25-Hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm.

BACKGROUND: The vitamin D-endocrine system is thought to play a role in physiologic processes that range from mineral metabolism to immune function. Serum 25-hydroxyvitamin D [25(OH)D] is the accepted biomarker for vitamin D status. Skin color is a key determinant of circulating 25(OH)D concentrations, and genes responsible for melanin content have been shown to be under strong evolutionary selection in populations living in temperate zones. Little is known about the effect of latitude on mean concentrations of 25(OH)D in dark-skinned populations. OBJECTIVE: The objective was to describe the distribution of 25(OH)D and its subcomponents in 5 population samples of African origin from the United States, Jamaica, Ghana, South Africa, and the Seychelles. DESIGN: Participants were drawn from the Modeling of the Epidemiologic Transition Study, a cross-sectional observational study in 2500 adults, ages 25-45 y, enrolled between January 2010 and December 2011. Five hundred participants, ∼50% of whom were female, were enrolled in each of 5 study sites: Chicago, IL (latitude: 41°N); Kingston, Jamaica (17°N); Kumasi, Ghana (6°N); Victoria, Seychelles (4°S); and Cape Town, South Africa (34°S). All participants had an ancestry primarily of African origin; participants from the Seychelles trace their history to East Africa. RESULTS: A negative correlation between 25(OH)D and distance from the equator was observed across population samples. The frequency distribution of 25(OH)D in Ghana was almost perfectly normal (Gaussian), with progressively lower means and increasing skewness observed at higher latitudes. CONCLUSIONS: It is widely assumed that lighter skin color in populations outside the tropics resulted from positive selection, driven in part by the relation between sun exposure, skin melanin content, and 25(OH)D production. Our findings show that robust compensatory mechanisms exist that create tolerance for wide variation in circulating concentrations of 25(OH)D across populations, suggesting a more complex evolutionary relation between skin color and the vitamin D pathway. This trial was registered at clinicaltrials.gov as NCT02111902.

Etude systématique, cladistique et biogéographique des Baetidae (Ephemeroptera) de Madagascar

