Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

Shared common variants in prostate cancer and blood lipids

BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.

METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.

RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.

CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

Economics of Non-Communicable Diseases in Indonesia

The Economics of Non-Communicable Diseases in Indonesia provides new data on the economic burden of NCDs in the country, and puts it in perspective by drawing a comparison with India and China. With this new addition to the series on the economics of NCDs, the World Economic Forum aims to advance the understanding of the expected economic output loss at the country level, particularly in countries in economic and epidemiological transition. The evidence presented provides a starting point in reorienting the dialogue on investing in healthy living and NCD prevention in Indonesia towards the view that a healthy population is an important factor for sustainable growth.

The dynamics of murid gammaherpesvirus 4 within wild, sympatric populations of bank voles and wood mice

Murid gammaherpesvirus 4 (MuHV-4) is widely used as a small animal model for understanding gammaherpesvirus infections in man. However, there have been no epidemiological studies of the virus in wild populations of small mammals. As MuHV-4 both infects cells associated with the respiratory and immune systems and attempts to evade immune control via various molecular mechanisms, infection may reduce immunocompetence with potentially serious fitness consequences for individuals. Here we report a longitudinal study of antibody to MuHV-4 in a mixed assemblage of bank voles (Clethrionomys glareolus) and wood mice (Apodemus sylvaticus) in the UK. The study was conducted between April 2001 and March 2004. Seroprevalence was higher in wood mice than bank voles, supporting earlier work that suggested wood mice were the major host even though the virus was originally isolated from a bank vole. Analyses of both the probability of having antibodies and the probability of initial seroconversion indicated no clear seasonal pattern or relationship with host density. Instead, infection risk was most closely associated with individual characteristics, with heavier males having the highest risk. This may reflect individual variation in susceptibility, potentially related to variability in the ability to mount an effective immune response.

Inbreeding uncovers fundamental differences in the genetic load affecting male and female fertility in a butterfly

Inbreeding depression is most pronounced for traits closely associated with fitness. The traditional explanation is that natural selection eliminates deleterious mutations with additive or dominant effects more effectively than recessive mutations, leading to directional dominance for traits subject to strong directional selection. Here we report the unexpected finding that, in the butterfly Bicyclus anynana, male sterility contributes disproportionately to inbreeding depression for fitness (complete sterility in about half the sons from brother-sister matings), while female fertility is insensitive to inbreeding. The contrast between the sexes for functionally equivalent traits is inconsistent with standard selection arguments, and suggests that trait-specific developmental properties and cryptic selection play crucial roles in shaping genetic architecture. There is evidence that spermatogenesis is less developmentally stable than oogenesis, though the unusually high male fertility load in B. anynana additionally suggests the operation of complex selection maintaining male sterility recessives. Analysis of the precise causes of inbreeding depression will be needed to generate a model that reliably explains variation in directional dominance and reconciles the gap between observed and expected genetic loads carried by populations. This challenging evolutionary puzzle should stimulate work on the occurrence and causes of sex differences in fertility load.

Endoscopic tri-modal imaging improves detection of gastric intestinal metaplasia among a high-risk patient population in Singapore

BACKGROUND: Detection of pre-neoplastic gastric mucosal changes and early gastric cancer (EGC) by white-light endoscopy (WLE) is often difficult. In this study we investigated whether combined autofluorescence imaging (AFI) and narrow band imaging (NBI) can improve detection of pre-neoplastic lesions and early gastric cancer in high-risk patients.

PATIENTS AND METHODS: Chinese patients who were 50-years-old or above with dyspepsia were examined by both high-resolution WLE and combined AFI followed by NBI (AFI-NBI), consecutively in a prospective randomized cross-over setting, by two experienced endoscopists. The primary outcome was diagnostic ability of the two methods for patients with pre-neoplastic lesions such as intestinal metaplasia (IM) and mucosal atrophy.

RESULTS: Sixty-five patients were recruited. One patient with large advanced gastric cancer was found and excluded from the analysis. Among the remaining 64 patients, 38 (59%) had IM; of these, 26 (68%) were correctly identified by AFI-NBI (sensitivity 68%, specificity 23%) and only 13 (34%) by WLE (sensitivity 34%, specificity 65%). AFI-NBI detected more patients with IM than did WLE (p=0.011). Thirty-one patients (48%) had mucosal atrophy. Ten patients (32%) were identified by AFI-NBI (sensitivity 32%, specificity 79%) and four patients (13%) by WLE (sensitivity 13%, specificity 88%) (p=0.100). No dysplasia or EGC was found.

CONCLUSION: AFI-NBI identified significantly more patients with IM than did WLE. Our result warrants further studies to define the role of combined AFI-NBI endoscopy for detection of precancerous conditions.

"Things I did not know”: Retrospectives on a Canadian rural male youth suicide using an instrumental photo voice case study

In Canada, it is young rural based men who are at the greatest risk for suicide. While there is no consensus on the reasons for this, evidence points to contextual social factors including isolation, lack of confidential services and pressure to uphold restrictive norms of rural masculinity. In this article we share findings drawn from an instrumental photo voice case study to distil factors contributing to the suicide of a young Canadian rural based man. Integrating photo voice methods and in-depth qualitative we conducted interviews with 7 family members and close friends of the deceased. The interviews and image data were analyzed using constant comparative methods to discern themes related to participants’ reflections on and perceptions about rural male suicide. Three inductively derived themes, “Missing the signs”, “Living up to his public image” and “Down in Rural Canada ” reflect the challenges that survivors and young rural men can experience in attempting to be comply with restrictive dominant ideals of masculinity. We conclude that community based suicide prevention efforts would benefit from gender-sensitive and place specific approaches to advancing men’s mental health by making tangibly available and affirming an array of masculinities to foster the well-being of young rural based men.

