Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI‐EBI Catalog of published genome‐wide association studies

We conducted a hypothesis‐free cross‐trait analysis for waist‐to‐hip ratio adjusted for body mass index (WHR_adjBMI) loci derived through genome‐wide association studies (GWAS). Summary statistics from published GWAS were used to capture all WHR_adjBMI single‐nucleotide polymorphisms (SNPs), and their proxy SNPs were identified. These SNPs were used to extract cross‐trait associations between WHR_adjBMI SNPs and other traits through the NHGRI‐EBI GWAS Catalog. Pathway analysis was conducted for pleiotropic WHR_adjBMI SNPs. We found 160 WHR_adjBMI SNPs and 3675 proxy SNPs. Cross‐trait analysis identified 239 associations, of which 100 were for obesity traits. The remaining 139 associations were filtered down to 101 unique linkage disequilibrium block associations, which were grouped into 13 categories: lipids, red blood cell traits, white blood cell counts, inflammatory markers and autoimmune diseases, type 2 diabetes‐related traits, adiponectin, cancers, blood pressure, height, neuropsychiatric disorders, electrocardiography changes, urea measurement, and others. The highest number of cross‐trait associations were found for triglycerides (n = 10), high‐density lipoprotein cholesterol (n = 9), and reticulocyte counts (n = 8). Pathway analysis for WHR_adjBMI pleiotropic SNPs found immune function pathways as the top canonical pathways. Results from our original methodology indicate a novel genetic association between WHR_adjBMI and reticulocyte counts and highlight the pleiotropy between abdominal obesity, immune pathways, and other traits.     

Discovery of critical host factor, IL-28B, associated with response to hepatitis C virus treatment

Chronic hepatitis C affects 2.2-3.0% of the world population (130 million-170 million). Pegylated interferon-α (PEG-IFN-α) in combination with ribavirin (RBV), the approved and standard therapy, leads to viral eradication in about 50% of treated patients. In 2009, genome-wide association studies (GWAS) identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). A correlated set of polymorphisms in the region of the interleukin-28B (IL-28B) gene on chromosome 19, coding for interferon (IFN)-λ3 were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with PEG-IFN-α and RBV. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. In addition, prediction of viral response to PEG-IFN-α and RBV therapy of patients with recurrent HCV infection after orthotopic liver transplantation depends on the IL-28B genotype of both recipient and donor tissues. Diagnosis of a patient's IL-28B genotype is likely to aid in clinical decision making with standard-of-care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL-28B genotype. As GWAS yield unexpected data, this approach could lead to the development of novel drug therapy, such as already appears promising with IFN-λ. In this Okuda lecture, I present the current understanding in regard to the relationship between host variations and clinical outcome of hepatitis C.     

Genome‐wide association studies (GWAS): impact on elucidating the aetiology of diabetes

It has proven to be challenging to isolate the genes underlying the genetic components conferring susceptibility to type 1 and type 2 diabetes. Unlike previous approaches, ‘genome‐wide association studies’ have extensively delivered on the promise of uncovering genetic determinants of complex diseases, with a number of novel disease‐associated variants being largely replicated by independent groups. This review provides an overview of these recent breakthroughs in the context of type 1 and type 2 diabetes, and outlines strategies on how these findings will be applied to impact clinical care for these two highly prevalent disorders. Copyright © 2011 John Wiley & Sons, Ltd.     

Amyloid‐ß‐directed immunotherapy for Alzheimer's disease

Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid‐ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti‐amyloid immunotherapy remains one of the most promising emerging strategies for developing disease‐modifying treatments for AD. In this review, we examine the presently ongoing Aß‐directed immunotherapies that have passed clinical development Phase IIa.     

Genetics of type 2 diabetes in European populations

Type 2 diabetes (T2D) has become a leading health problem throughout the world. It is caused by environmental and genetic factors, as well as interactions between the two. However, until very recently, the T2D susceptibility genes have been poorly understood. During the past 5 years, with the advent of genome‐wide association studies (GWAS), a total of 58 T2D susceptibility loci have been associated with T2D risk at a genome‐wide significance level (P < 5 × 10^?8), with evidence showing that most of these genetic variants influence pancreatic β‐cell function. Most novel T2D susceptibility loci were identified through GWAS in European populations and later confirmed in other ethnic groups. Although the recent discovery of novel T2D susceptibility loci has contributed substantially to our understanding of the pathophysiology of the disease, the clinical utility of these loci in disease prediction and prognosis is limited. More studies using multi‐ethnic meta‐analysis, gene–environment interaction analysis, sequencing analysis, epigenetic analysis, and functional experiments are needed to identify new susceptibility T2D loci and causal variants, and to establish biological mechanisms.     