Les Ephéméroptères constituent un ordre très archaïque d?insectes ailés, comprenant un nombre réduit d?espèces (actuellement environ 2500 espèces). Les larves sont aquatiques; la durée de ce stade est en général d?une année. Le stade adulte est par contre extrêmement bref: de quelques heures à quelques jours. La fonction quasi unique de ce stade est la reproduction. Par sa superficie, Madagascar est la quatrième île du monde. Elle est située dans la partie occidentale de l?Océan Indien à plus de 300 km de la côte africaine. Madagascar faisait partie du super-continent Gondwana. Elle s?est séparée de l?Afrique (-165 M.a.), puis a migré vers le Sud (-125 M.a.) avant de se détacher du sous-continent indien (-65 M.a.). La connaissance des Ephéméroptères malgaches était, jusqu?à très récemment, extrêmement limitée. Grâce au programme Biodiversité et biotypologie des eaux continentales malgaches, lancé conjointement par l?ORSTOM (actuel IRD, France) et le CNRE (Madagascar), un inventaire à large échelle de la macrofaune benthique malgache a été entrepris. La systématique de plusieurs familles d?Ephéméroptères (Tricorythidae, Polymitarcyidae, Palingeniidae,?), ainsi que d?autres groupes d?invertébrés (Trichoptères, Simuliidae, macrocrustacés) a fait l?objet d?études approfondies. La présente étude consistue un des volets de ce programme. Jusqu?au milieu des années 1990, seules quatre espèces valides appartenant à trois genres différents étaient décrites de Madagascar. En 6 ans, ce ne sont pas moins de 25 articles qui sont consacrés à la systématique des Baetidae, permettant de décrire 50 espèces et 8 genres nouveaux. La faune malgache des Baetidae compte actuellement 22 genres et 54 espèces. Malgré sa taille, Madagascar possède une richesse, tant générique que spécifique équivalente à celle d?un continent. Notre connaissance des Baetidae est suffisamment avancée pour mener une étude cladistique et biogéographique. La reconstruction phylogénétique a permis de mettre en évidence cinq lignées principales à Madagascar et de préciser, pour chacune d?elles, les genres inclus et les caractères propres. La faune des Baetidae malgaches présente un taux d?endémicité très élevé: 53 des 54 espèces et un tiers des genres sont endémiques. Elle montre des affinités extrêmement fortes avec la faune africaine, puisque 90% des genres présents à Madagascar ou en Afrique ont une répartition strictement restreinte à cette région. Les autres composantes, notamment orientales et océaniennes, sont négligeables; ces régions n?ont en commun avec Madagascar qu?un nombre restreint de genres cosmopolites. Ces affinités sont en contradiction avec les données géologiques de la dislocation du Gondwana. Plusieurs explications peuvent être données pour résoudre cette contradiction. La plus vraisemblable est que le pouvoir de dispersion des Ephéméroptères, et des Baetidae en particulier, est nettement sous-estimé. L?étude des faunes des îles volcaniques récentes, telles que les Comores, démontre clairement que les Baetidae sont capables de dispersion sur une distance de plus de 300 km. Il est donc possible d?envisager une colonisation de Madagascar à partir de l?Afrique continentale postérieure à la séparation des deux plaques. Nous avons établi des scénarios retraçant l?histoire biogéographique de chacune des cinq lignées. Pour quatre d?entre elles, l?Afrique continentale est le centre d?origine. La cinquième lignée aurait une origine paléarctique; l?Afrique représenterait un centre secondaire de spéciation. Ces lignées auraient secondairement colonisé Madagascar à partir de l?Afrique continentale. Ce travail ouvre donc d?importantes perspectives. Il rend possible l?utilisation à un niveau générique, voire spécifique, des Baetidae pour des travaux de faunistique ou d?écologie, en particulier pour des études liées à la dégradation de la qualité de l?eau. Il devrait également pouvoir servir de base pour l?étude et la compréhension des phénomènes de dispersion et colonisation dans les îles et archipels de l?Ouest de l?Océan Indien.<br/><br/>Mayflies (Ephemeroptera) are among the oldest known flying insects and encompass a very small number of species (ca 2500 species). Larvae are strictly freshwater inhabitants; this stage lasts generally one year. The imaginal stage is extremely short, from few hours to few days, and is devoted almost entirely to reproduction. Madagascar is the fourth largest island in the world by area. It is situated in the western part of the Indian Ocean, at a distance of more than 300 km from the African coast. Madagascar belonged to Gondwana. It was first separated from the African plate (-165 M.y.), then moved to the South (-65 M.y.), before the break-off with the Indian plate (-65 M.y.). Knowledge of the Malagasy mayflies was until recently extremely poor. The program Biodiversity and Biotypology of Malagasy Freshwaters, jointly run by the French ORSTOM and the Malagasy CNRE, began a global survey of the freshwater macroinvertebrates. The systematics of several mayfly families (Tricorythidae, Polymitarcyidae, Palingeniidae,?), and other invertebrate groups (Caddisflies, Blackflies,?) was the subject of ground studies. Our present study is one part of this global program. Until the middle of the nineties, only four baetid species belonging to three different genera had been described from Madagascar. During the last six years, 25 papers were dedicated to the systematics of the Baetidae, allowing the description of 50 new species and 8 new genera. The Malagasy fauna encompasses now 22 genera and 54 species. Despite its size, Madagascar has the same diversity, at specific and generic level, as a continent. Our knowledge of the Baetidae is sufficient to perform a cladistic and biogeographical study. Our phylogenetic reconstruction allows us to propose five main lineages and to indicate, for each of them, the genera included and their features. The Malagasy fauna of Baetidae possesses a high level of endemicity: 53 of the 54 species and one third of the genera are endemic. It shows extremely strong affinities with the African fauna, as more than 90% of the genera present in Madagascar or in Africa have a distribution restricted to this area. Other components, especially Oriental and Oceanian, are negligible. These areas share with Madagascar only a few widespread genera. These African affinities are in contradiction with the geological events, especially the break-off history of Gondwana. Some explanations can be given to solve this contradiction. The most likely is that the dispersal power of the mayflies, especially of the Baetidae, is greatly underestimated. The study of recent volcanic islands, particularly of the Comoros, clearly demonstrates that the Baetidae are able to disperse over more than 300 km. Consequently, a colonisation by the Baetidae, of Madagascar from the continental Africa, after the break-off must be considered as possible. We have established scenarios explaining the biogeographical history of each of the five lineages. For four of them, Africa has to be regarded as the centre of origin. The fifth lineage probably has a Palearctic origin; Africa should be considered as a secondary centre of speciation. These lineages should have secondarily colonised Madagascar from continental Africa. This work opens up new perspectives. It allows the use of the Baetidae for faunistic and ecological studies, especially for problems related to water quality. It must be also considered as a first step for understanding the dispersion and colonisation of the islands of the western part of the Indian Ocean.

Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10-8).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

Copeptin is associated with kidney length, renal function, and prevalence of simple cysts in a population-based study.

Arginine vasopressin (AVP) has a key role in osmoregulation by facilitating water transport in the collecting duct. Recent evidence suggests that AVP may have additional effects on renal function and favor cyst growth in polycystic kidney disease. Whether AVP also affects kidney structure in the general population is unknown. We analyzed the association of copeptin, an established surrogate for AVP, with parameters of renal function and morphology in a multicentric population-based cohort. Participants from families of European ancestry were randomly selected in three Swiss cities. We used linear multilevel regression analysis to explore the association of copeptin with renal function parameters as well as kidney length and the presence of simple renal cysts assessed by ultrasound examination. Copeptin levels were log-transformed. The 529 women and 481 men had median copeptin levels of 3.0 and 5.2 pmol/L, respectively (P<0.001). In multivariable analyses, the copeptin level was associated inversely with eGFR (β=-2.1; 95% confidence interval [95% CI], -3.3 to -0.8; P=0.002) and kidney length (β=-1.2; 95% CI, -1.9 to -0.4; P=0.003) but positively with 24-hour urinary albumin excretion (β=0.11; 95% CI, 0.01 to 0.20; P=0.03) and urine osmolality (β=0.08; 95% CI, 0.05 to 0.10; P<0.001). A positive association was found between the copeptin level and the presence of renal cysts (odds ratio, 1.6; 95% CI, 1.1 to 2.4; P=0.02). These results suggest that AVP has a pleiotropic role in renal function and may favor the development of simple renal cysts.

Under-reporting of dietary energy intake in five populations of the African diaspora.

Studies on the role of diet in the development of chronic diseases often rely on self-report surveys of dietary intake. Unfortunately, many validity studies have demonstrated that self-reported dietary intake is subject to systematic under-reporting, although the vast majority of such studies have been conducted in industrialised countries. The aim of the present study was to investigate whether or not systematic reporting error exists among the individuals of African ancestry (n 324) in five countries distributed across the Human Development Index (HDI) scale, a UN statistic devised to rank countries on non-income factors plus economic indicators. Using two 24 h dietary recalls to assess energy intake and the doubly labelled water method to assess total energy expenditure, we calculated the difference between these two values ((self-report - expenditure/expenditure) × 100) to identify under-reporting of habitual energy intake in selected communities in Ghana, South Africa, Seychelles, Jamaica and the USA. Under-reporting of habitual energy intake was observed in all the five countries. The South African cohort exhibited the highest mean under-reporting ( - 52·1% of energy) compared with the cohorts of Ghana ( - 22·5%), Jamaica ( - 17·9%), Seychelles ( - 25·0%) and the USA ( - 18·5%). BMI was the most consistent predictor of under-reporting compared with other predictors. In conclusion, there is substantial under-reporting of dietary energy intake in populations across the whole range of the HDI, and this systematic reporting error increases according to the BMI of an individual.

Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome.

Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.

Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.

OBJECTIVES: To investigate, using a Mendelian randomisation approach, whether heavier smoking is associated with a range of regional adiposity phenotypes, in particular those related to abdominal adiposity. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene region) as a proxy for smoking heaviness, of the associations of smoking heaviness with a range of adiposity phenotypes. PARTICIPANTS: 148 731 current, former and never-smokers of European ancestry aged ≥16 years from 29 studies in the consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Waist and hip circumferences, and waist-hip ratio. RESULTS: The data included up to 66 809 never-smokers, 43 009 former smokers and 38 913 current daily cigarette smokers. Among current smokers, for each extra minor allele, the geometric mean was lower for waist circumference by -0.40% (95% CI -0.57% to -0.22%), with effects on hip circumference, waist-hip ratio and body mass index (BMI) being -0.31% (95% CI -0.42% to -0.19), -0.08% (-0.19% to 0.03%) and -0.74% (-0.96% to -0.51%), respectively. In contrast, among never-smokers, these effects were higher by 0.23% (0.09% to 0.36%), 0.17% (0.08% to 0.26%), 0.07% (-0.01% to 0.15%) and 0.35% (0.18% to 0.52%), respectively. When adjusting the three central adiposity measures for BMI, the effects among current smokers changed direction and were higher by 0.14% (0.05% to 0.22%) for waist circumference, 0.02% (-0.05% to 0.08%) for hip circumference and 0.10% (0.02% to 0.19%) for waist-hip ratio, for each extra minor allele. CONCLUSIONS: For a given BMI, a gene variant associated with increased cigarette consumption was associated with increased waist circumference. Smoking in an effort to control weight may lead to accumulation of central adiposity.

