Association of the IRF6 rs2235371 and rs861019 Polymorphisms with Non-Syndromic Cleft Lip with or without Cleft Palate in the Yakut Population

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.

Frequency of I148M Polymorphism of the PNPLA3 Gene Associated with a Risk of Steatosis and Liver Fibrosis in Residents of the Republic of Sakha (Yakutia)

Background Single nucleotide polymorphism (SNP) are the most common type of genetic polymorphism. SNP can significantly affect the expression activity of genes and the level of protein production. Researching the role of SNP in the occurrence of diseases is an important and urgent task, as it allows to predict the risk of pathology, its severity and outcome. Purpose of the study: study of the frequency of I148M polymorphism of the PNPLA3 gene in residents of the Republic of Sakha (Yakutia), associated with a high risk of steatosis and liver fibrosis. Methods A total of 3132 peripheral venous blood samples were used for population studies, studies patients with chronic hepatitis B and C, studies patients with NAFLD. Genotyping of DNA samples was carried out by real time-PCR. Reagent kits were used for genotyping I148M polymorphism of the PNPLA3 gene. Results In the present study, it was found that in the Yakut population the carriage of the GG genotype (49%) of the PNPLA3 gene I148M polymorphism predominates. When conducting a comparative frequency analysis, there were no statistically significant differences between the control group and the group with NAFLD patients(p=0,82). A comparative frequency analysis of the distribution of genotypes and alleles of I148M polymorphism of the PNPLA3 gene in the control group and the group of patients with chronic hepatitis B and C showed that we did not reveal significantly significant differences (p = 0.45). Conclusions The frequency of homozygotes for the mutant G allele of the I148M polymorphism of the PNPLA3 gene in the Yakut population significantly exceeds the frequency indicator of the G allele in other world populations.

The FTO, PNPLA3 and TM6SF2 Gene Polymorphisms and Genetic Predisposition to NAFLD in Yakut Population

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.

The structure of Haplotypes and Diplotypes in the PNPLA3 gene in the Yakut Population

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.

POLYMORPHISMS OF ENDOTHELIAL DYSFUNCTION GENES NOS3 AND CYBA IN YAKUT POPULATION

Polymorphisms of different genes can predispose people to various diseases. They can influence the body's physiological response to exogenous risk factors. Polymorphisms of the endothelial dysfunction genes NOS3 and CYBA contribute to the development of socially significant diseases, such as acute coronary syndrome, stroke, as well as diseases accompanied by fibrotic changes (cirrhosis of the liver, pulmonary fibrosis, etc.). Therefore, the study of these genes in the Yakut population seems relevant. The present study involved 124 healthy volunteers, their ethnicity is Yakuts (including Yakuts in the third generation, living in the Republic of Sakha (Yakutia)). Genetic analysis of polymorphisms was performed by the method of polymerase chain reaction of restriction fragment length polymorphisms (PCR-RFLP). The study found that healthy Yakuts have GG homozygote of rs1799983 of the NOS3 gene in 83.87%, GT - 15.32%, TT - 0.81%. The frequency of the G allele was 91.53%, the T allele - 8.47%. The study found that healthy Yakuts have CC homozygote of rs4673 of the CYBA gene in 75.0%, CT - 21.77%, TT - 3.23%. The frequency of C allele was 91.44%, T - 8.56%. These results are consistent with the literature data. Thus, the research of the polymorphism rs1799983 of the NOS3 gene and rs4673 of the CYBA gene in various ethnic groups could have encouraging prospects in the personalized medicine for predicting pathological conditions associated with endothelial dysfunction: liver fibrosis, cardiovascular diseases, obstetric and gynecological pathologies, dysfunctions of various organs and systems.

The prevalence of type 1 spinocerebellar ataxia in Yakutia: current status

Республика Саха (Якутия) является одним из крупнейших очагов накопления спиноцеребеллярной атаксии 1 типа в мире. В 1997 году показатель распространённости СЦА1 среди якутов составлял 35 случаев на 100000 населения, а в настоящее время данный показатель возрос до 77,6 случаев. Значительный прирост показателей распространённости СЦА1 может быть объяснён внедрением системы учёта семейных случаев и современных молекулярно-генетических методов диагностики мутации. С другой стороны, результаты мониторинга свидетельствуют о продолжающемся накоплении мутации в якутской популяции. Кроме того, установлено расширение границ известных географических очагов накопления мутации и сделано предположение о популяционной неоднородности носителей мутации по числу CAG повторов. The Republic of Sakha (Yakutia) is one of the largest centers of accumulation of type 1 spinocerebellar ataxia in the world. In 1997, the prevalence of the SCA1 mutation among Yakuts was 35 cases per 100,000 population, and now this indicator has increased to 77.6 cases. A significant increase in the prevalence rates of SCA1 can be explained by the introduction of a family case accounting system and modern molecular genetic methods for the diagnosis of mutations. On the other hand, the monitoring results indicate the ongoing accumulation of mutations in the Yakut population. In addition, it was found that the boundaries of the known geographical centers of mutation accumulation were expanded and an assumption was made about the population heterogeneity of mutation carriers by the number of CAG repeats.