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Segurel L.,CNRS Eco-anthropology and Ethnobiology | Segurel L.,University of Chicago | Austerlitz F.,CNRS Eco-anthropology and Ethnobiology | Toupance B.,CNRS Eco-anthropology and Ethnobiology | And 13 more authors.
European Journal of Human Genetics | Year: 2013

The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The 'thrifty genotype' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants. © 2013 Macmillan Publishers Limited.

Zhao L.,Imperial College London | Oliver E.,Imperial College London | Maratou K.,Physiological Genomics and Medicine Group | Atanur S.S.,Physiological Genomics and Medicine Group | And 17 more authors.
Nature | Year: 2015

The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension. © 2015 Macmillan Publishers Limited. All rights reserved.

Kojonazarov B.,Institute of Molecular Biology and Medicine | Kojonazarov B.,Justus Liebig University | Isakova J.,Institute of Molecular Biology and Medicine | Sovkhozova N.,Institute of Molecular Biology and Medicine | And 2 more authors.
High Altitude Medicine and Biology | Year: 2012

Endothelin-1 (ET-1) plays a critical role in the regulation of pulmonary vascular tone. The aim of this study was to investigate the role of ET-1 in the pathogenesis of high altitude pulmonary arterial hypertension (HAPH). Methods: Pulmonary artery pressure (PAP) was measured by echocardiography in permanent residents of the Kyrgyz Republic (3200-4000-m above sea level) both before and 3-h after a single oral dose of ET receptor antagonist, bosentan (125-mg). Plasma ET-1 levels were measured by ELISA assay. Genomic DNA was extracted from peripheral blood samples and the frequency of -3a and -4a alleles of the ET-1 gene determined by PCR. Results: Plasma ET-1 in HAPH highlanders was significantly higher than in healthy subjects (7.05±2.35 vs. 4.65±1.65-pg/ml, p<0.002). After the treatment with 125-mg bosentan, systolic PAP decreased from 46±1.9 to 37±2.2-mm Hg (p<0.01), and pulmonary artery acceleration time (PAAT) increased from 0.086±0.001 to 0.098±0.001-sec (p<0.001). The frequency of the -4a allele was significantly higher in HAPH patients compared to healthy highlanders (0.43 vs. 0.3, χ2=4.3, p=0.03). Conclusion: Increased ET-1 levels play an important role in development of HAPH. © Copyright 2012, Mary Ann Liebert, Inc.

Karmin M.,Estonian Biocentre | Karmin M.,University of Tartu | Saag L.,Estonian Biocentre | Saag L.,University of Tartu | And 121 more authors.
Genome Research | Year: 2015

It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males. © 2015 Karmin et al.

Mirrakhimov A.E.,Kyrgyz State Medical Academy | Kerimkulova A.S.,Kyrgyz State Medical Academy | Moldokeeva C.B.,Kyrgyz Russian Slavic University | Abilova S.S.,Kyrgyz State Medical Academy | And 3 more authors.
Cardiovascular Diabetology | Year: 2011

Backgrounds: B3 adrenoreceptors (ADRB3) are abundant in adipose tissue and play the role in its metabolism and lipolysis. Some variants of the ADRB3 gene may predispose subjects for the development obesity and metabolic abnormalities in the setting of modern sedentary lifestyle. ADRB3 gene polymorphism association with metabolic disturbances has never been studied before in the ethnic Kyrgyz population.Aim: To study an association between Trp64Arg polymorphism of the ADRB3 and metabolic syndrome (MS) components in an ethnic Kyrgyz group.Materials and methods: 213 Ethnic Kyrgyz volunteers over the age of 30 were enrolled in the study. The assessment plan for each individual comprised of general physical and anthropometric exams as well as laboratory tests (glucose, lipid panel, insulin) and genotyping by Trp64Arg polymorphism of the ADRB3. MS diagnosis was consistent with modified ATP III criteria (2005). Logistic regression analysis was performed to test the potential independent association between Arg64 allele with obesity, abdominal obesity (AO) and arterial hypertension (AH).Results: Trp64Arg polymorphism of the ADRB3 was assessed in 213 individuals (145 men, 68 women) aged 30-73 (mean age 50.7 ± 7.6). Arg64 allele frequency was 0.239; ADRB3 genotype distribution among participants was: Trp64 homozygotes 54.5%, Trp64Arg 43.2% and Arg64 homozygotes 2.3%. There was an association between Trp64Arg i{cyrillic} Arg64Arg genotypes and higher BMI, WC and obesity frequency (p < 0.00009), AO (p < 0.01), type 2 diabetes mellitus (DM) (p < 0.005) and lower high density cholesterol (HDL-C) level (p < 0.03). The logistic regression analysis showed the correlation of the Arg64 allele with obesity (OR 3.159; 95% CI 1.789-5.577) and AO (OR 1.973; 95% CI 1.118-3.481). The association between Arg64 allele and AH lost its significance after adjustment for obesity.Conclusion: Arg64 allele of the ADRB3 gene in the studied group has an association with MS components such as obesity, AO and decreased HDL-C level. © 2011 Mirrakhimov et al; licensee BioMed Central Ltd.

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