Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

FTO genotype is associated with phenotypic variability of body mass index.

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.

Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

The genome sequence of taurine cattle: a window to ruminant biology and evolution.

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Profitieren ältere Hypertoniker von einer medikamentösen Therapie? [Do elderly hypertensive patients benefit from drug therapy?].

Cet article présente les résultats de la revue systématique: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD000028. PMID: 19821263.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

The Role of Transnational Elites in shaping the evolving Field of Internet Governance

La gouvernance de l'Internet est une thématique récente dans la politique mondiale. Néanmoins, elle est devenue au fil des années un enjeu économique et politique important. La question a même pris une importance particulière au cours des derniers mois en devenant un sujet d'actualité récurrent. Forte de ce constat, c ette recherche retrace l'histoire de la gouvernance de l'Internet depuis son émergence comme enjeu politique dans les années 1980 jusqu'à la fin du Sommet Mondial sur la Société de l'Information (SMSI) en 2005. Plutôt que de se focaliser sur l'une ou l'autre des institutions impliquées dans la régulation du réseau informatique mondial, cette recherche analyse l'émergence et l'évolution historique d'un espace de luttes rassemblant un nombre croissant d'acteurs différents. Cette évolution est décrite à travers le prisme de la relation dialectique entre élites et non-élites et de la lutte autour de la définition de la gouvernance de l'Internet. Cette thèse explore donc la question de comment les relations au sein des élites de la gouvernance de l'Internet et entre ces élites et les non-élites expliquent l'emergence, l'évolution et la structuration d'un champ relativement autonome de la politique mondiale centré sur la gouvernance de l'Internet. Contre les perspectives dominantes réaliste et libérales, cette recherche s'ancre dans une approche issue de la combinaison des traditions hétérodoxes en économie politique internationale et des apports de la sociologie politique internationale. Celle-ci s'articule autour des concepts de champ, d'élites et d'hégémonie. Le concept de champ, développé par Bourdieu inspire un nombre croissant d'études de la politique mondiale. Il permet à la fois une étude différenciée de la mondialisation et l'émergence d'espaces de lutte et de domination au niveau transnational. La sociologie des élites, elle, permet une approche pragmatique et centrée sur les acteurs des questions de pouvoir dans la mondialisation. Cette recherche utilise plus particulièrement le concept d'élite du pouvoir de Wright Mills pour étudier l'unification d'élites a priori différentes autour de projets communs. Enfin, cette étude reprend le concept néo-gramscien d'hégémonie afin d'étudier à la fois la stabilité relative du pouvoir d'une élite garantie par la dimension consensuelle de la domination, et les germes de changement contenus dans tout ordre international. A travers l'étude des documents produits au cours de la période étudiée et en s'appuyant sur la création de bases de données sur les réseaux d'acteurs, cette étude s'intéresse aux débats qui ont suivi la commercialisation du réseau au début des années 1990 et aux négociations lors du SMSI. La première période a abouti à la création de l'Internet Corporation for Assigned Names and Numbers (ICANN) en 1998. Cette création est le résultat de la recherche d'un consensus entre les discours dominants des années 1990. C'est également le fruit d'une coalition entre intérêts au sein d'une élite du pouvoir de la gouvernance de l'Internet. Cependant, cette institutionnalisation de l'Internet autour de l'ICANN excluait un certain nombre d'acteurs et de discours qui ont depuis tenté de renverser cet ordre. Le SMSI a été le cadre de la remise en cause du mode de gouvernance de l'Internet par les États exclus du système, des universitaires et certaines ONG et organisations internationales. C'est pourquoi le SMSI constitue la seconde période historique étudiée dans cette thèse. La confrontation lors du SMSI a donné lieu à une reconfiguration de l'élite du pouvoir de la gouvernance de l'Internet ainsi qu'à une redéfinition des frontières du champ. Un nouveau projet hégémonique a vu le jour autour d'éléments discursifs tels que le multipartenariat et autour d'insitutions telles que le Forum sur la Gouvernance de l'Internet. Le succès relatif de ce projet a permis une stabilité insitutionnelle inédite depuis la fin du SMSI et une acceptation du discours des élites par un grand nombre d'acteurs du champ. Ce n'est que récemment que cet ordre a été remis en cause par les pouvoirs émergents dans la gouvernance de l'Internet. Cette thèse cherche à contribuer au débat scientifique sur trois plans. Sur le plan théorique, elle contribue à l'essor d'un dialogue entre approches d'économie politique mondiale et de sociologie politique internationale afin d'étudier à la fois les dynamiques structurelles liées au processus de mondialisation et les pratiques localisées des acteurs dans un