Alter Disease Risk Research Articles

Urban colonization through multiple genetic lenses: The city-fox phenomenon revisited.

Urbanization is driving environmental change on a global scale, creating novel environments for wildlife to colonize. Through a combination of stochastic and selective processes, urbanization is also driving evolutionary change. For instance, difficulty in traversing human‐modified landscapes may isolate newly established populations from rural sources, while novel selective pressures, such as altered disease risk, toxicant exposure, and light pollution, may further diverge populations through local adaptation. Assessing the evolutionary consequences of urban colonization and the processes underlying them is a principle aim of urban evolutionary ecology. In the present study, we revisited the genetic effects of urbanization on red foxes (Vulpes vulpes) that colonized Zurich, Switzerland. Through use of genome‐wide single nucleotide polymorphisms and microsatellite markers linked to the major histocompatibility complex (MHC), we expanded upon a previous neutral microsatellite study to assess population structure, characterize patterns of genetic diversity, and detect outliers associated with urbanization. Our results indicated the presence of one large evolutionary cluster, with substructure evident between geographic sampling areas. In urban foxes, we observed patterns of neutral and functional diversity consistent with founder events and reported increased differentiation between populations separated by natural and anthropogenic barriers. We additionally reported evidence of selection acting on MHC‐linked markers and identified outlier loci with putative gene functions related to energy metabolism, behavior, and immunity. We concluded that demographic processes primarily drove patterns of diversity, with outlier tests providing preliminary evidence of possible urban adaptation. This study contributes to our overall understanding of urban colonization ecology and emphasizes the value of combining datasets when examining evolutionary change in an increasingly urban world.

Maternal Influenza Vaccination and the Risk of Laboratory-Confirmed Influenza Among Household Contacts Under the Age of Five in Mali.

.Influenza transmission is increased among household contacts. Vaccination decreases transmission; however it is unclear how vaccinating a single individual alters disease risk among household contacts, particularly in regions with low vaccination coverage. Pregnant women were randomized to influenza or control vaccination. Households were visited weekly until infants born to enrolled women reached 6 months. Household contacts younger than 5 years were tested for laboratory-confirmed influenza (LCI). Incidence of LCI and rate ratios (RtR) comparing incidence between vaccine groups were calculated. The secondary infection rate (SIR) was calculated for households where LCI was detected. The H1N1 strain in the vaccine was a match for circulating H1N1 during the study, thus, all analyses were performed for H1N1-LCI and any LCI. A total of 5,345 household contacts younger than 5 years followed for a mean of 228 days (standard deviation [SD] = 45 days) experienced 2,957 influenza-like illness episodes. Incidence of any LCI and H1N1-LCI was 23 (N = 276) and 7.3 per 100,000 days (N = 89), respectively. Household contacts of women who received influenza vaccine had fewer LCI (RtR = 0.90; 95% CI: 0.71, 1.14) and fewer H1N1-LCI (RtR = 0.73; 95% CI: 0.48, 1.11) episodes than contacts in control households. Incidence of LCI and household SIR were low in households of women enrolled in an influenza vaccine trial in Mali. Although low incidence made statistical significance difficult to detect, there was a trend for decreased rates of H1N1-LCI in households where a pregnant mother received influenza vaccination.

Use of a Metabolic Syndrome Severity Z Score to Track Risk During Treatment of Prediabetes: An Analysis of the Diabetes Prevention Program.

OBJECTIVEWe assessed whether changes in metabolic syndrome (MetS) severity during the treatment of prediabetes are associated with reduced risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD).RESEARCH DESIGN AND METHODSWe analyzed data from the Diabetes Prevention Program (DPP) for 2,476 adults in 1996–1999 with prediabetes randomized to receive treatment with lifestyle modification, metformin, or placebo for 2–3 years and followed through 2014 for T2DM and CVD outcomes. We calculated effect sizes from baseline in a MetS severity z score (MetS-Z) and the individual MetS components, and assessed relationships between 1-year effect size and incident T2DM and CVD using hazard ratios (HRs) and mediation analysis.RESULTSBaseline MetS-Z and its components were associated with risk of incident T2DM and CVD. During year 1 of intervention, MetS-Z and its components decreased most with lifestyle modification, followed by treatment with metformin and placebo. Risk of T2DM within 1–5 years was most strongly associated with 1-year changes in MetS-Z and waist circumference (both HRs for a 1 SD increase = 1.80), whereas the risk of CVD was associated with a 1-year change in MetS-Z, glucose, and systolic blood pressure. In mediation analyses, the effect of lifestyle modification on T2DM risk was mediated by 1-year changes in MetS-Z, waist circumference, glucose, and triglycerides, whereas the effect of metformin was mediated by MetS-Z and glucose.CONCLUSIONSChanges in these risk indicators of MetS severity during intervention in the DPP reflect altered disease risk and may help in tracking earlier responses to treatment and in motivating patients.

