Genetics of Hypertension and Cardiovascular Disease and Their Interconnected Pathways: Lessons from Large Studies

Blood pressure (BP), hypertension (HT) and cardiovascular disease (CVD) are common complex phenotypes, which are affected by multiple genetic and environmental factors. This article describes recent genome-wide association studies (GWAS) that have reported causative variants for BP/HT and CVD/heart traits and analyzes the overlapping associated gene polymorphisms. It also examines potential replication of findings from the HyperGEN data on African Americans and whites. Several genes involved in BP/HT regulation also appear to be involved in CVD. A better picture is emerging, with overlapping hot-spot regions and with interconnected pathways between BP/HT and CVD. A systemic approach to full understanding of BP/HT and CVD development and their progression to disease may lead to the identification of gene targets and pathways for the development of novel therapeutic interventions.     

Genetic determinants of cardiovascular disease in Hispanics

Cardiovascular disease (CVD) affects many people in the United States. Compared with other population groups in the United States, epidemiologic data suggest that Hispanic Americans are at a disproportionate risk for CVD. The etiology of this disparity is complex, with genetic, behavioral, cultural, and other environmental factors acting in an independent, interactive, and/or synergistic fashion. Because many complex conditions mediate risk of CVD, including diabetes, obesity, and hyperlipidemia, genes associated with these conditions have been considered as possible contributors to CVD in Hispanics. In addition, the diversity of background and heritage within this population creates a plethora of environmental determinants that interact with behaviors, cultural practices, and genetic makeup to influence disease risk. In this review, we explore the recent literature on genetic determinants of CVD and explain that effective efforts to reduce CVD disparities in Hispanics in the United States will require an understanding of the interactions of genes, the environment, and health-related practices.     

Genetic Markers of Inflammation and Their Role in Cardiovascular Disease

Atherosclerosis and associated cardiovascular diseases (CVD) are multifaceted disorders, influenced by environmental and heritable risk factors. Inflammation plays a significant role in each stage of atherosclerosis and as such, discovery and characterization of inflammatory biomarkers associated with risk of CVD is an active area of research. Because of the strong predicted genetic components of both CVD and inflammatory biomarkers, there is interest in identifying genetic determinants of inflammatory markers and characterizing their role in CVD. Recent developments in the methodological approaches of genetic epidemiology, especially genome-wide association studies and Mendelian randomization studies, have been effective in identifying novel gene associations and determining the causality of these genes with CVD. In this review, we will summarize the current understanding of the genetic architecture of inflammatory markers. The markers selected for this review include C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6, and P-selectin.     

Genetic susceptibility to atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with an increasing prevalence in industrialized countries. AD belongs to the group of allergic disorders that includes food allergy, allergic rhinitis, and asthma. A multifactorial background for AD has been suggested, with genetic as well as environmental factors influencing disease development. Recent breakthroughs in genetic methodology have greatly augmented our understanding of the contribution of genetics to susceptibility to AD. A candidate gene association study is a general approach to identify susceptibility genes. Fifty three candidate gene studies (50 genes) have identified 19 genes associated with AD risk in at least one study. Significant associations between single nucleotide polymorphisms (SNPs) in chemokines (chymase 1-1903A > G), cytokines (interleukin13 Arg144Gln), cytokine receptors (interleukin 4 receptor 1727G > A) and SPINK 1258G > A have been replicated in more than one studies. These SNPs may be promising for identifying at-risk individuals. SNPs, even those not strongly associated with AD, should be considered potentially important because AD is a common disease. Even a small increase in risk can translate to a large number of AD cases. Consortia and international collaborative studies, which may maximize study efficacy and overcome the limitations of individual studies, are needed to help further illuminate the complex landscape of AD risk and genetic variations.     

Genetic determinants of urolithiasis

Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors involved in urolithiasis have remained less clear, partly owing to the candidate gene and linkage methods that have been available until now, being inherently low in their power of resolution and in assessing modest effects in complex traits. However, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors, these methods have afforded insights into biological pathways that seem to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in children and adolescents than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance owing to associated renal injury and other potentially treatable disease manifestations, but diagnosis is often delayed because of a lack of familiarity with these rare disorders. In this Review, we will discuss advances in the understanding of the genetics underlying polygenic and monogenic forms of urolithiasis.     

