The complete genome sequence of a Neandertal from the Altai Mountains

We present a high-quality genome sequence of a Neandertal woman from Siberia. We show that her parents were related at the level of half siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neandertal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neandertals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high quality Neandertal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neandertals and Denisovans

POSSIBILITIES OF USING THE GENOTYPING OF CYTOKINES WITH INFLAMMATION-REGULATORY ACTIVITY AS BIOLOGICAL MARKERS FOR PREDICTION OF THE EFFICIENCY OF THERAPY FOR RHEUMATOID ARTHRITIS

Objective. To reveal the genetic markers that may predict the efficiency of therapy for rheumatoid arthritis (RA). Subjects and methods. The study enrolled 104 patients (93 women and 11 men) (mean age 53.38+13.55 years). The duration of RA averaged 9.18+8.97 years. The patients were treated with basic anti-inflammatory drugs (BAIDs): 69.23% took methotrexate (MT), 10-17.5 mg/week; 30.77% received sulfasalazine, 2 g/day. Therapeutic effectiveness was evaluated using the European League Against Rheumatism (EULAR) criteria following 24 weeks. Clinical and laboratory parameters were similar in MT- and sulfasalazine-treated patients. The patients groups showing the varying efficacy of BAIDs were analyzed from the similar cutoffs of polymorphisms of the same cytokine genes. Results. The study indicated that some patients with certain combinations of allelic variants of promoter regions of cytokine genes had no benefits from BAID therapy. There was a preponderance of alleles in the genes associated with the high production of IL-1, the low generation of IL-6, and the low elaboration of cytokines with anti-inflammatory activity in the group of patients unresponsive to the basic therapy. The patients having many benefits from the performed treatment showed a predominance of alleles associated with the high production of IL-6 and the low generation of IL-1, with a tendency towards an increase in the frequency of alleles in the IL-1 and IL-10 genes that ensured a high elaboration of anti-inflammatory cytokines. Conclusion. The findings suggest that the effect of basic anti-rheumatic therapy with methotrexate or sulfasalazine largely depends on the cytokine genotype of a patient. Analysis of appropriate factors is likely to be used in rheumatological care

COMBINATION ANALYSIS OF CYTOKINE GENE PROMOTER POLYMORPHISMS OF IL1B T-31C, IL-6 G-174C, TNFA G-238A, TNFA G-308A, TNFA C-863A, IL4 C-590T, IL-10 C-592A FOR PREDICTION OF TREATMENT EFFICIENCY IN RHEUMATOID ARTHRITIS

The article contains results concerning combination frequency analysis for a wide number of three- to six-locus constellations of cytokine gene alleles, i.e., IL-1B T-31C, IL-6 G-174C, TNFA G-238A, TNFA G-308A, TNFA C-863A, IL-4 C-590T, IL-10 C-592A. The study was performed in a group of 104 patients with rheumatoid arthritis (RA) who were subject to basic therapy with methotrexate. An association was found between certain individual multi-locus allele combinations, and efficiency of the therapy, as defined by decrease in DAS28 index following 24 week of methotrexate treatment. An association was demonstrated between adverse effects of drugs used, and a "cytokine genotype" of the patients. Analysis of the results was carried out with respect to correlations between the levels of pro- and anti-inflammatory cytokine production and promoter polymorphisms of respective genes. We assume that further clinical research will allow to use our results as pharmacogenetic criteria in order to choose more effective personalized therapies, taking into account the genotypes of RA patients

KOMPLEKSNYY ANALIZ KLINIChESKOY ZNAChIMOSTI VYYaVLENIYaALLEL'NYKh VARIANTOV GENOV TsITOKINOV IL1B, IL6, IL10, TNFA IFAKTORA ROSTA VEGF V KAChESTVE GENETIChESKIKh FAKTOROV RISKARAZVITIYa OSTEOPOROZA PRI SAKhARNOM DIABETE 2 TIPA

Цель исследования. Комплексный анализ прогностической значимости выявления аллельных вариантов промоторных участков генов цитокинов в качестве генетических факторов риска развития остеопороза при сахарном диабете 2 типа. Материалы и методы. Было обследовано 625 человек. Контрольную группу составили 375 здоровых женщин без признаков остеопороза и сахарного диабета. С целью оценки роли генетических факторов при остеопорозе обследова- но 250 женщин находящихся в постменопаузальном периоде, разделенные на 3 группы: первая группа - 38 пациенток с первичным остеопорозом, вторая - 82 пациентки с остеопорозом на фоне сахарного диабета 2 типа, третья группа - 130 пациенток с сахарным диабетом 2 типа без признаков остеопороза. Группы были сравнимы по возрасту. Ис- следовались восемь полиморфизмов, локализованных в промоторных регионах генов интерлейкинов: TNFA в позициях С-863А, G-308A, G-238A, IL-1B T-31C, IL-4 C-590T, IL-6 G-174C, IL-10 C-592A, VEGFA С-2578А. Анализ исследуемых по- лиморфизмов проводился с использованием метода рестрикционного анализа продуктов амплификации. Результаты. Нами установлено, что наличие остеопороза является дискриминирующим фактором, разделяющим группу пациенток с сахарным диабетом по целому ряду генетических признаков. Группу этих признаков составили комбинации из 3-х, 4-х, 5-ти и 6-ти генотипов генов цитокинов: TNFA, IL-6, IL-1B, VEGF и IL-10. В группах больных сахарным диабетом 2 типа были проанализированы параметры, характеризующие инсулинорезистентность, эндо- телиальную дисфункцию и воспаление. У пациентов страдающих сахарным диабетом и остеопорозом отмечено до- стоверное повышение концентраций С-пептида, GLP-1 и снижение содержания GIP, лептина, PAI-1 и висфатина. В данной работе впервые описана ассоциированность уровней инсулина, резистина, лептина, глюкагона и PAI-1 с генотипами цитокинов при сахарном диабете 2 типа. Заключение. В результате исследования установлена связь развития системного остеопороза у здоровых женщин в постменопаузе и у пациенток с сахарным диабетом 2 типа с наличием определенными комбинациями аллельных вариантов генов цитокинов