Moldova has a rich historical and cultural heritage, which may be reflected in the current genetic makeup of its population. To date, no comprehensive studies exist about the population genetic structure of modern Moldavians. To bridge this gap with respect to paternal lineages, we analyzed 37 binary and 17 multiallelic (STRs) polymorphisms on the non-recombining portion of the Y chromosome in 125 Moldavian males. In addition, 53 Ukrainians from eastern Moldova and 54 Romanians from the neighboring eastern Romania were typed using the same set of markers. In Moldavians, 19 Y chromosome haplogroups were identified, the most common being I-M423 (20.8%), R-M17* (17.6%), R-M458 (12.8%), E-v13 (8.8%), R-M269* and R-M412* (both 7.2%). In Romanians, 14 haplogroups were found including I-M423 (40.7%), R-M17* (16.7%), R-M405 (7.4%), E-v13 and R-M412* (both 5.6%). In Ukrainians, 13 haplogroups were identified including R-M17 (34.0%), I-M423 (20.8%), R-M269* (9.4%), N-M178, R-M458 and R-M73 (each 5.7%). Our results show that a significant majority of the Moldavian paternal gene pool belongs to eastern/central European and Balkan/eastern Mediterranean Y lineages. Phylogenetic and AMOVA analyses based on Y-STR loci also revealed that Moldavians are close to both eastern/central European and Balkan-Carpathian populations. The data correlate well with historical accounts and geographical location of the region and thus allow to hypothesize that extant Moldavian paternal genetic lineages arose from extensive recent admixture between genetically autochthonous populations of the Balkan-Carpathian zone and neighboring Slavic groups.

A variety of hypotheses have been proposed to explain the association between trisomy and increasing maternal age in humans, virtually all of which assume that the underlying mechanisms involve meiotic errors. However, recently Hultén and colleagues [Hulten et al., 2010b] proposed a provocative model-the Oocyte Mosaicism Selection Model (OMSM)-that links age-dependent trisomy 21 to pre-meiotic errors in the ovary. Specifically, they propose that nondisjunctional events occur in a proportion of germ cells as they mitotically proliferate, resulting in mosaicism for trisomy 21. Assuming that the presence of an additional chromosome 21 delays meiotic progression, these cells would be ovulated later in reproductive life, resulting in an age-dependent increase in aneuploid eggs. Because this model has important clinical implications, we initiated studies to test it. We first analyzed oocytes from two trisomy 21 fetuses, combining immunostaining with FISH to determine the likelihood of detecting the additional chromosome 21 at different stages of meiosis. The detection of trisomy was enhanced during the earliest stage of prophase (leptotene), before homologs synapsed. Accordingly, in subsequent studies we examined the chromosome content of leptotene oocytes in seven second trimester female fetuses, analyzing three chromosomes commonly associated with human trisomies (i.e., 13, 16, and 21). In contrast to the prediction of the OMSM, we found no evidence of trisomy mosaicism for any chromosome. We conclude that errors in pre-meiotic germ cells are not a major contributor to human aneuploidy and do not provide an explanation for the age-related increase in trisomic conceptions.

Childhood asthma candidate gene PPP1R12B was identified in the first genomewide association study (GWAS) in Russians of west Siberia. Here, we report validation of this discovery in an independent cohort of Russians from the city of Kursk. Twenty-six single-nucleotide polymorphisms (SNP) in the gene were analysed, of which four were significantly associated with childhood asthma. Haplotypic structure of four markers was different in control and childhood asthma samples, implicating the importance of PPP1R12B haplotypes in predisposition to the disease. The haplotype comprising common alleles was protective against asthma, while other haplotypes were positively associated with the disease. We propose possible mechanisms of the association, including impact of the gene on airway hyperresponsiveness and C-C chemokine receptor 3 signalling pathway modulation.

Background: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.

Objective: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.

Methods: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics.

Results: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.

Conclusions and clinical relevance: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Multiple sclerosis (MS) is a serious, incurable neurological disease. In 2009, the ANZgene studies detected the suggestive association of located upstream of CD40 gene in chromosome 20q13 (p = 1.3×10(-7)). Identification of the causal variant(s) in the CD40 locus leads to a better understanding of the mechanism underlying the development of autoimmune pathologies. We determined the genotypes of rs6074022, rs1883832, rs1535045, and rs11086996 in patients with MS (n = 1684) and in the control group (n = 879). Two SNPs were significantly associated with MS: rs6074022 (additive model C allele OR = 1.27, 95% CI = [1.12-1.45], p = 3×10(-4)) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05-1.38], p = 7×10(-3)). In the meta-analysis of our results and the results of four previous studies, we obtain the association p-value of 2.34×10(-12), which confirmed the association between MS and rs6074022 at a genome-wide significant level. Next, we demonstrated that the model including rs6074022 only sufficiently described the association. From our analysis, we can speculate that the association between rs1883832 and MS was induced by LD, whereas rs6074022 was a marker in stronger LD with the functional variant or was the functional variant itself. Our results indicated that the functional variants were located in the upstream region of the gene CD40 and were in higher LD with rs6074022 than LD with rs1883832.