domaine précis. Elle insiste notamment sur l'apport de les notions de champ et d'élite du pouvoir et sur leur compatibilité avec les anlayses néo-gramsciennes de l'hégémonie. Sur le plan méthodologique, ce dialogue se traduit par une utilisation de méthodes sociologiques telles que l'anlyse de réseaux d'acteurs et de déclarations pour compléter l'analyse qualitative de documents. Enfin, sur le plan empirique, cette recherche offre une perspective originale sur la gouvernance de l'Internet en insistant sur sa dimension historique, en démontrant la fragilité du concept de gouvernance multipartenaire (multistakeholder) et en se focalisant sur les rapports de pouvoir et les liens entre gouvernance de l'Internet et mondialisation. - Internet governance is a recent issue in global politics. However, it gradually became a major political and economic issue. It recently became even more important and now appears regularly in the news. Against this background, this research outlines the history of Internet governance from its emergence as a political issue in the 1980s to the end of the World Summit on the Information Society (WSIS) in 2005. Rather than focusing on one or the other institution involved in Internet governance, this research analyses the emergence and historical evolution of a space of struggle affecting a growing number of different actors. This evolution is described through the analysis of the dialectical relation between elites and non-elites and through the struggle around the definition of Internet governance. The thesis explores the question of how the relations among the elites of Internet governance and between these elites and non-elites explain the emergence, the evolution, and the structuration of a relatively autonomous field of world politics centred around Internet governance. Against dominant realist and liberal perspectives, this research draws upon a cross-fertilisation of heterodox international political economy and international political sociology. This approach focuses on concepts such as field, elites and hegemony. The concept of field, as developed by Bourdieu, is increasingly used in International Relations to build a differentiated analysis of globalisation and to describe the emergence of transnational spaces of struggle and domination. Elite sociology allows for a pragmatic actor-centred analysis of the issue of power in the globalisation process. This research particularly draws on Wright Mill's concept of power elite in order to explore the unification of different elites around shared projects. Finally, this thesis uses the Neo-Gramscian concept of hegemony in order to study both the consensual dimension of domination and the prospect of change contained in any international order. Through the analysis of the documents produced within the analysed period, and through the creation of databases of networks of actors, this research focuses on the debates that followed the commercialisation of the Internet throughout the 1990s and during the WSIS. The first time period led to the creation of the Internet Corporation for Assigned Names and Numbers (ICANN) in 1998. This creation resulted from the consensus-building between the dominant discourses of the time. It also resulted from the coalition of interests among an emerging power elite. However, this institutionalisation of Internet governance around the ICANN excluded a number of actors and discourses that resisted this mode of governance. The WSIS became the institutional framework within which the governance system was questioned by some excluded states, scholars, NGOs and intergovernmental organisations. The confrontation between the power elite and counter-elites during the WSIS triggered a reconfiguration of the power elite as well as a re-definition of the boundaries of the field. A new hegemonic project emerged around discursive elements such as the idea of multistakeholderism and institutional elements such as the Internet Governance Forum. The relative success of the hegemonic project allowed for a certain stability within the field and an acceptance by most non-elites of the new order. It is only recently that this order began to be questioned by the emerging powers of Internet governance. This research provides three main contributions to the scientific debate. On the theoretical level, it contributes to the emergence of a dialogue between International Political Economy and International Political Sociology perspectives in order to analyse both the structural trends of the globalisation process and the located practices of actors in a given issue-area. It notably stresses the contribution of concepts such as field and power elite and their compatibility with a Neo-Gramscian framework to analyse hegemony. On the methodological level, this perspective relies on the use of mixed methods, combining qualitative content analysis with social network analysis of actors and statements. Finally, on the empirical level, this research provides an original perspective on Internet governance. It stresses the historical dimension of current Internet governance arrangements. It also criticise the notion of multistakeholde ism and focuses instead on the power dynamics and the relation between Internet governance and globalisation.