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Hematological malignancies are multifactorial diseases in the development of which play a role as environmental factors and genetic determination of leukemic process. Such genetic factors include the presence in human genome of allelic variants of the regulatory regions of the innate immune response genes. At present time, they are considered as real risk factors for these diseases in a person with a certain set of genetic variants. Their distribution among the population corresponds to the population laws and has its ethnographic features. Analysis of the individual associations of genes polymorphic variants involved in the implementation of the immune response does not sufficiently complete answer about their role in the formation of predisposition to the development of chronic lymphoproliferative disorders (CLD) and multiple myeloma (MM). It is noted that in the pathogenesis of hematological diseases contribute significantly to certain combinations of immune response genes.

Analysis of interactions between genes based on the distribution of immune response genes combinations in chronic lymphoproliferative disorders and multiple myeloma.

The study included 176 patients aged 22-86 years (median - 61 year), identifying themselves as Caucasians residing in one region in the northeast of the Russian Federation. This group consisted of 80 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (45%), 72 with multiple myeloma (41%), 10 with diffuse large B-cell lymphoma (6%) six with marginal zone lymphoma (3%) four with mantle cell lymphoma (2%), three with lymphoplasmacytic lymphoma (2%) and one patient with follicular lymphoma (1%). Genotyping of polymorphism of the innate immune response genes TLR2 (rs5743708), TLR3 (rs3775291), TLR6 (rs5743810), TLR9 (rs5743836), IL1β (rs2856841), IL2 (rs2069762), IL4 (rs2243250), IL6 (rs1800795), IL10 (rs1800871), IL17A (rs2275913), CD14 (rs34424920), TNFα (rs1800629), FCGR2A (rs1801274) was performed by polymerase chain reaction with allele-specific primers (Litech, Russia). Analysis of interactions between genes was performed using nonparametric GMDR program (Generalized Multifactor-Dimensionality Reduction) [Lou X.Y. et al, 2007.; http://www.healthsystem.virginia.edu/internet/addiction-genomics/Software/].

In the analyzed group of patients with CLD and MM identified almost 78 753 combinations of multi-locus genotypes of the 13 immune response genes is 1 594 323 theoretically possible, indicating the non-random nature of the combination of allelic variants of analyzed genes. A statistically significant two-, three-, four-, five-, six, seven- and eight-loci model of inter-gene interactions at the investigated hematological malignancies:

- IL4 (C-589T) and CD14 (C-159T) (χ²=8.39, p=0.0038);

- IL4 (C-589T) and CD14 (C-159T) and IL6 (C-174G) (χ²=12.14, p=0.0005);

- IL4 (C-589T) and IL17A (G-197A) and CD14 (C-159T) and IL6 (C-174G) (χ²=17.30, p<0.0001);

- IL4 (C-589T) and IL17A (G-197A) and IL10 (C-819T) and CD14 (C-159T) and IL6 (C-174G) (χ²=16.98, p<0.0001);

- IL4 (C-589T) and IL17A (G-197A) and IL10 (C-819T) and TNF (C-308A) and CD14 (C-159T) and IL2 (T-330G) (χ²=16.98, p<0.0001);

- IL4 (C-589T) and IL17A (G-197A) and IL10 (C-819T) and TNF (C-308A) and TLR9 (T-1237C) and CD14 (C-159T) and IL2 (T-330G) (χ²=16.98, p<0.0001);

- IL4 (C-589T) and IL17A (G-197A) and IL10 (C-819T) and TNF (C-308A) and TLR9 (T-1237C) and CD14 (C-159T) and IL2 (T-330G) and IL1b (T-31C) (χ²=16.98, p<0.0001);

- IL4 (C-589T) and IL17A (G-197A) and IL10 (C-819T) and TNF (C-308A) and TLR9 (T-1237C) and CD14 (C-159T) and IL2 (T-330G) and IL1b (T-31C) and TLR2 (Arg753Gln) (χ²=16.98, p<0.0001).

The findings suggest an important role of immune response genes in the development of a number of chronic lymphoproliferative disorders and multiple myeloma, and can later be used as diagnostic and prognostic markers of different types of hematological malignancies. In addition, provided bioinformatics model will reveal not only the genetic criteria for high and low risk of hematological malignancies studied, but also to determine their prognostic significance in the clinical course of these diseases.