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.     

Genetics of Human Hypertension

BACKGROUND: Hypertension is a multifactorial disease involving interactions among genetic, environmental, demographic, vascular and neuroendocrine factors. Essential hypertension is the most frequent diagnosis in this syndrome, indicating that a monocausal etiology has not been identified. However, a number of risk factors underlying essential hypertension have also been identified including age, sex, genetics, demographic factors, and others. Remarkable progress in molecular biological research has been achieved in clarifying the molecular basis of Mendelian hypertensive disorders. Causative genes and chromosomal fragments harboring disease susceptibility genes have been identified, e. g., for glucocorticoid-remediable aldosteronism, Liddle's syndrome, mineralocorticoid excess. MOLECULAR GENETIC STUDIES: Molecular genetic studies have now identified mutations in eight genes that cause Mendelian forms of hypertension and nine genes that cause Mendelian forms of hypotension in humans. No single genetic variant has emerged from linkage or association analyses as consistently related to blood pressure level in every sample and in all populations. However, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. Most prominent have been the polymorphisms in the renin-angiotensin-aldosterone system. CONCLUSION: Essential hypertension is likely to be a polygenic disorder that results from the 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 is intended.     

Genetics of osteoarthritis.

The available evidence suggests that genetic factors have a major role in osteoarthritis. It has been believed for over 50 years that a strong genetic component to certain forms of osteoarthritis is present. This genetic influence has now been estimated to be up to 65% in a recent twin study. The nature of the genetic influence in osteoarthritis is speculative and may involve either a structural defect (that is, collagen), alterations in cartilage or bone metabolism, or alternatively a genetic influence on a known risk factor for osteoarthritis such as obesity. Exciting work has showed that mutations in the collagen type 2 are important in some rare, familial forms of osteoarthritis. Further work is needed on isolating the gene or genes involved in the pathogenesis of this common, disabling condition.     

WNT signaling in osteoarthritis and osteoporosis: What is the biological significance for the clinician?

Osteoporosis and osteoarthritis are common musculoskeletal disorders in which cause and outcome are determined by genetic and environmental factors. The WNT signaling pathway plays an important role in skeletal development and growth. Polymorphisms in a number of genes that belong to this pathway are associated with osteoarthritis and/or osteoporosis. This suggests a role for this molecular signaling pathway in postnatal joint and bone homeostasis and pathology. Increased activity of WNT signaling strengthens the bone but may have adverse effects on the articular cartilage. Frizzled related protein (FRZB) plays a role in both bone and cartilage. Better understanding of the WNT pathway and its modulators may lead to specific therapeutics for both osteoarthritis and osteoporosis. This review focuses on recent studies in human genetics and animal models and highlights the potential clinical relevance of this rapidly evolving field of research.     

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.     

Immunogenetics in PSC

Primary sclerosing cholangitis (PSC) does not exhibit simple Mendelian inheritance attributable to a single gene locus and our knowledge of the genetics of this complex disease is based entirely on case-control studies of candidate genes. The prime candidates in PSC are inherited variation (polymorphism) in the genes that regulate the immune response, especially the genes of the major histocompatability complex (MHC). Thus far, five different human leukocyte antigen (HLA) haplotypes have been associated with PSC: three with increased risk of disease and two with reduced risk. More recently studies of non-MHC genes have failed to associate PSC with several cytokine genes (IL-1 and IL-10), with FAS (TNFRSF6), with TGFbeta-1, or with CCR-5 but have found genetic links with MMP-3 and disease progression, whilst the potential role of CTLA-4 gene polymorphism remains in question.With the completion of the human genome project, understanding the genetics of complex (non-Mendelian) disease is a major priority for the research community and the studies summarized herein may guide these future investigations.     

