Genetic outline of the hermeneutics of the diseases connection phenomenon in human.

The structure of diseases in humans is heterogeneous, which is manifested by various combinations of diseases, including comorbidities associated with a common pathogenetic mechanism, as well as diseases that rarely manifest together. Recently, there has been a growing interest in studying the patterns of development of not individual diseases, but entire families associated with common pathogenetic mechanisms and common genes involved in their development. Studies of this problem make it possible to isolate an essential genetic component that controls the formation of disease conglomerates in a complex way through functionally interacting modules of individual genes in gene networks. An analytical review of studies on the problems of various aspects of the combination of diseases is the purpose of this study. The review uses the metaphor of a hermeneutic circle to understand the structure of regular relationships between diseases, and provides a conceptual framework related to the study of multiple diseases in an individual. The existing terminology is considered in relation to them, including multimorbidity, polypathies, comorbidity, conglomerates, families, "second diseases", syntropy and others. Here we summarize the key results that are extremely useful, primarily for describing the genetic architecture of diseases of a multifactorial nature. Summaries of the research problem of the disease connection phenomenon allow us to approach the systematization and natural classification of diseases. From practical healthcare perspective, the description of the disease connection phenomenon is crucial for expanding the clinician's interpretive horizon and moving beyond narrow, disease-specific therapeutic decisions.

[Genetic Predisposition to Early Myocardial Infarction].

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

[Comparative analysis of gene expression in vascular cells of patients with advanced atherosclerosis]. / Sravnitel'nyi analiz ékspressii genov v kletkakh sosudov u bol'nykh s klinicheski vyrazhennym aterosklerozom.

In this study we performed a comparative gene expression analysis of carotid arteries in the area of atherosclerotic plaques and healthy internal mammary arteries of patients with advanced atherosclerosis by using microarray HumanHT-12 BeadChip ("Illumina"). The most down-regulated genes were APOD, FABP4, CIDEC and FOSB, and up-regulated gene was SPP1 (|FC|>64; pFDR<0.05). The majority of differentially expressed genes were down-regulated in advanced atherosclerotic plaques. Unexpectedly, genes involved in immune and inflammatory responses were down-regulated in advanced atherosclerotic plaques to compare with the healthy arteries (arachidonic acid metabolism, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, Jak-STAT signaling pathway, TNF signaling pathway). "Cellular response to metal ion" (metallothioneins) and "Extracellular matrix organization" were the most significant Gene ontology terms among the down- and up-regulated genes, respectively.

[Fibrogenesis Genes and Susceptibility to Coronary Atherosclerosis].

OBJECTIVES: To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course. METHODS: We included in this study 404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with "stats" and "genetics" packages. RESULTS: We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character of the course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; р=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; р=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; р=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; р=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; р=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; р=0.0274). CONCLUSION: Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).

Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium.

BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.

[Analysis of Heteroplasmy in the Major Noncoding Region of Mitochondrial DNA in the Blood and Atherosclerotic Plaques of Carotid Arteries].

For identification of somatic mitochondrial DNA (mtDNA) mutations, the mtDNA major noncoding region (D-loop) sequence in blood samples and carotid atherosclerosis plaques from patients with atherosclerosis was analyzed. Five point heteroplasmic positions were observed in 4 of 23 individuals (17%). Only in two cases could heteroplasmy have resulted from somatic mutation, whereas three heteroplasmic positions were found in both vascular tissue and blood. In addition, length heteroplasmy in a polycytosine stretches was registered at nucleotide positions 303-315 in 16 individuals, and also in the 16184-16193 region--in four patients. The results suggest that somatic mtDNA mutations can occur during atherosclerosis, but some heteroplasmic mutations may appear in all tissues, possibly being inherited.

[Genes for Fibrogenesis in the Determination of Susceptibility to Myocardial Infarction].

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19-2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05-2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06-4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07-2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03-2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02-2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

[The Study of Associations of Polymorphisms of Candidate Gene of Cardiovascular Diseases With Reduction of Glomerular Filtration Rate in Patients With ST Segment Elevation Myocardial Infarction].

AIM: to study associations of polymorphic genetic variants of inflammatory response, endothelial function, lipid metabolism, and blood coagulation with impaired renal function in patients with ST elevation myocardial infarction (STEMI). MATERIAL AND METHODS: We enrolled in the study 171 patients admitted to the Kemerovo Cardiology Dispensary within 24 hours after onset of STEMI. All patients underwent genotype identification of 25 polymorphic variants of 18 major candidate genes for cardiovascular disease. Genotyping was performed with DNA chip SINKAR-1 (Institute of Medical Genetics and LLC "Genomic Diagnosis"). Glomerular filtration rate (GFR) was estimated using serum creatinine level measured at admission. RESULTS: Comparison of allelic and genotype frequencies of the studied polymorphisms revealed that angiotensin-converting enzyme (ACE) gene rs4291 was associated with decreased GFR: odds ratio (OR) for carriers of rare TT genotype was 2.31 [1.01-5.25], =0.043. Analysis of genotype combinations of ACE rs4343 polymorphism and hepatic lipase gene (LIPC) rs1800588 showed that AA genotype of rs4343 polymorphism in combination with CC genotype of rs1800588 polymorphism was associated with lowest risk of renal dysfunction, whereas GG and AG genotypes of ACE rs4343 in combination with TT and CT genotypes of LIPC rs1800588.

