Prevalence of uncoupling protein one genetic polymorphisms and their relationship with cardiovascular and metabolic health.

Contribution of UCP1 single nucleotide polymorphisms (SNPs) to susceptibility for cardiometabolic pathologies (CMP) and their involvement in specific risk factors for these conditions varies across populations. We tested whether UCP1 SNPs A-3826G, A-1766G, Ala64Thr and A-112C are associated with common CMP and their risk factors across Armenia, Greece, Poland, Russia and United Kingdom. This case-control study included genotyping of these SNPs, from 2,283 Caucasians. Results were extended via systematic review and meta-analysis. In Armenia, GA genotype and A allele of Ala64Thr displayed ~2-fold higher risk for CMP compared to GG genotype and G allele, respectively (p<0.05). In Greece, A allele of Ala64Thr decreased risk of CMP by 39%. Healthy individuals with A-3826G GG genotype and carriers of mutant allele of A-112C and Ala64Thr had higher body mass index compared to those carrying other alleles. In healthy Polish, higher waist-to-hip ratio (WHR) was observed in heterozygotes A-3826G compared to AA homozygotes. Heterozygosity of A-112C and Ala64Thr SNPs was related to lower WHR in CMP individuals compared to wild type homozygotes (p<0.05). Meta-analysis showed no statistically significant odds-ratios across our SNPs (p>0.05). Concluding, the studied SNPs could be associated with the most common CMP and their risk factors in some populations.

Origin and diffusion of human Y chromosome haplogroup J1-M267.

Human Y chromosome haplogroup J1-M267 is a common male lineage in West Asia. One high-frequency region-encompassing the Arabian Peninsula, southern Mesopotamia, and the southern Levant-resides ~ 2000 km away from the other one found in the Caucasus. The region between them, although has a lower frequency, nevertheless demonstrates high genetic diversity. Studies associate this haplogroup with the spread of farming from the Fertile Crescent to Europe, the spread of mobile pastoralism in the desert regions of the Arabian Peninsula, the history of the Jews, and the spread of Islam. Here, we study past human male demography in West Asia with 172 high-coverage whole Y chromosome sequences and 889 genotyped samples of haplogroup J1-M267. We show that this haplogroup evolved ~ 20,000 years ago somewhere in northwestern Iran, the Caucasus, the Armenian Highland, and northern Mesopotamia. The major branch-J1a1a1-P58-evolved during the early Holocene ~ 9500 years ago somewhere in the Arabian Peninsula, the Levant, and southern Mesopotamia. Haplogroup J1-M267 expanded during the Chalcolithic, the Bronze Age, and the Iron Age. Most probably, the spread of Afro-Asiatic languages, the spread of mobile pastoralism in the arid zones, or both of these events together explain the distribution of haplogroup J1-M267 we see today in the southern regions of West Asia.

Insights into matrilineal genetic structure, differentiation and ancestry of Armenians based on complete mitogenome data.

Distinctive peculiarities of Armenians such as their millennia-long genetic isolation and strong national identity attract a keen interest while studying the demographic history of the West Asia. Here, to examine their fine-scale matrilineal genetic structure, ancestry and relationships with neighboring populations, we analyzed 536 complete mitogenomes (141 of which are novel) from 8 geographically different Armenian populations, covering the whole stretch of historical Armenia. The observed patterns highlight a remarkable degree of matrilineal genetic heterogeneity and weak population structuring of Armenians. Moreover, our phylogeographic analysis reveals common ancestries for some mtDNA lineages shared by West Asians, Transcaucasians, Europeans, Central Asians and Armenians. About third of the mtDNA subhaplogroups found in Armenian gene pool might be considered as Armenian-specific, as these are virtually absent elsewhere in Europe, West Asia and Transcaucasia. Coalescence ages of most of these lineages do not exceed 3.1 kya and coincide well with the population size growth started around 1.8-2.8 kya detectable only in the Bayesian Skyline Plots based on the Armenian-specific mtDNA haplotypes.

Author Correction: 137 ancient human genomes from across the Eurasian steppes.

with In this Article, Angela M. Taravella and Melissa A. Wilson Sayres have been added to the author list (associated with: School of Life Sciences, Center for Evolution and Medicine, The Biodesign Institute, Arizona State University, Tempe, AZ, USA). The author list and Author Information section have been corrected online.

