Three allele combinations associated with multiple sclerosis.
BACKGROUND
Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS.


METHODS
286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFbeta1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group.


RESULTS
We identified two previously unknown MS-associated tri-allelic combinations:-509TGFbeta1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Delta32, DRB1*04 were also reidentified as MS-associated.


CONCLUSIONS
These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles.
Favorova
Olga O
OO
Department of Molecular Biology and Medical Biotechnology, Russian State Medical University, 15 3d Cherepkovskaya ul,, Moscow 121552, Russia. olga_favorova@mail.ru
Favorov
Alexander V
AV
Boiko
Alexey N
AN
Andreewski
Timofey V
TV
Sudomoina
Marina A
MA
Alekseenkov
Alexey D
AD
Kulakova
Olga G
OG
Gusev
Eugenyi I
EI
Parmigiani
Giovanni
G
Ochs
Michael F
MF
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012426:Russia; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha