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The aim of this study was to investigate the relationship between the HTR2A 1438A/G (rs6311) SNP and the risk of nicotine addiction in Yakuts. Methods and Results: A total of 292 people of Yakut nationality were tested (77 women and 215 men). Two groups of examined persons were formed: smokers (n=141) and non-smokers (NS, n=151). To determine the association of the studied SNP with the degree of smoking, the smoker group was divided into two subgroups: Heavy smokers (HS) and Light smokers (LS). Subjects who were smokers were classified based on their consumption of cigarettes per day (cpd), as follows: LS (n=10), those who consumed between 1 and 10 cpd, and HS (n=131), those who consumed ≥20 cpd. The study of the HTR2A 1438A/G (rs6311) SNP was performed by PCR and RFLP analysis. The A allele of the HTR2A 1438A/G (rs6311) SNP was associated with more of a risk for the HS group than the LS. Using the A allele as a risk factor, RR analysis showed a significant association with a risk factor when comparing HS with LS (RR=1.086; 95% CI=1.032-1.142; P=0.049). The analysis of the OR and RR between the HS and LS showed that the AA and AG genotypes were associated with an increased risk for heavy smoking (OR=9.714; 95% CI=1.196-78.874; RR =1.126; 95% CI=1.027-1.235; P=0.026). We cannot dismiss the possibility that our results may reflect the small sample size. Despite this potential limitation, the significant associations should not be disregarded and merit further investigation for clarification of these results.

Background: Genome-wide association studies identified the region of chromosome 3p21.31 as having the strongest association with the severe COVID-19 and susceptibility to SARS-CoV-2 infection. The aim of our study was to investigate the frequency of the risk A allele of rs17713054 localized in the 3p21.31 COVID-19 risk locus in Yakuts. Methods and Results: A total of 382 DNA samples from healthy Yakut volunteers (184 men and 198 women; the average age of 41.8±0.05 years) were examined. Our results show that the frequency of the risk A allele of the rs17713054 SNP in the Yakut population occurs at a frequency of 2% and generally corresponds to the frequency of East Asian populations (from 0% to 2%), geographically close to the Yakuts and belonging to the same Mongoloid race.

Background: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects. NSCL/P can be broadly divided into cleft lip only (CLO), cleft palate only (CPO), and cleft lip with cleft palate (CLP) based on clinical presentation. The aim of this study was to investigate the relationship between the IRF6 gene polymorphisms and non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Yakut population. Methods and Results: In 23 OFC patients and 58 unrelated control subjects from the Yakut population, we tested two SNPs (rs2235371 and rs861019) with a minor allele frequency of more than 5% in the candidate gene IRF6. We found that the SNP marker rs861019 showed significant differences in allele frequencies (OR=2.07, 95%CI: 1.01–4.23, P=0.04) between the NSCL/P patients and the comparison group. Analysis of allele frequencies for rs861019 SNP in subgroups showed that there was a difference in the frequency between CLP and control (OR=5, 95% CI: 1.61-15.53, P=0.11); however, this result was not significant. Genotype analysis showed significant differences in patients from the CLP subgroup in comparison with controls for homozygous (AA compared with GG) (OR=9.00, 95% CI: 1.03–78.58, P=0.03), heterozygous (GA compared with GG) (OR=5.50, 95% CI: 1.05-28.75, P=0.04,), recessive (GG compared with GA + AA) (OR=6.67, 95% CI: 1.61-27.58; RR=4.78, 95% CI: 1.42–16.10, P=0.008,) and co-dominant (GG compared with GA, compared with AA) (P=0.02) inheritance models. Diplotype analysis showed that the NSCL/P group was more likely to have the [CC]-[GG] diplotype than the comparison group. This diplotype carries the risk GG genotype (rs861019) (30.4%) and does not carry the risk T allele(rs2235371). In the CLP subgroup, two diplotypes ([CT]-[GG] and [CC]-[GG]) were found more often than in the comparison group. Both diplotypes carry the risk GG genotype(rs861019; 33.3%). In the CPO subgroup, the [CT]-[GG] diplotype was more common. In the CLO subgroup, only two diplotypes ([CC]-[GA] and [CC]-[GG]) were found, both of which were more common than in the comparison group (75% and 25%).. It is likely that these results for the CLO and CPO subgroups were influenced by the small size of both samples. Unlike the NSCL/P and CLP groups, in these samples, diplotypes with the homozygous genotype GG (rs861019) without the homozygous genotype TT (rs2235371) were more common. Diplotypes with a homozygous genotype of the TT risk allele were not found in the studied groups except for the comparison group, where the [TT]-[AA] diplotype was represented by a low frequency (0.17%). Conclusion: The present study provides strong statistical support (for the first time to our knowledge) that genetic variants of the IRF6 rs861019 SNP are associated with NSCL/P in Yakuts.

The aim of our study was to investigate the relationship between the MDR1 and MTHFR gene polymorphisms and non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Yakut population in the Republic of Sakha (Yakutia). Methods and Results: The sample of examined persons consisted of 60 children with NSCL/P. The NSCL/P group was divided into the CLP (cleft lip with cleft palate) subgroup (n=31), CLO (cleft lip only) subgroup (n=14), and CPO (cleft palate only) subgroup (n=15). The comparison group (control) included 174 healthy volunteers who did not have relatives with OFCs. The study of the MDR1 rs1045642 SNP and the MTHFR rs1801133 SNP was performed by PCR and RFLP analysis. Analysis of the frequency distribution of alleles and genotypes depending on the severity of clefts showed that the carriage of the TT homozygous genotype of the MDR1 rs1045642 SNP was associated with significant risk for the development of NSCL/P (OR=2.52, 95% CI: 1.19-5.32, P=0.02). Analysis of the recessive model (TT vs CC + TC) also found a significant risk of NSCL/P with the TT genotype carriage (OR=2.20, 95% CI: 1.06-4.57, P=0.04). Analysis of the over-dominant model (TC vs TT + CC) showed that the heterozygous TC genotype had a protective effect (OR=0.41; 95% CI: 0.22-0.77, P=0.01) on the development of NSCL/P. Subgroup analysis according to NSCL/P subtypes (CLO, CPO and CLP) showed that the MDR1 rs1045642 SNP was significantly associated with a high risk of CPO in three genetic models: heterozygous [(TT vs TC): OR=5.03; 95% CI: 1.55-16.32; P=0.01], recessive [(TT vs CC + TC): OR=3.96; 95% CI: 1.32-11.95; P=0.02], and over-dominant [(TC vs TT + CC): OR=0.23; 95% CI: 0.08-0.66; P=0.01]. Conclusion: A study of two SNPs in the MDR1and MTHFR genes revealed a statistically significant increased risk for NSCL/P in carriers of the TT genotype of the MDR1 rs1045642 SNP.

The goal of this study was to investigate the distribution of alleles and genotypes of the KCNJ11 rs5219, PPARG rs1801282, TCF7L2 rs7903146/rs12255372 SNPs in Yakuts with T2D, in comparison with other ethnic populations. Methods and Results: The study cohort consisted of 26 Yakut patients diagnosed with T2D (YKT2D). Genotyping of rs5219 (KCNJ11), rs1801282 (PPARG), rs7903146 and rs12255372 (TCF7L2) SNPs was performed by pyrosequencing using PyroMark Q48 Autoprep sequencer (QIAGEN). The genotyping of the studied group of Yakuts did not reveal statistically significant differences between control groups and YKT2D patients with respect to the polymorphic variants of the KCNJ11, PPARG, and TCF7L2 genes. The allele frequency analysis of the polymorphisms of the KCNJ11, PPARG, and TCF7L2 genes demonstrated a low frequency of the risk T-allele in the TCF7L2 (rs7903146, rs12255372) in Asian populations, compared to other human populations. We identified three haplotypes [CG (90.5%), TT (6.8%), and TG (2.7%)] in the YKT2D cohort. Also, we observed a strong LD between two SNPs (rs7903146 and rs12255372) of the TCF7L2 gene in the majority of groups, including YKT2D (D '= 1, LOD = 4.92), except for African populations, where a very weak LD (D '= 0.001-0.435, LOD = 0.0-0.73) was observed.

Background: The ABCB1 gene is responsible for resistance to various cytotoxic drugs. The product of the ABCB1 gene, P-glycoprotein (P-gp), acts as a transmembrane pump and influences the action of many drugs. More than 40 SNPs of the ABCB1 gene that alter the expression of P-gp have been identified. The ABCB1 rs1045642 SNP, designated as C3435T (C-the wild-type allele, T-the variant allele), correlates with the activity of P-gp. The aim of our research was to study the distribution of alleles and genotypes of the ABCB1 C3435T polymorphism in Yakuts, in comparison with other human populations. Methods and Results: The studied cohort included 149 healthy Yakut volunteers (36 men and 113 women). The average age of participants was 30.67±0.06 years. The ABCB1 gene is a highly polymorphic gene; the allele frequency of the C3435T polymorphism differs widely among the studied populations. The frequency of the mutant T-allele among the Yakuts was 51% .In the studied group of Yakuts, we revealed the prevalence of the heterozygous CT genotype (75.8%). The Yakuts have a relatively low frequency of CC (10.7%) and TT (13.4%) genotypes. This preliminary study did not include the objective of proving the relationship between the ABCB1 C3435T polymorphism and addictive disorders in Yakuts. The further search for functional polymorphisms of the ABCB1 gene and associations with addictive behavior using a systematic approach on larger samples is of great practical importance.

The aim of our research was to study the distribution of alleles and genotypes of the FTO rs9939609 SNP, the PNPLA3 rs738409 SNP, and the TM6SF2 rs58542926 SNP in the Yakut population. Methods and Results: A total of 85 DNA samples from the population were tested. An analysis of the frequency distribution of alleles and genotypes of the FTO rs9939609 SNP in the study group did not reveal significant differences. An analysis of the frequency distribution of alleles and genotypes of the PNPLA3 rs738409 SNP revealed that in men and women the G allele and the homozygous GG genotype prevailed. The results of the analysis of the frequency distribution of alleles and genotypes of the TM6SF2 rs58542926 SNP showed the predominance of individuals with the C allele (89% in men and 90% in women) with statistical significance in women. Conclusion: The further studies with a larger sample size are required to detect the features of the distribution of alleles and genotypes of the FTO rs9939609 SNP and the TM6SF2 rs58542926 SNP in that population.

Background: The pathogenetic mechanisms of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are closely related. Currently, multiple studies have demonstrated a link between the PNPLA3 148M variant and the development and progression of NAFLD, including liver fibrosis. The aim of our research was to study the distribution of alleles and genotypes of the PNPLA3 rs738409 SNP in Russians and Yakuts living in Yakutia, as well as to search for associations of the PNPLA3 rs738409 SNP in patients with T2D and non-alcoholic fatty liver disease / non-alcoholic steatohepatitis. Methods and Results: The study included 179 patients (28 Russians and 151 Yakuts) with T2D and concomitant liver diseases of non-infectious origin. The comparison group consisted of 147 healthy volunteers of Russian ethnicity and 246 healthy volunteers of Yakut ethnicity. The PNPLA3 738409 SNP was analyzed by PCR-RFLP reaction. The results found a significant difference between the frequencies of the PNPLA3 rs738409 genotypes and alleles in Russians and Yakuts, both among healthy volunteers and in T2D patients with liver diseases. The frequency of the G allele occurrence in the group of healthy Yakuts was significantly higher (OR- 3.313; 95% CI: 2.444-4.499; P

Background: The first GWAS searching for such genetic factors identified the PNPLA3 gene as a major genetic determinant for the predisposition to nonalcoholic fatty liver disease in Hispanic, African American, and European American populations, according to liver fat contents, a finding that was subsequently confirmed by liver biopsy in Europeans and Asians. The aim of our research was to study the distribution of alleles, genotypes, haplotypes and diplotypes of polymorphic variants of the PNPLA3 gene (rs2294918 and rs738409) in Yakuts. Methods and Results: The PNPLA3 SNPs (rs2294918 and rs738409) were analyzed by PCR-RFLP reaction. The PNPLA3 rs738409 SNP in the Yakut population is characterized by a high frequency of the risk G allele (72%). According to the PNPLA3 rs2294918 SNP, which suppresses the negative effect of rs738409, the protective PNPLA3 (rs2294918) A allele was found only in 10.7% of study subjects. Analysis of the distribution of the frequency of genotypes in the studied sample of Yakuts showed the predominance of the carriage of the PNPLA3 rs738409 GG genotype (57.3%) and the PNPLA3 rs2294918 GG genotype (80.7%). The frequency of the PNPLA3 (rs2294918) AA and AG genotypes was 2.0% and 17.3%, respectively. The Yakuts often have two diplotypes [GG]-[GG] and [CG]-[GG]. Both diplotypes carry the PNPLA3 rs738409 G allele (45.3% and 28%) and do not carry the PNPLA3 rs2294918 A allele. The high frequency of the [GG]-[GG] and [CG]-[GG] diplotypes in Yakuts (45.3% and 25%, respectively), carrying mutant alleles G (rs738409) and not carrying the A allele (rs2294918), indicates that these diplotypes were probably adaptively favorable to the Yakuts. Conclusion: The analysis of haplotypes and diplotypes based on the markers rs738409 and rs2294918 of the PNPLA3 gene may contribute to future new biomarkers for the diagnosis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, as well as provide fundamental knowledge on human adaptation to cold.

Background: Mutations in the JAK2, CALR, and MPL genes are key factors of the classical Ph-negative CMPD pathogenesis with demonstrated diagnostic and prognostic value. The aim of this research was to study the prevalence of JAK2, CALR, and MPL mutations in patients with CMPD and healthy individuals in the Republic of Sakha (Yakutia) (RS(Y)). Methods and Results: The study included patients with previously confirmed diagnoses of PV (n=15), ET (n=16), and PMF (n=11) and 68 people with peripheral blood changes, suspected to have CMPD. The control group included 184 healthy volunteers. All patients and participants in the control group were genotyped according to the following SNPs: the JAK2 rs77375493 SNP, the CALR rs765476509 SNP, the CALR rs1450785140 SNP, the MPL rs121913616 SNP, and the MPL rs121913615. The prevalence of the JAK2V617F mutation among PV patients in the RS(Y) was 90.9%. Patients with ET in 61.3% of cases were carriers of the JAK2V617F mutation, in 6.4% of CALR mutations, and in 3.2% of the MPLW515L mutations. In PMF patients, the JAK2V617F mutation was detected in 64.7% of cases, and the Type 1 CALR mutation was detected in 17.6% of cases. Carriage of the JAK2V617F mutation was revealed in 1.1% of healthy individuals and in 4.4% of individuals with initial signs of a myeloproliferative process. Conclusion: Early molecular genetic testing will improve the timely diagnosis of CMPD and possibly reduce the number of complications.

Background: The aim of this study was to search for associations between polymorphisms of the IRF6, MDR1, and MTHFR genes and the risk of congenital orofacial cleft (OFCs) among the population of the Republic of Sakha (Yakutia). Methods and Results: The sample of the studied individuals consisted of 94 children (46 girls and 48 boys) with OFCs and their parents (75 mothers and 18 fathers). The children with OFCs were divided into 3 groups. Group 1 included 48 children with cleft lip and palate (CLP); Group 2 included 22 children with cleft lip (CL); Group 3 included 24 children with cleft palate (CP). The comparison group included 156 healthy volunteers (118 women and 38 men) who did not have a history of relatives with OFCs. Analysis of the distribution of alleles and genotypes of studied SNPs in children with all OFCs and healthy children showed a significant (P=0.000) difference only in MDR1 genetic variant rs1045642 SNP. The carriage of the TT genotype of the MDR1 rs1045642 SNP was associated with increased risk of OFCs (OR=2.711, 95% CI=1.459-5.037; P=0.000). Analysis of the frequency distribution of alleles and genotypes depending on the severity of clefts showed that the carriage of the TT genotype of the MDR1 rs1045642 SNP was associated with significant risk for development of CL (OR = 3.114; 95% CI = 1.123-8.634) and CLP (OR = 2.804; 95% CI = 1.333-5.895). In children with CP, we found significant risk with carriage of the TT genotype of the IRF6 rs2235371 SNP (OR = 5,429, 95% CI = 1,135-25,962; P=0.035). Conclusion: A study of four SNPs in the IRF6, MDR1, and MTHFR genes revealed statistically significant increased risks for OFCs in carriers of the TT genotype of the MDR1 rs1045642 SNP; in addition, the carriage of the TT genotype of the IRF6 rs2235371 SNP significantly increased the risk of CP development.