[ Mitochondrial DNA polymorphism association with myocardial infarction and prognostic signs for atherosclerosis].

We have performed association analysis for mtDNA most common variants and haplogroups with myocardial infarction and some prognostic characteristics in patients. Comparison of patients (N=406) and controls (N=183) has shown higher frequency of HV0 haplogroup in patients (6.9% vs. 2.2%; p=0.033). Patients with early infarction (before age 55), comparing to patiens older than 55 and the first infarction, had higher frequency of 16189C variant (24.1 vs. 12.5%; p=0.008); also, haplogroup U2e was registered only in the subgroup with early infarction (4.4%; p=0.004). On the other side, haplogroup U5 was less frequent in the patients with early infarction (5.1% vs. 15.4%; p=0.002). The patients with recurring cardiovascular incidents during one year follow-up had higher frequency of haplogroup H1 (20% versus 4.5% in the patients without complications, p=0.002) and variant 16189C (30% versus 13.5%; p=0.018). Haplogroup U5 was more frequent in the group of patients with left ventricular ejection fraction less than 40%: 17.1% comparing to 8.2% in the group with ejection fraction>40%; p=0.034. The results suggest that mtDNA polymorphism contributes to coronary atherosclerosis. The associations could be explained by the polymorphism effect on oxidative phosphorylation and reactive oxygen production in mitochondria.

[Characteristic of the Genetic Variability of Four Polymorphic Variants (rs2069705, rs17880053, rs11126176, and rs804271) in Representative Samples of Indigenous and Alien Populations of Siberia].

The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the alien Russian population. All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.

Genomic Study of Cardiovascular Continuum Comorbidity.

Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.

[Genetic Bases of Human Comorbidity].

In this review, the development of ideas focused on the phenomenon of disease combination (comorbidity) in humans is discussed. The genetic bases of the three forms of the phenomenon, comorbidity (syntropias), inverse comorbidity (dystropias), and comorbidity of Mendelian and multifactorial diseases, are analyzed. The results of personal genome-wide association studies of the genetic risk profile that may predispose an individual to cardiovascular disease continuum (CDC), including coronary heart disease, type 2 diabetes, hypertension, and hypercholesterolemia (CDC syntropy), as well as the results of bioinformatic analysis of common genes and the networks of molecular interactions for two (bronchial asthma and pulmonary tuberculosis) diseases rarely found in one patient (dystropy), are presented. The importance of the diseasome and network medicine concepts in the study of comorbidity is emphasized. Promising areas in genomic studies of comorbidities for disease classification and the development of personalized medicine are designated.

[TOMM40 gene polymorphism association with lipid profile].

The distribution of the allele and genotype frequency for the TOMM40 gene polymorphic variants rs741780, rs157580, rs1160985, rs2075650, and rs8106922 was analyzed in a sampling of ethnic Russians from the city of Kemerovo. The study of the structure of linkage disequilibrium in terms of five studied polymorphic variants showed the presence ofa haplotype block 2 Kb in length, which includes three polymorphic variants, i.e., rs741780, rs1160985, and rs8106922. The differences in the frequencies of alleles and genotypes in terms of the polymorphic rs2075650 and rs157580 variants between ethnic Russians from the city of Kemerovo and other European populations were detected. It was discovered that polymorphic variants of TOMM40 rs741780, rs1160985, and rs8106922 are associated with serum triglyceride concentrations. In men, the polymorphic variant rs2075650 is associated with low-density lipoprotein cholesterol levels. In women, the polymorphic variant rs741780 is associated with diastolic blood pressure levels.

[Somatic genome variations in vascular tissues and peripheral blood leukocytes in patients with atherosclerosis].

The first data on the existence of multiple genomic rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity, in vascular tissues and peripheral blood leukocytes from patients with atherosclerosis, are presented. Compared to internal mammary arteries and peripheral blood leukocytes, right coronary arteries in the atherosclerotic plaque area presented with a higher CNV length and number of genes located in their vicinity. In each of the patients, 6-16% of CNVs were common to the three types of tissues examined. Therefore, most of the copy number variations in the tissues affected by atherosclerosis (from 68 to 91% in each of the patients) were of somatic origin. The gains in 3p21.31 (CACNA2D2), 7q32.1 (FLNC), 19p13.3 (C19orf29, PIP5K1C), and 21q22.3 (COL6A1) were detected in vascular tissues but not in peripheral blood leukocytes. Moreover, the gain in 7p15.2 (SKAP2), detected in the patients with atherosclerosis, did not overlap with any CNV regions currently reported in The Database of Genomic Variants. The loss of heterozygosity in 12 out of 13 chromosomal regions was copy neutral and covered tumor suppressor genes (SFRP1, CEBPD, RB1CC1, DIRAS3, TUSC3, and ZDHHC2).

