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.

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.

Клинико-генеалогический и молекулярно-генетический анализ на наличие мутаций в гене ATXN1 был проведен среди всей выборки-177 человек. Из них у 104 пациентов с экспансией CAG-повторов в гене ATXN1 выявлен средний возраст начала заболевания в зависимости от количества патологических CAGповторов. Выявлено, что чем больше количество патологического повтора, тем раньше появляются симптомы заболевания. На базе больницы ЯНЦ КМП с октября 2017 г. по сентябрь 2018 г. прошли стационарное лечение 22 больных из 104 пациентов, с подтвержденным диагнозом СЦА 1. Всем был назначен поддерживающий курс терапии: аминоплазмаль 250,0 через день №5, сосудистая терапия, ЛФК. Всех больных подвергали оценке по шкале SARA (Scale for the Assessment and Rating of Ataxia). 19 больных хорошо перенесли курс аминокислот и отмечали отчетливое субъективное и объективное улучшение специфических атаксических дисфункций координации движений. Мы предполагаем, что более быстрый и длительный эффект от курса поддерживающей терапии дают пациенты с наименьшим количеством патологического CAG-повтора. Для подтверждения своей теории требуется наблюдение больных в динамике в более большой выборке. Экспансия CAG-повторов в гене ATN1 была найдена у 5 человек из одной якутской семьи, у 4 взрослых с клиникой атаксии и 1 ребенка без признаков атаксии. У всех четверых был поздний дебют заболевания, в клинике: атаксия, хореоатетоз и психические нарушения. Ключевые слова: полиглутаминовые заболевания, спиноцеребеллярная атаксия 1 типа, дентаторубропаллидолюисовая атрофия, экспансия тринуклеотидных повторов, аутосомно-доминантное заболевание, якуты.

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.

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