Rheumatoid arthritis genetics: 2009 update

Recent human genetic discoveries have increased our understanding of rheumatoid arthritis (RA) susceptibility. Genome-wide association studies have expanded the number of validated RA risk loci beyond HLA-DRB1 “shared epitope” alleles to include additional major histocompatibility complex (MHC) risk alleles and more than 10 regions outside the MHC. The newly discovered risk alleles are common in the general population, have a modest effect on RA risk, and together explain less than 5% of the variance in disease risk. Whereas the actual causal mutation and causal gene for most loci remain to be determined, these studies are beginning to reveal general themes: many risk loci are associated with other autoimmune diseases; many genes fall within discrete biological pathways (eg, the nuclear factor κ-light-chain-enhancer of activated B cells signaling pathway); and human genetics can group diseases into clinically meaningful subset categories (eg, presence or absence of autoantibodies). This review discusses recent RA genetic discoveries in terms of their potential to improve patient care.     

Advances in the genetics of inflammatory bowel disease

Research efforts in the inflammatory bowel diseases have been uniquely successful in identifying genetic linkage regions likely containing susceptibility genes for Crohn’s disease and ulcerative colitis. In two of these regions, definitive gene associations have been established, namely for the NOD2/ CARD 15 gene on chromosome 16 (IBD1) and the OCTN1/ SLC22A4-OCT/SLC22A5 genes on chromosome 5q (IBD5), both conferring increased risk for developing Crohn’s disease. Recently, significant gene associations have been reported for additional genes, including DLG5, MDR1, and TLR4 as well. The NOD2/CARD15 gene mutations are associated with ileal disease location and a modestly earlier age of onset compared with NOD2/CARD15 wild-type Crohn’s disease patients. Future progress in the genetics of inflammatory bowel disease will likely involve systematic phenotyping, including the incorporation of clinical subtypes and novel biomarkers. The ultimate goal of genetic research in inflammatory bowel disease is to identify the earliest biologic pathways that are altered, resulting in disease pathogenesis. Identification of these key pathways will potentially highlight novel therapeutic targets.     

Genetic factors in the pathogenesis of gastroesophageal reflux disease

Multiple factors play a role in the pathogenesis of gastroesophageal reflux disease (GERD). Two landmark studies showing higher concordance of disease in monozygotic than dizygotic twin pairs suggested the role of host genetic factors in its pathogenesis. Recent studies have shown that genetic polymorphism in genes influencing host’s inflammatory response, drug metabolism, cell cycle regulation, xenobiotic pathways, DNA repair, mutagenesis, esophageal sensory function and gene silencing are associated with risk of GERD and its sequelae—Barrett’s esophagus and esophageal adenocarcinoma. However, more studies on larger sample size are needed before reaching a definite conclusion on the role of an individual gene.     

Molecular genetics of essential hypertension

Hypertension is a major public health problem in the developing as well as in developed countries due to its high prevalence and its association with coronary heart disease, renal disease, stroke, peripheral vascular disease, and related disorders. Essential hypertension (EH) is the most common diagnosis in this disease, suggesting that a monocausal etiology has not been identified. However, a number of risk factors associated with EH have also been identified such as age, sex, demographic, environmental, genetic, and vascular factors. Recent advances in molecular biological research had achieved clarifying the molecular basis of Mendelian hypertensive disorders. Molecular genetic studies have now identified mutations in several genes that cause Mendelian forms of hypertension in humans. However, none of the single genetic variants has emerged from linkage or association analyses as consistently related to the blood pressure level in every sample and in all populations. Besides, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. The most prominent candidate has been the polymorphisms in the renin–angiotensin–aldosterone system. In total, EH is likely to be a polygenic disorder that results from inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors was intended. In this review, recent genetic studies exploring the molecular basis of EH, including different molecular pathways, are highlighted.     

Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.     

Genomic progress in pediatric arthritis: recent work and future goals

PURPOSE OF REVIEW: Pediatric arthritis is a heterogeneous group of chronic arthropathies that are influenced by complex genetic and perhaps environmental factors. Interacting genetic traits may one day be identified that provide the basis for predicting disease risk and other characteristics such as course, age of onset, and disease severity. The purpose of this review is to describe the recent progress towards identifying the multiple genes related to pediatric arthritis and understand how they relate to each other and to disease pathology. RECENT FINDINGS: Candidate gene studies are by far the most widely reported type of genetic studies to date for juvenile arthritis with only one genome-wide screen for juvenile rheumatoid/idiopathic arthritis published. Particular attention is paid to studies of candidate genes with potential immunological roles and those associated with other forms of autoimmunity. SUMMARY: Genomic studies may perhaps one day provide information to allow future classification systems of childhood arthritis to include molecular biomarkers as a complement to clinical observations, as well as understand how these genes or proteins relate to each other and to disease pathogenesis.     