This study aimed to investigate the relationship of ten single nucleotide polymorphisms (SNPs) in the MTHFR, MTR, MTRR, DHFR, MTHFD1, TS, RFC1 and DNMT3b genes with cancer survival, therapeutic response to neoadjuvant chemotherapy and clinicopathological characteristics in 300 pre- and postmenopausal breast cancer patients of a Russian Western Siberian population. We found that the MTHFR 677CT genotype as well as combination of MTHFR 677CT and 677TT genotype was related to tumor size and estrogen-positive status in postmenopausal group. The RFC1 80А allele was associated with an increased risk of lymph node metastases among postmenopausal women. The MTHFR 677TT genotype was significantly correlated with a better progression-free survival in premenopausal patients. In contrast, a worse outcome was observed in this group patient with MTHFD1 1958AA genotype. In the multivariate analysis, the MTHFD1 1958AA genotype was identified as an independent prognostic factor for premenopausal breast cancer survival. Our findings provide evidence for associations of breast cancer survival with folate-related SNPs in a population of Western Siberian region of Russia and the MTHFD1 (1958G>A) may have additional prognostic value especially among premenopausal patients.

Background: Bronchial asthma is a common disease caused by interplay between multiple determinants, including genetic and immune variations.

Objective: To investigate the main indices of humoral and cellular branches of immunity, features of cytokine regulation and cytokine genes in children with atopic bronchial asthma (BA) with different levels of disease control.

Design: Fifty children with controlled BA (CBA) and 50 with uncontrolled BA (UBA) were analyzed. Mean age in the sample was 13.36 ± 2.24 years. A control group of healthy children (n = 50) was also studied. All individuals were Russians (Eastern Slavs) from the Krasnoyarsk Territory, West Siberia. Diagnoses, severity and level of disease control were defined according to the Global Initiative for Asthma (GINA) recommendations. The lymphocytes were counted in blood using fluorescent microscopy. Humoral branch indices and cytokine levels (IL-2, IL-4, IL-10 and TNF-α) in blood serum were measured by ELISA. Genotyping of single-nucleotide polymorphism (SNP) in -590 position of the IL4 and -597 position of the IL10 gene was performed by restriction fragment length analysis.

Results: No statistically significant differences in total IgE and cytokines blood levels were found in CBA and UBA. However, significant differences between the groups were found for CD(3+), CD(4+) and CD(8+) cell counts. The T-590 allele of the IL4 gene, which is responsible for an increased serum level of IL-4, showed a tendency to an association with UBA. A decreased level of IL-10 enhances control over BA, which proves its association with the allelic variant A-597 IL10.

Conclusion: Our data show that children with UBA have higher counts of CD(3+) cells and an increase of sub-population of CD(4+)-cells as well as higher levels of IgE, IL-4 and TNF-α in blood serum as compared to CBA. Polymorphisms of the IL4 and IL10 genes are associated with allergic inflammation in UBA.

Type-I recessive congenital methemoglobinemia (RCM) is a rare autosomal disease characterized by a deficiency of the soluble form of nicotineamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) and clinically manifests as cyanosis of skin and mucous membranes. In the Russian Federation, type-I RCM is widely disturbed in Yakutia due to the local founder effect. The molecular genetics cause of type-I RCM in Yakutia is mutation c.806C>T in the CYB5R3 gene. In this work we used 13 polymorphic markers, which flanking the CYB5R3 gene to establish the founder haplotype. The age of the mutation was estimated as about 285 ± 135 years. In this work, we have evaluated the frequency of the c.806C>T mutation in Yakutia, which averaged 55 : 1000 Yakuts. The calculated frequency of disease was 1: 1250 Yakuts.

Наследственная метгемоглобинемия первого типа (наследственная энзимопеническая метгемоглобинемия, НЭМ) – аутосомно-рецессивное заболевание, характеризующееся резким снижением активности растворимой формы NADH-цитохром-b5-редуктазы и клинически проявляющееся цианозом кожных покровов и слизистых оболочек. Молекулярно-генетической причиной заболевания в Якутии является мутация с.806С>T в гене CYB5R3, накопление которой обусловлено “эффектом основателя”. В настоящей работе на основе анализа неравновесия по сцеплению 13 микросателлитных маркеров, фланкирующих ген CYB5R3, с заболеванием установлен гаплотип хромосомы основателя. Определено время распространения данной мутации в Якутии, которое составило 285 ± 135 лет. Установлена частота гетерозиготного носительства мутации с.806С>T в гене CYB5R3, составившая 55 на 1000 здоровых якутов и рассчитана частота наследственной метгемоглобинемии первого типа в Якутии (1 на 1250 якутов).