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

A comparison of indices of glucose metabolism in five black populations: data from modeling the epidemiologic transition study (METS).

BACKGROUND: Globally, Africans and African Americans experience a disproportionate burden of type 2 diabetes, compared to other race and ethnic groups. The aim of the study was to examine the association of plasma glucose with indices of glucose metabolism in young adults of African origin from 5 different countries. METHODS: We identified participants from the Modeling the Epidemiologic Transition Study, an international study of weight change and cardiovascular disease (CVD) risk in five populations of African origin: USA (US), Jamaica, Ghana, South Africa, and Seychelles. For the current study, we included 667 participants (34.8 ± 6.3 years), with measures of plasma glucose, insulin, leptin, and adiponectin, as well as moderate and vigorous physical activity (MVPA, minutes/day [min/day]), daily sedentary time (min/day), anthropometrics, and body composition. RESULTS: Among the 282 men, body mass index (BMI) ranged from 22.1 to 29.6 kg/m(2) in men and from 25.8 to 34.8 kg/m(2) in 385 women. MVPA ranged from 26.2 to 47.1 min/day in men, and from 14.3 to 27.3 min/day in women and correlated with adiposity (BMI, waist size, and % body fat) only among US males after controlling for age. Plasma glucose ranged from 4.6 ± 0.8 mmol/L in the South African men to 5.8 mmol/L US men, while the overall prevalence for diabetes was very low, except in the US men and women (6.7 and 12 %, respectively). Using multivariate linear regression, glucose was associated with BMI, age, sex, smoking hypertension, daily sedentary time but not daily MVPA. CONCLUSION: Obesity, metabolic risk, and other potential determinants vary significantly between populations at differing stages of the epidemiologic transition, requiring tailored public health policies to address local population characteristics.

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.

INTRODUCTION: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout. METHODS: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. RESULTS: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. CONCLUSION: There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β - the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout.

No association between ApoE polymorphism and febrile seizures.

Seizures associated with fever are a common pediatric problem, affecting about 2-7 % of children between 3 months and 5 years of age. Differentiation of febrile seizures from acute symptomatic seizures secondary to central nervous system infections or seizures associated with fever in children with epilepsy is essential to provide appropriate treatment and follow-up care. Here, we tested the hypothesis that children who exhibit simple febrile seizures during early childhood, but do not develop epileptic seizures later in life, might preferentially carry the ApoE2 allele of the gene coding for the apolipoprotein E. We did not find any differences in the distribution of ApoE alleles or genotypes between individuals who exhibited simple febrile seizures (n = 93) and age-matched, typically developing subjects (n = 80). We found that the observed allele and genotype frequencies did not deviate from Hardy-Weinberg equilibrium, which suggests that the frequencies of ApoE alleles and genotypes are stable in the Swiss population from which our samples were derived. Across both groups of subjects (n = 173), we found an ApoE2 allele frequency of 0.064, an ApoE3 frequency of 0.829 and an ApoE4 frequency of 0.107. Our findings are consistent with previous reports of the distribution of ApoE polymorphism for European subjects free of any neurological disorders, and show that the different alleles of the gene coding for the apolipoprotein E are not associated with the occurrence of simple febrile seizures.

Association of car ownership and physical activity across the spectrum of human development : Modeling the Epidemiologic Transition Study (METS).