Targeting the complement system for the management of retinal inflammatory and degenerative diseases

The retina, an immune privileged tissue, has specialized immune defense mechanisms against noxious insults that may exist in diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), uveoretinitis and glaucoma. The defense system consists of retinal innate immune cells (including microglia, perivascular macrophages, and a small population of dendritic cells) and the complement system. Under normal aging conditions, retinal innate immune cells and the complement system undergo a low-grade activation (parainflammation) which is important for retinal homeostasis. In disease states such as AMD and DR, the parainflammatory response is dysregulated and develops into detrimental chronic inflammation. Complement activation in the retina is an important part of chronic inflammation and may contribute to retinal pathology in these disease states. Here, we review the evidence that supports the role of uncontrolled or dysregulated complement activation in various retinal degenerative and angiogenic conditions. We also discuss current strategies that are used to develop complement-based therapies for retinal diseases such as AMD. The potential benefits of complement inhibition in DR, uveoretinitis and glaucoma are also discussed, as well as the need for further research to better understand the mechanisms of complement-mediated retinal damage in these disease states.

Home and Workplace Built Environment Supports for Physical Activity

BACKGROUND: Physical inactivity has been associated with obesity and related chronic diseases. Understanding built environment (BE) influences on specific domains of physical activity (PA) around homes and workplaces is important for public health interventions to increase population PA.

PURPOSE: To examine the association of home and workplace BE features with PA occurring across specific life domains (work, leisure, and travel).

METHODS: Between 2012 and 2013, telephone interviews were conducted with participants in four Missouri metropolitan areas. Questions included sociodemographic characteristics, home and workplace supports for PA, and dietary behaviors. Data analysis was conducted in 2013; logistic regression was used to examine associations between BE features and domain-specific PA.

RESULTS: In home neighborhoods, seven of 12 BE features (availability of fruits and vegetables, presence of shops and stores, bike facilities, recreation facilities, crime rate, seeing others active, and interesting things) were associated with leisure PA. The global average score of home neighborhood BE features was associated with greater odds of travel PA (AOR=1.99, 95% CI=1.46, 2.72); leisure PA (AOR=1.84, 95% CI=1.44, 2.34); and total PA (AOR=1.41, 95% CI=1.04, 1.92). Associations between workplace neighborhoods' BE features and workplace PA were small but in the expected direction.

CONCLUSIONS: This study offers empirical evidence on BE supports for domain-specific PA. Findings suggest that diverse, attractive, and walkable neighborhoods around workplaces support walking, bicycling, and use of public transit. Public health practitioners, researchers, and worksite leaders could benefit by utilizing worksite domains and measures from this study for future BE assessments.

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS: Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment.

METHODS AND RESULTS: This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries.

CONCLUSION: Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

Persistent endothelial activation and inflammation after Plasmodium falciparum Infection in Malawian children

Endothelial dysregulation is central to the pathogenesis of acute Plasmodium falciparum infection. It has been assumed that this dysregulation resolves rapidly after treatment, but this return to normality has been neither demonstrated nor quantified. We therefore measured a panel of plasma endothelial markers acutely and in convalescence in Malawian children with uncomplicated or cerebral malaria. Evidence of persistent endothelial activation and inflammation, indicated by increased plasma levels of soluble intracellular adhesion molecule 1, angiopoetin 2, and C-reactive protein, were observed at 1 month follow-up visits. These vascular changes may represent a previously unrecognized contributor to ongoing malaria-associated morbidity and mortality.

Human melioidosis, Malawi, 2011

A case of human melioidosis caused by a novel sequence type of Burkholderia pseudomallei occurred in a child in Malawi, southern Africa. A literature review showed that human cases reported from the continent have been increasing.

The spectrum of paediatric cardiac disease presenting to an outpatient clinic in Malawi

BACKGROUND: As progress is made towards attaining Millennium Development Goal 4, further reductions in paediatric mortality will only be achieved by concentrating on the burden of non-communicable or neglected diseases. The literature relating to paediatric cardiac disease in sub-Saharan Africa is sparse. There are no published descriptions of paediatric cardiac disease from Malawi, making it impossible to estimate the contribution it makes to childhood morbidity and mortality.

FINDINGS: In 2008, a paediatric cardiac clinic with echocardiogram scanning was established in Blantyre, southern Malawi. Between January 2009 and February 2011, the age and cardiac diagnosis of every child with an abnormal echocardiogram was recorded in a database. Of 250 children, 139 (55.6%) had congenital heart disease, and 111 (44.4%) acquired heart disease. Ventricular septal defect (VSD) (24%), Tetralogy of Fallot (10%) and patent ductus arteriousus (7.2%) were the commonest forms of congenital heart disease. Rheumatic heart disease (RHD) (22.4%) and dilated cardiomyopathy (13.6%) were the commonest acquired diseases. The mean age of presentation was 3 years 2 months for VSD and 11 years 6 months for RHD.

CONCLUSIONS: In this cohort of children from one centre in Malawi, acquired heart disease - in particular rheumatic heart disease was almost as common as congenital heart disease. Most presented late. It is likely that untreated cardiac disease causes a large number of childhood deaths in Malawi. In addition to renewing secondary preventative efforts against rheumatic heart disease, adequate and accessible cardiothoracic surgical services should be established at a regional level.