137 ancient human genomes from across the Eurasian steppes.

For thousands of years the Eurasian steppes have been a centre of human migrations and cultural change. Here we sequence the genomes of 137 ancient humans (about 1× average coverage), covering a period of 4,000 years, to understand the population history of the Eurasian steppes after the Bronze Age migrations. We find that the genetics of the Scythian groups that dominated the Eurasian steppes throughout the Iron Age were highly structured, with diverse origins comprising Late Bronze Age herders, European farmers and southern Siberian hunter-gatherers. Later, Scythians admixed with the eastern steppe nomads who formed the Xiongnu confederations, and moved westward in about the second or third century BC, forming the Hun traditions in the fourth-fifth century AD, and carrying with them plague that was basal to the Justinian plague. These nomads were further admixed with East Asian groups during several short-term khanates in the Medieval period. These historical events transformed the Eurasian steppes from being inhabited by Indo-European speakers of largely West Eurasian ancestry to the mostly Turkic-speaking groups of the present day, who are primarily of East Asian ancestry.

Eight Millennia of Matrilineal Genetic Continuity in the South Caucasus.

The South Caucasus, situated between the Black and Caspian Seas, geographically links Europe with the Near East and has served as a crossroad for human migrations for many millennia [1-7]. Despite a vast archaeological record showing distinct cultural turnovers, the demographic events that shaped the human populations of this region is not known [8, 9]. To shed light on the maternal genetic history of the region, we analyzed the complete mitochondrial genomes of 52 ancient skeletons from present-day Armenia and Artsakh spanning 7,800 years and combined this dataset with 206 mitochondrial genomes of modern Armenians. We also included previously published data of seven neighboring populations (n = 482). Coalescence-based analyses suggest that the population size in this region rapidly increased after the Last Glacial Maximum ca. 18 kya. We find that the lowest genetic distance in this dataset is between modern Armenians and the ancient individuals, as also reflected in both network analyses and discriminant analysis of principal components. We used approximate Bayesian computation to test five different demographic scenarios explaining the formation of the modern Armenian gene pool. Despite well documented cultural shifts in the South Caucasus across this time period, our results strongly favor a genetic continuity model in the maternal gene pool. This has implications for interpreting prehistoric migration dynamics and cultural shifts in this part of the world.

Origin and spread of human mitochondrial DNA haplogroup U7.

Human mitochondrial DNA haplogroup U is among the initial maternal founders in Southwest Asia and Europe and one that best indicates matrilineal genetic continuity between late Pleistocene hunter-gatherer groups and present-day populations of Europe. While most haplogroup U subclades are older than 30 thousand years, the comparatively recent coalescence time of the extant variation of haplogroup U7 (~16-19 thousand years ago) suggests that its current distribution is the consequence of more recent dispersal events, despite its wide geographical range across Europe, the Near East and South Asia. Here we report 267 new U7 mitogenomes that - analysed alongside 100 published ones - enable us to discern at least two distinct temporal phases of dispersal, both of which most likely emanated from the Near East. The earlier one began prior to the Holocene (~11.5 thousand years ago) towards South Asia, while the later dispersal took place more recently towards Mediterranean Europe during the Neolithic (~8 thousand years ago). These findings imply that the carriers of haplogroup U7 spread to South Asia and Europe before the suggested Bronze Age expansion of Indo-European languages from the Pontic-Caspian Steppe region.

Genetic Structure of the Armenian Population.

Located at the crossroads of Europe and the Middle East, the Armenian Highland served as a transition corridor for major waves of prehistoric and historic migrations. The genetic history of Armenians as an indigenous population of the region attracts keen scientific interest to resolve the puzzle of ancient Middle Eastern populations' expansion and the spread of Indo-European languages. Here, we review the current state of studies on the genetic structure of both modern and ancient inhabitants of the Armenian Highland and outline further steps to be fulfilled in this regard.

Different waves and directions of Neolithic migrations in the Armenian Highland.