Targeting epigenetic mechanisms in periodontal diseases.

Epigenetic factors are heritable genome modifications that potentially impact gene transcription, contributing to disease states. Epigenetic marks play an important role in chronic inflammatory conditions, as observed in periodontal diseases, by allowing microbial persistence or by permitting microbial insult to play a role in the so-called 'hit-and-run' infectious mechanism, leading to lasting pathogen interference with the host genome. Epigenetics also affects the health sciences by providing a dynamic mechanistic framework to explain the way in which environmental and behavioral factors interact with the genome to alter disease risk. In this article we review current knowledge of epigenome regulation in light of the multifactorial nature of periodontal diseases. We discuss epigenetic tagging in identified genes, and consider the potential implications of epigenetic changes on host-microbiome dynamics in chronic inflammatory states and in response to environmental stressors. The most recent advances in genomic technologies have placed us in a position to analyze interaction effects (eg, between periodontal disease and type 2 diabetes mellitus), which can be investigated through epigenome-wide association analysis. Finally, because of the individualized traits of epigenetic biomarkers, pharmacoepigenomic perspectives are also considered as potentially novel therapeutic approaches for improving periodontal disease status.

Approaches and advances in the genetic causes of autoimmune disease and their implications.

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology.

PregOMICS-Leveraging systems biology and bioinformatics for drug repurposing in maternal-child health.

Obstetric diseases remain underserved and understudied. Drug repurposing-utilization of a drug whose use is accepted in one condition for a different condition-could represent a rapid and low-cost way to identify new therapies that are known to be safe. In diseases of pregnancy, the known safety profile is a strong additional incentive. We describe the techniques and steps used in the use of 'omics data for drug repurposing. We illustrate these techniques using case studies of published drug repurposing projects. We provide a set of available databases with low barriers to entry which investigators can use to perform their own projects. The promise of 'omics techniques is unbiased screening, either of all drug targets or of all patients using particular drugs to find which are likely to alter disease risk or progression. However, we caution that reproducibility across the underlying studies, and thus the drugs suggested for repurposing, can be poor. We suggest that improved nosology, for example correlating patient clinical conditions with placental pathology, could yield more robust associations. We conclude that 'omics-driven drug repurposing represents a potential fruitful path to discover new, safe treatments of obstetric diseases.

The Diet‐microbiota‐mucus Layer Axis as a Mediator of Intestinal Health and Disease

Despite the accepted health benefits of consuming dietary fiber, little is known about the precise mechanisms by which fiber levels impact the gut microbiota and alters disease risk or how the precise chemistry of fiber polysaccharides interfaces with the hundreds of gut microbiota species. Using gnotobiotic mouse models, functional genomics, biochemical and genetic studies we have explored these interactions in mechanistic depth. In recent studies in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria, we have elucidated the functional interactions between dietary fiber, the gut microbiota and the colonic mucus barrier, which serves as a primary defense against enteric pathogens. During chronic or intermittent dietary fiber deficiency, the gut microbiota resorts to host‐secreted mucus glycoproteins as a nutrient source, leading to erosion of the colonic mucus barrier. Dietary fiber deprivation, together with a fiber‐deprived, mucus‐eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium, or inflammatory disease in the absence of pathogen in IL‐10‐deficient mice. Our work has begun to unravel the intricate pathways linking diet, the gut microbiome and intestinal barrier dysfunction, which could be exploited to improve health using dietary fiber or prebiotic therapeutics. As such, it is anticipated that our research will provide direct paths to future dietary intervention studies in humans, which are built on a firm foundation of functional and mechanistic knowledge of fiber‐microbiota interactions gathered in tractable model systems.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P133: Epigenome-Wide Association Study of Moderate-Vigorous Physical Activity in Adult African Americans Identifies Loci Near HCCA2