Shared Genetic Contribution of Type 2 Diabetes and Cardiovascular Disease: Implications for Prognosis and Treatment

Purpose of Review

The increased cardiovascular disease (CVD) risk in subjects with type 2 diabetes (T2D) is well established. This review collates the available evidence and assesses the shared genetic background between T2D and CVD: the causal contribution of common risk factors to T2D and CVD and how genetics can be used to improve drug development and clinical outcomes.

Recent Findings

Large-scale genome-wide association studies (GWAS) of T2D and CVD support a shared genetic background but minimal individual locus overlap.

Summary

Mendelian randomisation (MR) analyses show that T2D is causal for CVD, but GWAS of CVD, T2D and their common risk factors provided limited evidence for individual locus overlap. Distinct but functionally related pathways were enriched for CVD and T2D genetic associations reflecting the lack of locus overlap and providing some explanation for the variable associations of common risk factors with CVD and T2D from MR analyses.

     

Hearts and bones

Cardiovascular disease (CVD) and osteoporosis (OP) are two common degenerative processes that contribute in great measure to the decline in performance and quality of life of the elderly population. Traditionally, these disorders have been considered as distinct and unrelated entities. However, over the last few years, there has been increasing evidence supporting an important link between CVD and OP. Several genetic association and linkage studies have shown the existence of common genetic determinants for cardiovascular and skeletal diseases. These genes code for several key players on the metabolism of nutrients, such as lipids, calcium and folate, as well as other factors (e.g. sex hormone receptors) that are known to be subject to dietary modulation, suggesting the links at the level of dietary response. Some dietary factors have shown similarities in influencing the risks of both conditions. However, some others act differently in relation with their effects on the development of cardiovascular disease and osteoporosis. We therefore suggest that, any dietary and behavioral recommendations targeting to the 'global health' of the ageing population would take a comprehensive consideration of their potentially diverse effects (beneficial or deleterious) on the risks of various ageing related disorders, and would be tailored to the individual genetic background.     

Apolipoprotein E Genotype and Cardiovascular Diseases in the Elderly

The apolipoprotein E (APOE) genotype is a genetic risk factor for dementia, Alzheimer’s disease, and cardiovascular disease (CVD). It includes three alleles (e2, e3, e4) that are located on chromosome 19q3.2. The e3 allele is the most common and is more common in people of Northern European ancestry and less common in those of Asian ancestry. Those with at least one e4 allele are at increased risk for CVD outcomes. It is well established that the presence of an e4 allele is linked to higher low-density lipoprotein cholesterol levels, even at young ages. Even though most CVD occurs in older people, there are few studies of the effects of APOE on CVD in older people. This review addresses recent research on the links between APOE, CVD, and vascular mechanisms by which APOE may affect CVD in the elderly.     

Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group

Atherosclerotic cardiovascular disease (CVD) is a major health problem in the United States and around the world. Evidence accumulated over decades convincingly demonstrates that family history in a parent or a sibling is associated with atherosclerotic CVD, manifested as coronary heart disease, stroke, and/or peripheral arterial disease. Although there are several mendelian disorders that contribute to CVD, most common forms of CVD are believed to be multifactorial and to result from many genes, each with a relatively small effect working alone or in combination with modifier genes and/or environmental factors. The identification and the characterization of these genes and their modifiers would enhance prediction of CVD risk and improve prevention, treatment, and quality of care. This scientific statement describes the approaches researchers are using to advance understanding of the genetic basis of CVD and details the current state of knowledge regarding the genetics of myocardial infarction, atherosclerotic CVD, hypercholesterolemia, and hypertension. Current areas of interest and investigation--including gene-environment interaction, pharmacogenetics, and genetic counseling--are also discussed. The statement concludes with a list of specific recommendations intended to help incorporate usable knowledge into current clinical and public health practice, foster and guide future research, and prepare both researchers and practitioners for the changes likely to occur as molecular genetics moves from the laboratory to clinic.     

Genetics of HDL-C: A Causal Link to Atherosclerosis?

Prospective epidemiological studies have consistently reported an inverse association between HDL cholesterol (HDL-C) levels and the risk of cardiovascular disease (CVD). However, large intervention trials on HDL-C-increasing drugs and recent Mendelian randomization studies have questioned a causal relationship between HDL-C and atherosclerosis. HDL-C levels have been shown to be highly heritable, and the combination of HDL-C-associated SNPs in recent large-scale genome-wide association studies (GWAS) only explains a small proportion of this heritability. As a large part of our current understanding of HDL metabolism comes from genetic studies, further insights in this research field may aid us in elucidating HDL functionality in relation to CVD risk. In this review we focus on the question of whether genetically defined HDL-C levels are associated with risk of atherosclerosis. We also discuss the latest insights for HDL-C-associated genes and recent GWAS data.     