[Association of polymorphism Rs6737848 in the Socs5 gene with bronchial asthma].

AIM: To investigate the role of polymorphic variants of immune-response modifying genes in predisposition to asthma. PATIENTS AND METHODS: The analysis of restriction fragments length polymorphism was used to investigate 10 single-nucleotide polymorphisms: IFNG rs2069705, IFNGR2 rs17880053, IL4 rs 2070874, IL4RA rs 1805010, GATA3 rs10905277, TBX21 rs11652969, PIASY rs3760903, PIAS3 rs12756687, STATS rs16967593, and SOCS5 rs6737848 in 106 asthma patients and 115 healthy people. RESULTS: The rs6737848 SOCS5 polymorphism was significantly associated with asthma in additive model (p = 0.05, OR = 0.338, 95% CI 0.158-0.723) and in dominant model (p = 0.02, OR = 0.284, CI 0.126-0.638). None of the polymorphisms of the studied genes was associated with total IgE levels. CONCLUSIONS: This is the first report on the association of rs6737848 SOCS5 with asthma.

[Effect of additional disease (comorbidity) on association of allergic rhinitis with KCNE4 gene rs12621643 variant].

Analysis of association of allergic rhinitis with the KCNE4 gene rs12621643 variant was conducted in Russian residents of Western Siberia (taking into account comorbidity with bronchial asthma). It was found that, among individuals without bronchial asthma, the frequencies of the KCNE4*G allele and KCNE4*G/G genotype are significantly higher in patients with rhinitis compared to individuals without it. At the same time, no association of rs12621643 with rhinitis was detected in the group of individuals with bronchial asthma. The data obtained indicate the association of the KCNE4 gene variability with allergic rhinitis, although the effect of this gene relative to the development of the disease can be leveled against a background of the manifestation of another atopic disease.

[DNA methylation profiling of the vascular tissues in the setting of atherosclerosis].

To date the question of epigenetic mechanisms of gene regulation in the context of cardiovascular diseases is of a considerable interest. Here, for the first time DNA methylation profiles of vascular tissues of atherosclerotic patients have been analyzed with using the microarray Infinium HumanMethylation27 BeadChip ("Illumina", USA). As the result, within 286 genes 314 CpG-sites that varied significantly in the DNA methylation level between the tissue samples of carotid (in the area of atherosclerotic plaques and nearby macroscopically intact tissues of the vascular wall) and mammary arteries as well saphenous veins have been identified. The most pronounced differences in the methylation level were registered for CpG-sites of homeobox genes HOXA2 and HOXD4 as well as imprinted gene MEST. In particular, these genes were found to be hypomethylated in the carotid atherosclerotic plaques compared to their methylation patterns in intact tissues of internal mammary arteries and saphenous veins.

[Expression profile of calcineurin pathway genes in myocardium tissues in relation to ischemic heart remodeling in humans].

Calcineurin pathway plays the critical role in the cardiac remodeling of various origin, development of chambers dilatation and progression of heart failure. Components of calcineurin pathway are involved in myocardium hypertrophy regulation, angiogenesis and apoptosis. Results of quantitative expression profiling study of main calcineurin pathway genes PPP3CA, PPP3R1, PPP3CB, GATA4 and NFATC4 in myocardium of right atrium auricle of patients with a coronary heart disease, exposed to various types of surgical treatments depending on weight of a clinical finding (surgical reconstruction of the geometry of left ventricle (LV) (postinfarction aneurysm) or coronary artery bypass grafting in case of unaltered morphology of LV) are presented. In patients with sizable postinfarction LV dilatation (n = 21) expression level of calcineurin catalytic subunit genes PPP3CA and PPP3CB was 1.3 and 1.6 times lower (p = 0.018 and 0.023, accordingly) compared to patients with unaltered shape of the heart (n = 34). Expression level of PPP3R1 gene encoding calcineurin regulatory subunit B and GATA4 and NFATC4 genes for transcription factors did not differ in studied subgroups of patients. Thus, lower expression of PPP3CA and PPP3CB genes in atrium myocardium can be related to expressed postinfarction LV remodeling. Further studies of relation quantitative expression profiling of calcineurin pathway genes with the level of damage of myocardium is essential what may have important outcome for the prevention of adverse events of cardiosurgical treatments in patients with postinfarction remodeling.

[The first results of a combined all-Russian study on clinical genetics of multiple sclerosis].

Multiple sclerosis is a classic multifactorial disease in which etiology interaction of external factors and structural features of a large number of genes plays an important role. Identifying risk factors for multiple sclerosis and creating an integrated model of pathogenesis are urgent tasks of neurology. Revealing true risk factors is possible only in studies with sufficient statistical power, so with a large amount of samples. We conducted the association study of CD40 gene's polymorphisms and multiple sclerosis among residents of the Russian Federation. The results demonstrated the need to combine data from different researchers in clinical studies to increase the power of the study.