BACKGROUND: Variations in physical activity (PA) across nations may be driven by socioeconomic position. As national incomes increase, car ownership becomes within reach of more individuals. This report characterizes associations between car ownership and PA in African-origin populations across 5 sites at different levels of economic development and with different transportation infrastructures: US, Seychelles, Jamaica, South Africa, and Ghana. METHODS: Twenty-five hundred adults, ages 25-45, were enrolled in the study. A total of 2,101 subjects had valid accelerometer-based PA measures (reported as average daily duration of moderate to vigorous PA, MVPA) and complete socioeconomic information. Our primary exposure of interest was whether the household owned a car. We adjusted for socioeconomic position using household income and ownership of common goods. RESULTS: Overall, PA levels did not vary largely between sites, with highest levels in South Africa, lowest in the US. Across all sites, greater PA was consistently associated with male gender, fewer years of education, manual occupations, lower income, and owning fewer material goods. We found heterogeneity across sites in car ownership: after adjustment for confounders, car owners in the US had 24.3 fewer minutes of MVPA compared to non-car owners in the US (20.7 vs. 45.1 minutes/day of MVPA); in the non-US sites, car-owners had an average of 9.7 fewer minutes of MVPA than non-car owners (24.9 vs. 34.6 minutes/day of MVPA). CONCLUSIONS: PA levels are similar across all study sites except Jamaica, despite very different levels of socioeconomic development. Not owning a car in the US is associated with especially high levels of MVPA. As car ownership becomes prevalent in the developing world, strategies to promote alternative forms of active transit may become important.

Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension

Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.

Dispersal is a major driver of the latitudinal diversity gradient of Carnivora

AimUnderstanding the relative contribution of diversification rates (speciation and extinction) and dispersal in the formation of the latitudinal diversity gradient - the decrease in species richness with increasing latitude - is a main goal of biogeography. The mammalian order Carnivora, which comprises 286 species, displays the traditional latitudinal diversity gradient seen in almost all mammalian orders. Yet the processes driving high species richness in the tropics may be fundamentally different in this group from that in other mammalian groups. Indeed, a recent study suggested that in Carnivora, unlike in all other major mammalian orders, net diversification rates are not higher in the tropics than in temperate regions. Our goal was thus to understand the reasons why there are more species of Carnivora in the tropics. LocationWorld-wide. MethodsWe reconstructed the biogeographical history of Carnivora using a time-calibrated phylogeny of the clade comprising all terrestrial species and dispersal-extinction-cladogenesis models. We also analysed a fossil dataset of carnivoran genera to examine how the latitudinal distribution of Carnivora varied through time. ResultsOur biogeographical analyses suggest that Carnivora originated in the East Palaearctic (i.e. Central Asia, China) in the early Palaeogene. Multiple independent lineages dispersed to low latitudes following three main paths: toward Africa, toward India/Southeast Asia and toward South America via the Bering Strait. These dispersal events were probably associated with local extinctions at high latitudes. Fossil data corroborate a high-latitude origin of the group, followed by late dispersal events toward lower latitudes in the Neogene. Main conclusionsUnlike most other mammalian orders, which originated and diversified at low latitudes and dispersed out of the tropics', Carnivora originated at high latitudes, and subsequently dispersed southward. Our study provides an example of combining phylogenetic and fossil data to understand the generation and maintenance of global-scale geographical variations in species richness.

Functional studies of a germ-line polymorphism at codon 47 within the p53 gene.

A rare germ-line polymorphism in codon 47 of the p53 gene replaces the wild-type proline (CCG) with a serine (TCG). Restriction analysis of 101 human samples revealed the frequency of the rare allele to be 0% (n = 69) in Caucasians and 4.7% (3/64, n = 32) among African-Americans. To investigate the consequence of this amino acid substitution, a cDNA construct (p53 mut47ser) containing the mutation was introduced into a lung adenocarcinoma cell line (Calu-6) that does not express p53. A growth suppression similar to that obtained after introduction of a wild-type p53 cDNA construct was observed, in contrast to the result obtained by introduction of p53 mut143ala. Furthermore, expression of neither p53 mut47ser nor wild-type p53 was tolerated by growing cells. In transient expression assays, both mut47ser and wild-type p53 activated the expression of a reporter gene linked to a p53 binding sequence (PG13-CAT) and inhibited the expression of the luciferase gene under the control of the Rous sarcoma virus promoter (RSVluc). In the same assay, mut143ala did not activate the expression of PG13-CAT and produced only a slight inhibitory effect on RSVluc. These findings indicate that the p53 variant with a serine at codon 47 should be considered as a rare germ-line polymorphism that does not alter the growth-suppression activity of p53.