Research article
Three allele combinations associated with Multiple Sclerosis
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* Corresponding author: Olga O Favorova olga_favorova@mail.ru
1 Department of Molecular Biology and Medical Biotechnology, Russian State Medical University, 15 3d Cherepkovskaya ul., Moscow 121552, Russia
2 Cardiology Research Center, 15 3d Cherepkovskaya ul., Moscow 121552, Russia
3 Bioinformatics Laboratory, GosNIIGenetika, 1 1st Dorozhny pr., Moscow 117545, Russia
4 Department of Neurology and Neurosurgery, Russian State Medical University, 1 Ostrovitianova ul., Moscow 117997, Russia
5 Departments of Oncology, Pathology and Biostatistics, Johns Hopkins University, 550 North Broadway, s. 1103, Baltimore, Maryland 21205, USA
6 Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA
BMC Medical Genetics 2006, 7:63 doi:10.1186/1471-2350-7-63
Published: 26 July 2006Abstract
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, TGFβ1, 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:
-509TGFβ1*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 CCR5Δ32, DRB1*04 were also reidentified as MS-associated.
Conclusion
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.