Regular moderate-vigorous physical activity (MVPA) reduces the risk of cardiovascular and other chronic diseases, among other important benefits at all life stages. It is hypothesized that physical activity may alter disease risk via epigenetic modifications, including potentially long-standing changes in DNA methylation as previous research has shown epigenetic changes following exercise interventions. Most existing reports examine global methylation or study acute exercise effects on DNA methylation. To our knowledge, there are no published epigenome-wide association studies (EWAS) of habitual MVPA. In this analysis, we tested associations between leisure time MVPA and genome-wide variation in CpG methylation, an epigenetic mark, in 2,601 African American participants (1,663 women; mean age 56.6 years) in the Atherosclerosis Risk in Communities (ARIC) study. The Illumina HM450K Bead Chip was used to measure methylation in 471,035 CpG sites in stored frozen leukocyte samples, from visit 2 (1990-1992) or 3 (1993-1995). Linear regression models tested the cross-sectional association of DNA methylation M-value with self-reported leisure time MVPA at the visit of sample collection, modeled as minutes of MVPA per week and by category based on the AHA guidelines for physical activity in adults (none, less than 150, or at least 150 minutes MVPA per week), adjusting for age, sex, body mass index, education, alcohol use in grams per week, smoking status, cancer status, white blood cell count, imputed cell-type proportions using the Houseman method, and batch effects with the top 30 HM450K built-in nonnegative control probe principal components. Three CpGs, cg08269485, cg20272155, and cg08966208, upstream of the cathepsin D encoding gene, CTSD, were observed to be significantly inversely associated (q<0.05, FDR) with MVPA minutes/week. This is a strongly imprinted genomic region (chr11p15.5) and the region has also been reported to include DNA methylation variants that changed in response to an exercise training intervention. Additionally, 163 CpGs that we identified in the literature to be associated with habitual MVPA were also tested using the same models. One CpG, cg07863043, upstream of the adenomatosis polyposis coli gene, APC, in the 5q22.2 genomic region, was observed to be significantly positively associated with achieving at least 150 minutes of MVPA per week compared to none (q=0.0001, FDR). APC encodes a tumor suppressor protein that is an antagonist of the Wnt signaling pathway, and is involved in carcinogenesis and embryonic development. Replication in other populations is ongoing to confirm these findings as well as to identify additional physical activity-related DNA methylation variants.

Chromatin modifications in metabolic disease: Potential mediators of long-term disease risk.

Metabolic diseases such as obesity and diabetes are complex diseases resulting from multiple genetic and environmental factors, such as diet and activity levels. These factors are well known contributors to the development of metabolic diseases. One manner by which environmental factors can influence metabolic disease progression is through modifications to chromatin. These modifications can lead to altered gene regulatory programs, which alters disease risk. Furthermore, there is evidence that parents exposed to environmental factors can influence the metabolic health of offspring, especially if exposures are during intrauterine growth periods. In this review, we outline the evidence that chromatin modifications are associated with metabolic diseases, including diabetes and obesity. We also consider evidence that these chromatin modifications can lead to long‐term disease risk and contribute to disease risk for future generations.This article is categorized under: Biological Mechanisms > MetabolismDevelopmental Biology > Developmental Processes in Health and DiseasePhysiology > Organismal Responses to Environment

Generating diversity in human glucocorticoid signaling through a racially diverse polymorphism in the beta isoform of the glucocorticoid receptor

Alternative splicing of the human glucocorticoid receptor gene generates two isoforms, hGRα and hGRβ. hGRβ functions as a dominant-negative regulator of hGRα activity and but also has inherent transcriptional activity, collectively altering glucocorticoid sensitivity. Single-nucleotide polymorphisms in the 3′ UTR of hGRβ have been associated with altered receptor protein expression, glucocorticoid sensitivity, and disease risk. Characterization of the hGRβ G3134T polymorphism has been limited to a relatively small, homogenous population. The objective of this study was to determine the prevalence of hGRβ G3134T in a diverse population and assess the association of hGRβ G3134T in this population with physiological outcomes. In a prospective cohort study, 3730 genetically diverse participants were genotyped for hGRβ G3134T and four common GR polymorphisms. A subset of these participants was evaluated for clinical and biochemical measurements. Immortalized human osteosarcoma cells (U-2 OS), stably transfected with wild-type or G3134T hGRβ, were evaluated for receptor expression, stability, and genome-wide gene expression. Glucocorticoid-mediated gene expression profiles were investigated in primary macrophages isolated from participants. In a racially diverse population, the minor allele frequency was 74% (50.7% heterozygous carriers and 23.3% homozygous minor allele), with a higher prevalence in Caucasian non-Hispanic participants. After adjusting for confounding variable, carriers of hGRβ G3134T were more likely to self-report allergies, have higher serum cortisol levels, and reduced cortisol suppression in response to low-dose dexamethasone. The presence of hGRβ G3134T in U-2 OS cells increased hGR mRNA stability and protein expression. Microarray analysis revealed that the presence of the hGRβ G3134T polymorphism uniquely altered gene expression profiles in U-2 OS cells and primary macrophages. hGRβ G3134T is significantly present in the study population and associated with race, self-reported disease, and serum levels of glucocorticoids. Underlying these health differences may be changes in gene expression driven by altered receptor stability.

Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. We sequenced a ≈158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.

Genetic Variation in Choline‐Metabolizing Enzymes Alters Choline Dynamics in Women Meeting Current Dietary Recommendations

Choline Kinase-α (CHKA) rs10791957, choline dehydrogenase (CHDH) rs9001, and CHDH rs12676 are genetic risk factors for disease and choline deficiency. While these single nucleotide polymorphisms are known to alter disease risk and the minimum choline intake needed for prevention of acute muscle and liver pathologies, their underlying metabolic signatures are not well characterized and it is unknown whether metabolic differences persist under conditions of nutrient adequacy. We sought to determine if these genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting current recommendations. Women consumed 480 or 930 mg choline/d (22% as choline-d9, a metabolic tracer) for 10–12 weeks in a controlled feeding study and stable isotope methodology was used to investigate the effect of genetic differences on choline dynamics. CHKA rs10791957 (Figure 1), CHDH rs9001 (Figure 2), and CHDH rs12676 (Figure 3) all influenced choline dynamics under the study conditions of nutrient adequacy. Variants associated with decreased risk for choline deficiency (CHKA rs10791957, CHDH rs9001) appeared to favor cytidine diphosphate (CDP)-phosphatidylcholine (PC) synthesis relative to phosphatidylethanolamine N-methyltransferase (PEMT)-PC synthesis as compared to non-variants, while the CHDH rs12676 genotype, which is associated with increased risk, favored PEMT-PC synthesis. These results are consistent with the effect of these variants on choline requirements when one considers efficiency of PC production. While each unit of choline directed to the CDP-choline pathway yields one unit of PC, choline converted to betaine (and eventually S-adenosylmethionine) has many metabolic fates besides PEMT-PC production, and three choline-derived methyl groups are needed to yield just one additional unit of PC via the PEMT pathway. Therefore, greater PEMT-PC production may constitute a drain on choline status and exacerbate disease risk during choline deficiency. Our results indicate that these SNPs have metabolic effects at choline intakes relevant to the general population and such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term. In fact, decreased PEMT activity observed among CHKA rs10791957 variant women (decreased turnover of choline-derived methionine → PEMT-PC; p=0.0005) may provide a metabolic basis for the decreased risk of type 2 diabetes among CHKA rs10791957 variant individuals given that PEMT knockout mice are protected from high-fat diet induced obesity and insulin resistance. Overall, these findings highlight the need for further study to examine the effects of genetic differences in choline metabolism on chronic disease outcomes. Support or Funding InformationThis work was supported by the National Institutes of Health under award T32-DK007158 and by the USDA National Institute of Food and Agriculture, Hatch project 231646. The content is the responsibility of the authors and does not necessarily represent the views of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institutes of Health or the National Institute of Food and Agriculture (NIFA) or the United States Department of Agriculture(USDA). Figure 1Open in figure viewerPowerPoint Effect of the CHKA rs10791957 variant on the metabolite flux and partitioning of dietary choline Figure 2Open in figure viewerPowerPoint Effect of the CHDH rs9001 variant on the metabolite flux and partitioning of dietary choline. Figure 3Open in figure viewerPowerPoint Effect of the CHDH rs12676 variant on the metabolite flux and partitioning of dietary choline.

Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes.

Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p.Ser17Ter and the established HOXB13 p.Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p.Met59Val and CHAD p.Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p.Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations.

The association of variants in PNPLA3 and GRP78 and the risk of developing hepatocellular carcinoma in an Italian population.

Hepatocellular carcinoma (HCC) has one of the worst prognoses amongst all malignancies. It commonly arises in patients with established liver disease and the diagnosis often occurs at an advanced stage. Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter disease risk and thus may have use as predictive markers of disease outcome. The aims of this study were (i) to assess the association of two SNPs, rs430397 in GRP78 and rs738409 in PNPLA3 with the risk of developing HCC in a Sicilian association cohort and, (ii) to use a machine learning technique to establish a predictive combinatorial phenotypic model for HCC including rs430397 and rs738409 genotypes and clinical and laboratory attributes. The controls comprised of 304 healthy subjects while the cases comprised of 170 HCC patients the majority of whom had hepatitis C (HCV)–related cirrhosis. Significant associations were identified between the risk of developing HCC and both rs430397 (p=0.0095) and rs738409 (p=0.0063). The association between rs738409 and HCC was significantly stronger in the HCV positive cases. In the best prediction model, represented graphically by a decision tree with an acceptable misclassification rate of 17.0%, the A/A and G/A genotypes of the rs430397 variant were fixed and combined with the three rs738409 genotypes; the attributes were age, sex and alcohol. These results demonstrate significant associations between both rs430397 and rs738409 and HCC development in a Sicilian cohort. The combinatorial predictive model developed to include these genetic variants may, if validated in independent cohorts, allow for earlier diagnosis of HCC.

A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility

Despite the accepted health benefits of consuming dietary fiber, little is known about the mechanisms by which fiber deprivation impacts the gut microbiota and alters disease risk. Using a gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria, we elucidated the functional interactions between dietary fiber, the gut microbiota, and the colonic mucus barrier, which serves as a primary defense against enteric pathogens. We show that during chronic or intermittent dietary fiber deficiency, the gut microbiota resorts to host-secreted mucus glycoproteins as a nutrient source, leading to erosion of the colonic mucus barrier. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium. Our work reveals intricate pathways linking diet, the gut microbiome, and intestinal barrier dysfunction, which could be exploited to improve health using dietary therapeutics.

Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β-cell are associated with glucose intolerance in humans and mice.

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved.

Evolutionary triangulation: informing genetic association studies with evolutionary evidence.

Genetic studies of human diseases have identified many variants associated with pathogenesis and severity. However, most studies have used only statistical association to assess putative relationships to disease, and ignored other factors for evaluation. For example, evolution is a factor that has shaped disease risk, changing allele frequencies as human populations migrated into and inhabited new environments. Since many common variants differ among populations in frequency, as does disease prevalence, we hypothesized that patterns of disease and population structure, taken together, will inform association studies. Thus, the population distributions of allelic risk variants should reflect the distributions of their associated diseases. Evolutionary Triangulation (ET) exploits this evolutionary differentiation by comparing population structure among three populations with variable patterns of disease prevalence. By selecting populations based on patterns where two have similar rates of disease that differ substantially from a third, we performed a proof of principle analysis for this method. We examined three disease phenotypes, lactase persistence, melanoma, and Type 2 diabetes mellitus. We show that for lactase persistence, a phenotype with a simple genetic architecture, ET identifies the key gene, lactase. For melanoma, ET identifies several genes associated with this disease and/or phenotypes related to it, such as skin color genes. ET was less obviously successful for Type 2 diabetes mellitus, perhaps because of the small effect sizes in known risk loci and recent environmental changes that have altered disease risk. Alternatively, ET may have revealed new genes involved in conferring disease risk for diabetes that did not meet nominal GWAS significance thresholds. We also compared ET to another method used to filter for phenotype associated genes, population branch statistic (PBS), and show that ET performs better in identifying genes known to associate with diseases appropriately distributed among populations. Our results indicate that ET can filter association results to improve our ability to discover disease loci.Electronic supplementary materialThe online version of this article (doi:10.1186/s13040-016-0091-7) contains supplementary material, which is available to authorized users.