Genetics of Type 2 diabetes.

Type 2 diabetes (T2D) has become a health-care problem worldwide, with the rise in disease prevalence being all the more worrying as it not only affects the developed world but also developing nations with fewer resources to cope with yet another major disease burden. Furthermore, the problem is no longer restricted to the ageing population, as young adults and children are also being diagnosed with T2D. In recent years, there has been a surge in the number of genetic studies of T2D in attempts to identify some of the underlying risk factors. In this review, I highlight the main genes known to cause uncommon monogenic forms of diabetes (e.g. maturity-onset diabetes of the young--MODY--and insulin resistance syndromes), as well as describe some of the main approaches used to identify genes involved in the more common forms of T2D that result from the interaction between environmental risk factors and predisposing genotypes. Linkage and candidate gene studies have been highly successful in the identification of genes that cause the monogenic variants of diabetes and, although progress in the more common forms of T2D has been slow, a number of genes have now been reproducibly associated with T2D risk in multiple studies. These are discussed, as well as the main implications that the diabetes gene discoveries will have in diabetes treatment and prevention.     

Triglyceride, small, dense low-density lipoprotein, and the atherogenic lipoprotein phenotype

This review provides an overview of the recent data evaluating triglyceride and low-density lipoprotein (LDL) size, two highly interrelated, genetically influenced, risk factors for cardiovascular disease (CVD). An examination of new epidemiologic studies continues to demonstrate that plasma triglyceride levels predict CVD. The first prospective study of the familial forms of hypertriglyceridemia has shown that relatives in familial-combined hyperlipidemia families are at increased risk for CVD mortality and that triglyceride levels predicted 20-year, CVD mortality among relatives in familial hypertriglyceridemia families. A meta-analysis of three, large-scale, prospective studies in men, and the first study to examine the correlation of LDL particle size distribution and vascular changes measured by B-mode ultrasound, add to growing evidence that small, dense LDL is atherogenic. Quantitative genetic analysis has recently shown substantial pleiotropic (common) genetic effects on triglyceride and LDL size. At least part of this may be explained by variation at the cholesterol ester transfer protein locus on chromosome 16, possibly through its role in reverse cholesterol transport. Taken together, these data provide new insights into the importance of triglyceride and LDL particle size for understanding genetic susceptibility to cardiovascular disease and its prevention.     

Cardiovascular Risk in the Old Order Amish

Cardiovascular disease is a heterogeneous disease caused by the interaction of multiple pathologies affecting various systems, genetic predisposition, and environmental factors. Recently, novel “non-classic” risk factors have been recognized to play, together with well-characterized risk factors, a role in the pathophysiology of cardiovascular disease. The heterogeneity of causative factors makes identifying the genetic background along with the contribution of environmental influences on the development and progression of cardiovascular disease a major challenge. The Old Order Amish of Lancaster County, Pennsylvania, a close founder population with a very traditional and uniform lifestyle and well-traceable genealogy, is a unique and valuable source of information with respect to the genetic contribution of risk factors that potentially lead to the development of cardiovascular disease. In this review, the major findings from studies of the Old Order Amish are described along with the relevance of these findings to larger population groups.     

Obesity genetics and cardiometabolic health: Potential for risk prediction

The increasing burden of obesity worldwide and its effect on cardiovascular disease (CVD) risk is an opportunity for evaluation of preventive approaches. Both obesity and CVD have a genetic background and polymorphisms within genes which enhance expression of variant proteins that influence CVD in obesity. Genome-based prediction may therefore be a feasible strategy, but the identification of genetically driven risk factors for CVD manifesting as clinically recognized phenotypes is a major challenge. Clusters of such risk factors include hyperglycaemia, hypertension, ectopic liver fat, and inflammation. All involve multiple genetic pathways having complex interactions with variable environmental influences. The factors that make significant contributions to CVD risk include altered carbohydrate homeostasis, ectopic deposition of fat in muscle and liver, and inflammation, with contributions from the gut microbiome. A futuristic model depends on harnessing the predictive power of plausible genetic variants, phenotype reversibility, and effective therapeutic choices based on genotype–phenotype interactions. Inverting disease phenotypes into ideal cardiovascular health metrics could improve genetic and epigenetic assessment, and form the basis of a future model for risk detection and early intervention.