Genetic variants associated with predisposition to prostate cancer and potential clinical implications

Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.     

Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer's disease‐like pathology

Translational research on Alzheimer's disease (AD) has often focused on reducing the high cerebral levels of amyloid‐β (Aβ) as a key characteristic of AD pathogenesis. There is, however, a growing body of evidence that synaptic dysfunction may be crucial for the development of the most common (sporadic) form of AD. The applicability of melatonin (mainly produced by the pineal gland) to the treatment of AD is actively evaluated, but usually, such studies are based on animal models of early‐onset AD, which is responsible for only ~5% of AD cases. We have shown previously that in OXYS rats (an established model of sporadic AD), accumulation of toxic forms of Aβ in the brain occurs later than does the development of signs of neurodegenerative changes and synaptic failure. In this regard, recently, we uncovered beneficial neuroprotective effects of melatonin (prophylactic dietary supplementation) in OXYS rats. Our aim here was to evaluate, starting at the age of active progression of AD‐like pathology in OXYS rats, the effects of long‐term oral administration of melatonin on the structure of synapses and on neuronal and glial cells of the hippocampus. Melatonin significantly increased hippocampal synaptic density and the number of excitatory synapses, decreased the number of inhibitory synapses, and upregulated pre‐ and postsynaptic proteins (synapsin I and PSD‐95, respectively). Furthermore, melatonin improved the ultrastructure of neuronal and glial cells and reduced glial density. Based on our past and present results, the repair of neuroplasticity by melatonin is a promising strategy against AD.     

Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer's disease

Alzheimer''s disease (AD) is a serious neurodegenerative disease, and microRNAs (miRNAs) have been linked to its pathogenesis. miR-603, a novel primate-specific miRNA and an intronic miRNA of a human brain highly expressed gene KIAA1217, is implicated in the risk and pathogenesis of AD. The rs11014002 single nucleotide polymorphism (SNP) (C/U), which locates in miR-603 precursor (pre-miR-603), exhibits a protective effect towards AD risk. Additionally, the rs11014002 SNP promotes the biogenesis of mature miR-603. miR-603 downregulates LRPAP1 mRNA and protein levels through directly binding the 3′ untranslated region (3′UTR) of LRPAP1. Moreover, miR-603 increases LRP1 protein expression. LRPAP1 and LRP1, playing opposite roles, are involved in Aβ clearance and pathogenesis of AD. Strikingly, miR-603 exhibits a relatively higher expression and there is a loss of a negative correlation between miR-603 and LRPAP1/RND1 mRNA levels in the hippocampi of patients with AD. In addition, miR-603 directly downregulates a key neuronal apoptotic component-E2F1, and prevents HeLa cells from undergoing H₂O₂-induced apoptosis. This work suggests that miR-603 may be a novel AD-relevant miRNA and that its rs11014002 SNP may serve as a protective factor against AD.     

Genetics of Coronary Artery Disease: An Update

In 2007, the first genetic risk variant, 9p21, was simultaneously discovered by two independent groups. 9p21 increases the risk of coronary artery disease in individuals with premature heart disease by twofold, and in the overall population the heterozygote is associated with a 25% increased risk and the homozygote with a 50% increased risk. It is of note that the risk mediated by 9p21 is independent of known risk factors. Since then, with the development of new technologies and the international consortium of CARDIoGRAM, there is now a total of 50 genetic risk variants confirmed and replicated for CAD. Of these 50, 35 mediate their risk by unknown mechanisms, indicating that the pathogenesis of atherosclerosis and myocardial infarction is due to additional factors as yet unknown. The role of genetic risk factors in the management of CAD is yet to be determined. Since many of them are independent of known risk factors, the genetic risk will in the future have to be incorporated into the guidelines, which recommend the target level of plasma LDL-C to be achieved based on the number of risk factors.