 homozygous, allowing us to deduce the extended genotype at risk as DRB1*15, TAP1-0101, TAP2-0101/DRB1*0301, TAP1-0101, TAP2-0101 which was carried by only 3 controls out of the 130 tested (p < 0.01, OR = 6.68).


CONCLUSIONS
This study confirmed the role of the MHC region in the susceptibility to Sjögren's disease, and for the first time suggests a synergistic interaction between two HLA-DRB1 extended haplotypes in the genetic mechanisms controlling the disease.
Jean
S
S
Laboratoire Universitaire d'Immunologie, ETS Bretagne Est, CHRU Fontenoy, Rennes, France.
Quelvennec
E
E
Alizadeh
M
M
Guggenbuhl
P
P
Birebent
B
B
Perdriger
A
A
Grosbois
B
B
Pawlotsky
P Y
PY
Semana
G
G
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D012859:Sjogren's Syndrome / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D014409:Tumor Necrosis Factor-alpha; C071692:TAP2 protein, human