Variants of the Coagulation and Inflammation Genes Are Replicably Associated with Myocardial Infarction and Epistatically Interact in Russians.

BACKGROUND: In spite of progress in cardiovascular genetics, data on genetic background of myocardial infarction are still limited and contradictory. This applies as well to the genes involved in inflammation and coagulation processes, which play a crucial role in the disease etiopathogenesis. METHODS AND RESULTS: In this study we found genetic variants of TGFB1, FGB and CRP genes associated with myocardial infarction in discovery and replication groups of Russian descent from the Moscow region and the Republic of Bashkortostan (325/185 and 220/197 samples, correspondingly). We also found and replicated biallelic combinations of TGFB1 with FGB, TGFB1 with CRP and IFNG with PTGS1 genetic variants associated with myocardial infarction providing a detectable cumulative effect. We proposed an original two-component procedure for the analysis of nonlinear (epistatic) interactions between the genes in biallelic combinations and confirmed the epistasis hypothesis for the set of alleles of IFNG with PTGS. The procedure is applicable to any pair of logical variables, e.g. carriage of two sets of alleles. The composite model that included three single gene variants and the epistatic pair has AUC of 0.66 both in discovery and replication groups. CONCLUSIONS: The genetic impact of TGFB1, FGB, CRP, IFNG, and PTGS and/or their biallelic combinations on myocardial infarction was found and replicated in Russians. Evidence of epistatic interactions between IFNG with PTGS genes was obtained both in discovery and replication groups.

Comparative pharmacogenetics of multiple sclerosis: IFN-ß versus glatiramer acetate.

Various diseases require the selection of preferable treatment out of available alternatives. Multiple sclerosis (MS), an autoimmune inflammatory/neurodegenerative disease of the CNS, requires long-term medication with either specific disease-modifying therapy (DMT) - IFN-ß or glatiramer acetate (GA) - which remain the only first-line DMTs in all countries. A significant share of MS patients are resistant to treatment with one or the other DMT; therefore, the earliest choice of preferable DMT is of particular importance. A number of conventional pharmacogenetic studies performed up to the present day have identified the treatment-sensitive genetic biomarkers that might be specific for the particular drug; however, the suitable biomarkers for selection of one or another first-line DMT are remained to be found. Comparative pharmacogenetic analysis may allow the identification of the discriminative genetic biomarkers, which may be more informative for an a priori DMT choice than those found in conventional pharmacogenetic studies. The search for discriminative markers of preferable first-line DMT, which differ in carriage between IFN-ß responders and GA responders as well as between IFN-ß nonresponders and GA nonresponders, has been performed in 253 IFN-ß-treated MS patients and 285 GA-treated MS patients. A bioinformatics algorithm for identification of composite biomarkers (allelic sets) was applied on a unified set of immune-response genes, which are relevant for IFN-ß and/or GA modes of action, and identical clinical criteria of treatment response. We found the range of discriminative markers, which include polymorphic variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes, in different combinations. Every allelic set includes the CCR5 genetic variant, which probably suggests its crucial role in the modulation of the DMT response. Special attention should be given to the (CCR5*d+ IFNAR1*G) discriminative combination, which clearly points towards IFN-ß treatment choice for carriers of this combination. As a whole the comparative approach provides an option for the identification of prognostic composite biomarkers for a preferable medication among available alternatives.

Allelic combinations of immune-response genes as possible composite markers of IFN-ß efficacy in multiple sclerosis patients.

BACKGROUND: IFN-ß is widely used as the first-line disease-modifying treatment for multiple sclerosis. However, 30-50% of multiple sclerosis patients do not respond to this therapy. Identification of genetic variants and their combinations that predict responsiveness to IFN-ß could be useful for treatment prognosis. MATERIALS & METHODS: The combinations of alleles of nine polymorphic loci in immune-response genes were analyzed in 253 Russian multiple sclerosis patients as possible determinants of clinically optimal IFN-ß treatment response using APSampler software. RESULTS: Carriage of TGFB1*-509C and CCR5*d was associated with favorable IFN-ß response by itself. CCR5*d, IFNAR1*16725G, IFNG*874T and IFNB1*153T/T were the components of the combinations, associated with clinically optimal response to IFN-ß. Carriage of composite markers (CCR5*d + IFNAR1*G + IFNB1*T/T) or (CCR5*d + IFNAR1*G + IFNG*T) is beneficial for IFN-ß treatment efficacy. DISCUSSION: The data obtained provides evidence of the cumulative effect of immune-response genes on IFN-ß treatment efficacy. This joint contribution may reflect the additive effect of independent allelic variants and epistatic interactions between some of them.

Allelic combinations of immune-response genes associated with glatiramer acetate treatment response in Russian multiple sclerosis patients.

BACKGROUND: Glatiramer acetate (GA) is widely used as a first-line disease-modifying treatment for multiple sclerosis (MS). However, a significant proportion of MS patient appears to experience modest benefit from GA-treatment. Genetic variants affecting the clinical response to GA are believed to be relevant as biomarkers of GA-treatment efficiency. PATIENTS & METHODS: Nine polymorphisms in candidate genes were analyzed as possible determinants of GA response in 285 Russian MS patients. Special attention was given to identification of response-associated allelic combinations by means of the APSampler algorithm. RESULTS: No significant associations were found for individual polymorphisms. Alleles DRB1*15, TGFB1*T, CCR5*d and IFNAR1*G were the components of the combinations, of which carriage was significantly higher in nonresponders than in responders. Carriers of the most significant combinations: DRB1*15 + TGFB1*T + CCR5*d + IFNAR1*G and DRB1*15 + TGFB1*T + CCR5*d (permutation p-values: 0.0056 and 0.013, respectively) had a 14 to 15-times increased risk of ineffective response to GA therapy. DISCUSSION: The results suggest that the influence of immune-response genes on GA-induced response has a polygenic nature. The data are interpreted as evidence of additive and epistatic influences of the genes on GA efficiency for MS treatment.

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. 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.