Изучено распределение биохимических маркёров генов HP, GC, EsD, AcP, полиморфизм нуль-аллелей ферментов биотрансформации - трансфераз GSTT1, GSTM1, а также полиморфизм VNTR4 гена NOS3 у больных антракосиликозом и у лиц, не имеющих этой профессиональной патологии. Показано, что заболеванию наиболее подвержены обладатели генотипов HP 1-1, GC 1-2, GC 2-2, EsD 1-2, AcP bb, а резистентны обладатели HP 2-2, GC 1-1. Es D1-1, AcP aa, AcP bc. В старшей возрастной группе больных лиц (50-59 лет) в большинстве случаев частота генотипов риска ниже, а частота генотипов резистентности выше, чем в более младшей возрастной группе (40-49 лет), что может указывать на профессиональный отбор у работников угледобывающих предприятий.

Исследование вошли 63 больных, прооперированных по поводу плоскоклеточного рака легкого. Материалом для морфологического исследования явились находящиеся на расстоянии 4–5 см от опухоли фрагменты ткани удаленного легкого с бронхом. Для оценки особенностей характера воспалительной реакции при различных вариантах дисрегенерации исследовали наличие клеток, экспрессирующих Ki67, p53, bcl-2, CD138, CD117, CD68 и CD79α, в инфильтрате каждого из вариантов дисрегенераторных изменений. Воспалительный инфильтрат при плоскоклеточной метаплазии характеризовался наличием большого количества пролиферирующих клеток и клеток, экспрессирующих p53 и bcl-2. Выраженность инфильтрации стромы плазматическими, тучными клетками и макрофагами в этом случае снижалась. Базальноклеточная гиперплазия в присутствии плоскоклеточной метаплазии характеризовалась большим числом пролиферирующих клеток и лейкоцитов, экспрессирующих p53 и bcl-2, большим количеством плазматических клеток и уменьшением числа макрофагов. Характер воспалительной реакции при плоскоклеточной метаплазии был одинаков и не зависел от того, сочетается или нет плоскоклеточная метаплазия с базальноклеточной гиперплазией и неоплазией. Исключение составляла только более выраженная инфильтрация в участках плоскоклеточной метаплазии CD68+ макрофагами в случаях ее сочетания с неоплазией.

Представлено клиническое описание семейного случая классической галактоземии. У соматически здоровых родителей, не являющихся кровными родственниками, двое детей погибли в первый месяц жизни. Второму ребенку в результате неонатального скринига на галактоземию был определен повышенный уровень общей галактозы в крови. Ребенку от третьей беременности со вторых суток жизни была назначена безлактозная диета, что в совокупности с проводимым лечением позволило скорректировать состояние новорожденного.

Проанализировано распределение генотипов и аллелей полиморфного варианта Ala16Val (rs 4880) гена SOD2 в выборке мужчин, больных ишемической болезнью сердца (n=155), и в популяционной выборке мужчин г. Томска (n=129). Для проведения генотипирования использовали рестрикционный анализ с определением полиморфизма длин рестрикционных фрагментов. Выявлена статистически значимо более высокая частота аллеля Т в группе больных ишемической болезнью сердца (ИБС) мужчин - 54,84% по сравнению с мужчинами популяционной выборки - 44,14% (ƒ2=5,998; p=0,014; OR=1,54). Частота генотипа ТТ у больных ИБС мужчин составила 27,10%, что также значимо выше, чем в контрольной группе - 17,97% (ƒ2=7,265; p=0,026; OR=1,70). Таким образом показано, что аллель Т и генотип ТТ ассоциирован с ИБС.

Проанализировано распределение генотипов и аллелей полиморфного варианта Thr12Ser (rs1937) гена TFAM в выборке лиц, больных ишемической болезнью сердца, и в популяционной выборке жителей г. Томска. Для проведения генотипирования использовали полиморфизм длин рестрикционных фрагментов. Выявлена статистически значимо более высокая частота генотипа СС у мужчин, больных ишемической болезнью сердца, — 4,52% по сравнению с популяционной выборкой мужчин — 0,45% (χ 2 = 6,315; р = 0,043; OR = 10,45). Таким образом, генотип СС ассоциирован с ишемической болезнью сердца у мужчин в популяции г. Томска.

В обзоре обобщены результаты фармакогенетических исследований детерминации ответа на лекарственные средства, используемые для терапии бронхиальной астмы. Применение фармакогенетической информации сделает возможным использование персонифицированного подхода к терапии бронхиальной астмы, что позволит скорректировать технологии ведения пациента и повысить вероятность достижения контроля болезни.