BACKGROUND: The peopling of Europe and the nature of the Neolithic agricultural migration as a primary issue in the modern human colonization of the globe is still widely debated. At present, much uncertainty is associated with the reconstruction of the routes of migration for the first farmers from the Near East. In this context, hospitable climatic conditions and the key geographic position of the Armenian Highland suggest that it may have served as a conduit for several waves of expansion of the first agriculturalists from the Near East to Europe and the North Caucasus. RESULTS: Here, we assess Y-chromosomal distribution in six geographically distinct populations of Armenians that roughly represent the extent of historical Armenia. Using the general haplogroup structure and the specific lineages representing putative genetic markers of the Neolithic Revolution, haplogroups R1b1a2, J2, and G, we identify distinct patterns of genetic affinity between the populations of the Armenian Highland and the neighboring ones north and west from this area. CONCLUSIONS: Based on the results obtained, we suggest a new insight on the different routes and waves of Neolithic expansion of the first farmers through the Armenian Highland. We detected at least two principle migratory directions: (1) westward alongside the coastline of the Mediterranean Sea and (2) northward to the North Caucasus.

Management of familial Mediterranean fever by colchicine does not normalize the altered profile of microbial long chain fatty acids in the human metabolome.

In our previous works we established that in an autoinflammatory condition, familial Mediterranean fever (FMF), the gut microbial diversity is specifically restructured, which also results in the altered profiles of microbial long chain fatty acids (LCFAs) present in the systemic metabolome. The mainstream management of the disease is based on oral administration of colchicine to suppress clinical signs and extend remission periods and our aim was to determine whether this therapy normalizes the microbial LCFA profiles in the metabolome as well. Unexpectedly, the treatment does not normalize these profiles. Moreover, it results in the formation of new distinct microbial LCFA clusters, which are well separated from the corresponding values in healthy controls and FMF patients without the therapy. We hypothesize that the therapy alters the proinflammatory network specific for the disease, with the concomitant changes in gut microbiota and the corresponding microbial LCFAs in the metabolome.

Paternal lineage analysis supports an Armenian rather than a Central Asian genetic origin of the Hamshenis.

The Hamshenis are an isolated geographic group of Armenians with a strong ethnic identity who, until the early decades of the twentieth century, inhabited the Pontus area on the southern coast of the Black Sea. Scholars hold alternative views on their origin, proposing Eastern Armenia, Western Armenia, and Central Asia, respectively, as their most likely homeland. To ascertain whether genetic data from the nonrecombining portion of the Y chromosome are supportive of any of these suggestions, we screened 82 Armenian males of Hamsheni descent for 12 biallelic and 6 microsatellite Y-chromosomal markers. These data were compared with the corresponding data set from the representative populations of the three candidate regions. Genetic difference between the Hamshenis and other groups is significant and backs up the hypothesis of the Armenian origin of the Hamshenis, indicating central historical Armenia as a homeland of the ancestral population. This inference is further strengthened by the results of admixture analysis, which does not support the Central-Asian hypothesis of the Hamshenis' origin. Genetic diversity values and patterns of genetic distances suggest a high degree of genetic isolation of the Hamshenis consistent with their retention of a distinct and ancient dialect of the Armenian language.

Comparative analysis of cytokine profiles in autoinflammatory and autoimmune conditions.

BACKGROUND: Many disease states are characterized by a biased cytokine profile and determining the level of certain cytokines becomes an important diagnostic and research tool in clinical medicine. We hypothesized that, despite the highly dynamic nature, the profile of cytokines may be characteristic of disease. METHODS: The level of systemic cytokines was studied in an autoinflammatory condition, familial Mediterranean fever; in an autoimmune disease, systemic lupus erythematosus (SLE), and in healthy controls. RESULTS: Multivariate statistics with the use of seven variables clustered the patients and control subjects into the four well separated and distinct groups, corresponding to the SLE, FMF attack, FMF remission, and healthy states. CONCLUSIONS: The model suggested the existence of specific patterns in cytokine levels reflecting the healthy and specific disease states. These findings warrant further investigations to establish whether this approach may serve as a potential meta-biomarker for other inflammatory disorders.

Profiles of Microbial Fatty Acids in the Human Metabolome are Disease-Specific.