The purpose of this study was to determine T1D-susceptible HLA DR-DQ haplotypes in Yakuts using 3 single nucleotide polymorphisms (rs3104413C/G, rs2854275G/T and rs9273363A/C). A total of 92 patients with a verified diagnosis of T1D (Group 1) were examined. The comparison group consisted of 210 people (Group 2) without autoimmune diseases and without hereditary predisposition. All participants were Yakuts by ethnicity. According to the results of genotyping, it was established that the haplotype DRB1*03:01-DQA1*05:01-DQB1*02:01 corresponds to the rs3104413C/C-rs2854275T/T combination and the rs3104413C/G-rs2854275G/T-rs9273363C/C combination. DRB1*04:01–DQA1*03:01-DQB1*03:02 haplotype (DR4-DQ8) is the rs3104413G/G-rs9273363A/C combination, the rs3104413C/G-rs2854275G/G-rs9273363A/C combination, and the rs3104413C/G-rs2854275G/G-rs9273363A/A combination. DR3/4-DQ8 haplotype is the rs3104413C/G-rs2854275G/T-rs9273363A/A combination and the rs3104413C/G-rs2854275G/T-rs9273363A/C combination. DRB1*04:01-DQA1*03:01-DQB1*03:01 haplotype is the rs3104413G/G-rs9273363C/C combination, the rs3104413C/G-rs2854275G/G-rs9273363C/C combination, and the rs3104413C/G-rs2854275G/T-rs9273363C/C combination. A combination of rs3104413C/C with rs2854275G/G was characterized by the absence of DR3 and DR4, which may be due to the presence of a different genetic variant in these individuals. A combination of rs3104413C/C with rs2854275G/T was characterized by the presence of only one type of DR3 and a variant of the type that does not belong to either DR3 or DR4. An analysis of the evaluation of the effectiveness of a diagnostic test using the Youden index demonstrated significance for all combinations of genotypes of the studied polymorphisms.

The purpose of the present study was to evaluate a possible interrelation of the FTO rs9939609 SNP and the DAT1 rs27072 SNP with BMI and grade of obesity in the population of Yakuts Materials and Methods: A total of 191 people of Yakut nationality were tested (143 women and 48 men). Two groups of subjects were formed: the control group (CG) with BMI˂25 kg/m2 and the obesity group (OG) with BMI≥30 kg/m2. The study of the FTO rs9939609 SNP and the DAT1 rs27072 SNP was performed by PCR and restriction fragment length polymorphism. Results: According to the results obtained from all persons surveyed, the frequency of the A risk allele of the FTO rs9939609 SNP was 27% with the AA genotype frequency of 9.4%. Analysis of the distribution of alleles and genotypes of the DAT1 rs27072 SNP showed the predominance of the wild-type G allele (90.8%) and the GG genotype in all groups (82.7%). Thus, in the Yakut population, a reliable relationship was found between the carriage of the A risk allele of the FTO SNP rs9939609 SNP with obesity and the degree of obesity. A significantly higher BMI was found in carriers of the wild-type G allele of the DAT1 rs27072 SNP, both in the heterozygous and homozygous forms than in the carriers of the homozygous AA genotype, which is probably related to the small number of people studied and requires careful research on larger samples of populations of Yakutia.

The research objective was to conduct a retrospective study of patients with Juvenile arthritis (JA) in association with the carriage of the HLA-B27 allele. Materials and Methods: A total of 73 patients (39 boys and 34 girls aged from 1 to 16 years, mean age of 10.28±4.24 years) living in Yakutia with Juvenile Chronic Arthritis (JCA), Juvenile Ankylosing Spondylitis (JAS), Juvenile Psoriatic Arthritis (JPsA), and reactive arthritis (RA) were examined. Among them, 62(84.9%) children were of Yakut nationality, and 11(15.1%) – the Russian nationality. The control group included 85 Yakuts without clinical diagnosis of arthritis. Testing for the HLA-B27 allele was performed according to Dominquez et al. (1992) as modified by Steffens-Nakken et al. (1995). Results: According to the genotyping results, in 30 of 73 examined samples an association was found between the HLA-B27 allele carriage and JA. The HLA-B27 allele was diagnosed in 24(38.7%) Yakuts and 6(54.5%) ethnic Russians. For further analysis, all patients (Yakuts, Russians) were divided into diagnosis-related groups. Diagnoses of JAS (n=10) and JCA (n=9) prevailed in Yakuts. In the Russian children, RA was more common (n=4). In population sampling of Yakuts, the frequency of the HLA-B27 allele was 33%. A comparison of the frequencies of the HLA-B27 allele among the Yakut patient groups and the control group found a statistically significant association with JAS. The carriage of the HLA-B27 allele in Yakut females did not increase the risk of JAS development, whereas in male Yakuts this risk increased by 5.6 times.