Landscape Effects on the Presence, Abundance and Diversity of Mosquitoes in Mediterranean Wetlands.

Environment determines the distribution of mosquito-borne diseases in that it influences the vector-host-pathogen transmission cycle, including vector distribution, abundance and diversity. In this study, we analyse the relationship between environmental variables estimated by remote sensing and the spatial distribution (presence, abundance and diversity) of seven mosquito species vectors of West Nile and other pathogens (Usutu, avian malaria and dirofilariasis) in the Doñana Natural Park, Spain. Traps were distributed over an area of 54,984 ha divided into six ecological units: marshland, sand dunes, scrubland, ricefields, crops and fishponds. We collected mosquitoes once a month from up to 112 locations using BG-Sentinel traps baited with BG-lure and CO2 during March-November 2010. Hydroperiod, NDVI and Inundation surface were estimated at several resolution scales (100, 250, 500, 1000 and 2000 metres) from corrected and normalized Landsat Images. We sampled 972,346 female mosquitoes, the most abundant species being Culex theileri, Ochlerotatus caspius, Culex modestus, Culex perexiguus, Culex pipiens, Anopheles atroparvus and Ochlerotatus detritus. Our results suggest that: (1) hydroperiod, inundation surface and NDVI are strongly related to the spatial distribution of mosquitoes; (2) the spatial scales used to measure these variables affected quantification of these relationships, the larger scale being more informative; (3) these relationships are species-specific; (4) hydroperiod is negatively related to mosquito presence and richness; (5) Culex abundance is positively related to hydroperiod; (6) NDVI is positively related to mosquito diversity, presence and abundance, except in the case of the two salt marsh species (Oc. caspius and Oc. detritus); and (7) inundation surfaces positively condition the abundance and richness of most species except the salt marsh mosquitoes. Remote sensing data provided reliable information for monitoring mosquito populations. Landscape significantly affected mosquito distribution and abundance, and as a result may alter disease risk. These results suggest that while environmental conditions affect the distribution and abundance of mosquitoes, other factors such as human modification of landscapes may give rise to significant changes in mosquito populations and consequently disease risk.

Maternal circulating angiogenic factors in twin and singleton pregnancies

The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies. Placental growth factor (PlGF), soluble feline McDonough sarcoma (fms)-like tyrosine kinase (sFlt)-1, and soluble endoglin from healthy pregnant women were quantified at 10, 18, 26, and 35 weeks' gestation (n=91), and during the third trimester (31-39 weeks) and at delivery (33-41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age-adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies. Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 (sFlt-1: 36,916 vs 10,151 pg/mL; P<.0001; sFlt-1/PlGF: 168.4 vs 29.0; P<.0001). Maternal concentrations of soluble endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only (219.2 vs 350.2 pg/mL; P<.0001). Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of pregnancy in both twins and singletons. Higher maternal antiangiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted.

DNA methylation: the pivotal interaction between early-life nutrition and glucose metabolism in later life.

Traditionally, it has been widely acknowledged that genes together with adult lifestyle factors determine the risk of developing some metabolic diseases such as insulin resistance, obesity and diabetes mellitus in later life. However, there is now substantial evidence that prenatal and early-postnatal nutrition play a critical role in determining susceptibility to these diseases in later life. Maternal nutrition has historically been a key determinant for offspring health, and gestation is the critical time window that can affect the growth and development of offspring. The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that exposures during early life play a critical role in determining the risk of developing metabolic diseases in adulthood. Currently, there are substantial epidemiological studies and experimental animal models that have demonstrated that nutritional disturbances during the critical periods of early-life development can significantly have an impact on the predisposition to developing some metabolic diseases in later life. The hypothesis that epigenetic mechanisms may link imbalanced early-life nutrition with altered disease risk has been widely accepted in recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic processes play a significant role in regulating tissue-specific gene expression, and hence alterations in these processes may induce long-term changes in gene function and metabolism that persist throughout the life course. The present review focuses on how nutrition in early life can alter the epigenome, produce different phenotypes and alter disease susceptibilities, especially for impaired glucose metabolism.