The human gastrointestinal tract is inhabited by a diverse and dense symbiotic microbiota, the composition of which is the result of host-microbe co-evolution and co-adaptation. This tight integration creates intense cross-talk and signaling between the host and microbiota at the cellular and metabolic levels. In many genetic or infectious diseases the balance between host and microbiota may be compromised resulting in erroneous communication. Consequently, the composition of the human metabolome, which includes the gut metabolome, may be different in health and disease states in terms of microbial products and metabolites entering systemic circulation. To test this hypothesis, we measured the level of hydroxy, branched, cyclopropyl and unsaturated fatty acids, aldehydes, and phenyl derivatives in blood of patients with a hereditary autoinflammatory disorder, familial Mediterranean fever (FMF), and in patients with peptic ulceration (PU) resulting from Helicobacter pylori infection. Discriminant function analysis of a data matrix consisting of 94 cases as statistical units (37 FMF patients, 14 PU patients, and 43 healthy controls) and the concentration of 35 microbial products in the blood as statistical variables revealed a high accuracy of the proposed model (all cases were correctly classified). This suggests that the profile of microbial products and metabolites in the human metabolome is specific for a given disease and may potentially serve as a biomarker for disease.

Elevated systemic antibodies towards commensal gut microbiota in autoinflammatory condition.

BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory condition, which is characterized by acute, self-limiting episodes of fever and serositis and chronic subclinical inflammation in remission. Here we investigated the consequence of this condition on the level of systemic antibodies directed towards common intestinal bacteria. METHODOLOGY/PRINCIPAL FINDINGS: The level of systemic antibodies towards the antigens of Bacteroides, Parabacteroides, Escherichia, Enteroccocus and Lactobaccilus was measured by ELISA in FMF patients at various stages of the disease and in healthy controls. The difference between remission and attack was not significant. IgG antibodies against the antigens of Bacteroides, Parabacteroides, Escherichia and Enteroccocus were significantly increased in FMF compared to control while IgA levels were not significantly affected. Western blot analyses demonstrated the IgG reactivity against multiple antigens of commensal bacteria in FMF. Serological expression cloning was performed to identify these antigens. No single dominant antigen was identified; the response was generalized and directed against a variety of proteins from Bacteroides, Parabacteroides, Escherichia, and other gut commensals. CONCLUSIONS/SIGNIFICANCE: This autoinflammatory syndrome is characterized by the increased systemic reactivity against commensal gut microbiota. This is probably the consequence of hypersensitivity of the inflammasome in FMF that triggers the inflammation and contributes to the excessive translocation of bacteria and bacterial antigens through the gut barrier.

Predominant role of host genetics in controlling the composition of gut microbiota.

BACKGROUND: The human gastrointestinal tract is inhabited by a very diverse symbiotic microbiota, the composition of which depends on host genetics and the environment. Several studies suggested that the host genetics may influence the composition of gut microbiota but no genes involved in host control were proposed. We investigated the effects of the wild type and mutated alleles of the gene, which encodes the protein called pyrin, one of the regulators of innate immunity, on the composition of gut commensal bacteria. Mutations in MEFV lead to the autoinflammatory disorder, familial Mediterranean fever (FMF, MIM249100), which is characterized by recurrent self-resolving attacks of fever and polyserositis, with no clinical signs of disease in remission. METHODOLOGY/PRINCIPAL FINDINGS: A total of 19 FMF patients and eight healthy individuals were genotyped for mutations in the MEFV gene and gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries and FISH analysis. These analyses demonstrated significant changes in bacterial community structure in FMF characterized by depletion of total numbers of bacteria, loss of diversity, and major shifts in bacterial populations within the Bacteroidetes, Firmicutes and Proteobacteria phyla in attack. In remission with no clinical signs of disease, bacterial diversity values were comparable with control but still, the bacterial composition was substantially deviant from the norm. Discriminant function analyses of gut bacterial diversity revealed highly specific, well-separated and distinct grouping, which depended on the allele carrier status of the host. CONCLUSIONS/SIGNIFICANCE: This is the first report that clearly establishes the link between the host genotype and the corresponding shifts in the gut microbiota (the latter confirmed by two independent techniques). It suggests that the host genetics is a key factor in host-microbe interaction determining a specific profile of commensal microbiota in the human gut.