The genetics of systemic lupus erythematosus and implications for targeted therapy

Observations of familial aggregation (λs=8-29) and a 40% identical twin concordance rate prompted recent work towards a comprehensive genetic analysis of systemic lupus erythematosus (SLE). Since 2007, the number of genetic effects known to be associated with human lupus has increased by fivefold, underscoring the complexity of inheritance that probably contributes to this disease. Approximately 35 genes associated with lupus have either been replicated in multiple samples or are near the threshold for genome-wide significance (p > 5 x 10??). Some are rare variants that convincingly contribute to lupus only in specific subgroups. Strong associations have been found with a large haplotype block in the human leucocyte antigen region, with Fcγ receptors, and with genes coding for complement components, in which a single gene deletion may cause SLE in rare familial cases and copy number variation is more common in the larger population of SLE patients. Examples of newly discovered genes include ITGAM, STAT4 and MECP2/IRAK1. Ongoing studies to build models in which combinations of associated genes might contribute to specific disease manifestations should contribute to improved understanding of disease pathology. In addition, pharmacogenomic components of ongoing clinical trials are likely to provide insights into fundamental disease pathology as well as contributing to informed patient selection for targeted treatments and biomarkers to guide dosing and gauge responsiveness. Besides these potentially valuable new insights into the pathophysiology of an enigmatic, potentially deadly, and, as yet, unsolved disease, genetic studies are likely to suggest novel molecular targets for strategic development of safer and more effective therapeutics.     

Genetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis

Familial and acquired erythrocytosis and thrombocytosis are characterized by myeloid lineage hyperproliferation, which is either single or multi‐lineage in origin. The single lineage disorders exhibit Mendelian inheritance with polyclonal hematopoiesis and often arise from a single genetic defect. In contrast, the multi‐lineage disorders exhibit complex patterns of inheritance with multi‐genetic origins and clonal hematopoiesis. They have the potential to acquire JAK2 somatic mutations, but this is not the primary event. Identification of the disease‐causing genes will enable better classification of familial and acquired erythrocytosis and thrombocytosis. Furthermore, it will provide an insight into the mechanisms regulating myeloid cell proliferation. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc.     

The genetic background of inflammatory bowel disease

Available evidence indicates that genetic factors are essential in providing the susceptibility to the majority of the various forms of inflammatory bowel disease occurring in man. It is also clear that the genetic susceptibility to these diseases is complex, and that more than one gene may predispose (the concept of multilocus/oligogenic inheritance), and likely in different etiologic combinations (the concept of genetic heterogeneity). Paradigms are now available that should lead to the identification of a number of these predisposing genes. These paradigms include the candidate gene approach, systematic genome wide scans, and mouse human synteny. While genome wide scans are currently limited to multiplex family linkage studies, both candidate genes and mouse human synteny can be approached in either linkage or association paradigms. Eventually whole genome association studies will be available as well. Identification of inflammatory bowel disease predisposing genes should lead to their incorporation in studies of natural history, investigation of environmental risk factors, and especially utilization of genetic markers in clinical trials. This will allow us to identify the best therapy available for the individual patient based on their unique genetic constitution. With advances in molecular technology, the search for genes influencing traits and diseases with a complex genetic background, such as the inflammatory bowel diseases, has become a realistic task. Although exogenous or infectious agents may contribute to the pathogenesis or may trigger the onset of disease, and the immune system almost certainly mediates the tissue damage, it is clear from available data that genetic factors determine the susceptibility of a given individual to inflammatory bowel disease (reviewed below). Thus, genetic studies are essential for the delineation of the basic etiologies of the various forms of inflammatory bowel disease and thus can aid in the development of radically new and specific therapies. In this review, we will discuss the importance and complexity of genetic factors in inflammatory bowel disease, methods and problems in the genetic dissection of complex traits, and future directions of genetic studies in inflammatory bowel disease.     

Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism

Children's intellectual development is influenced by both genetic inheritance and environmental experiences. Breastfeeding is one of the earliest such postnatal experiences. Breastfed children attain higher IQ scores than children not fed breast milk, presumably because of the fatty acids uniquely available in breast milk. Here we show that the association between breastfeeding and IQ is moderated by a genetic variant in FADS2, a gene involved in the genetic control of fatty acid pathways. We confirmed this gene-environment interaction in two birth cohorts, and we ruled out alternative explanations of the finding involving gene-exposure correlation, intrauterine growth, social class, and maternal cognitive ability, as well as maternal genotype effects on breastfeeding and breast milk. The finding shows that environmental exposures can be used to uncover novel candidate genes in complex phenotypes. It also shows that genes may work via the environment to shape the IQ, helping to close the nature versus nurture debate.     

Genetics of inflammatory bowel disease. A personal view on progress and prospects

Clinical, epidemiological and molecular data reported in the last 5 years have provided strong evidence that genetic factors are important in susceptibility to both Crohn's disease and ulcerative colitis. The model of disease inheritance which best fits the epidemiological data is that Crohn's disease and ulcerative colitis are related polygenic diseases. However, genetic heterogeneity is likely to be extensive, and may well underlie the variability in clinical presentation associated with inflammatory bowel disease. Considerable progress has already been made in identifying potential disease susceptibility loci using the technique of genome-wide scanning. There is optimism that international collaborative studies will allow fine mapping of the loci implicated on chromosomes 16 and 12. The identification of novel susceptibility genes has become a realistic goal for investigators. Once this has been achieved, there are likely to be immediate clinical benefits, both in understanding disease pathophysiology, and in disease management.     

The new genetics and chronic obstructive pulmonary disease

Epidemiological and family studies provide evidence for genetic factors contributing to chronic obstructive airways disease (COPD) susceptibility. Studies to date have focused on candidate genes implicated in the pathogenesis of the disease. In general, many of these studies have been underpowered or have not been extensive enough in investigating the full extent of genetic variation in these genes. This has resulted in conflicting data with potential false positives or findings that have not been replicated. More recently, larger studies and extensive coverage of candidate genes have implicated genetic variants that may contribute to the disease. The use of unbiased genome-wide association studies offer the prospect of identifying new genes involved in COPD susceptibility and genetic modifiers of disease phenotypes. There is cause for optimism as a number of major complex diseases have been successfully tackled in this way. The review will highlight what has been achieved by genetic studies to date, some of the related problems and the future impact of high throughput technologies such as genome-wide association studies on our understanding of the genetic basis of COPD.     

An overview of the genetic analysis of complex diseases, with reference to type 1 diabetes

Despite extensive efforts by many groups, progress in the mapping of complex diseases has been exceedingly slow, only a few genes and some genetic regions having been identified. The general picture is one of difficulty in locating disease genes and in the replication of linkages. This results from the role in disease of a large number of genes, many with a relatively minor effect and many involving common genetic variation. A multi-strategy approach to the mapping of complex diseases is required: no single method is sufficient or optimal. The role of human leukocyte antigens in type 1 diabetes has been known for nearly 30 years, and the associations, linkage and genetic contribution to disease are all strong, but all the human leukocyte antigen region genes involved in the disease process have not yet been identified. The methods used in study of this component to type 1 diabetes are a model for all complex diseases.     

Allele-sharing of cytokine genes in familial inflammatory bowel disease

BACKGROUND/AIMS: The pathogenesis of inflammatory bowel disease is complex, multifactorial, and involves genetic predisposition. This predisposition is likely to include various chromosomal loci, but simple Mendelian inheritance cannot be excluded in a subset of families with inflammatory bowel disease. METHODOLOGY: We evaluated allele-sharing in 17 sib-pairs with inflammatory bowel disease as an approach to select candidate genes for further studies in individual families. It was determined whether each sib-pair had inherited the same alleles for interleukin-2, interleukin-2 receptor beta, interleukin-4, interleukin-4 receptor, interleukin-10, interleukin-10 receptor, tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 and 2. RESULTS: The results were very different per individual family. The estimated probability of sharing both alleles identical-by-descent at interleukin-4 receptor, interleukin-10, interleukin-10 receptor, and tumor necrosis factor alpha were 50%, 39%, 40%, and 33% respectively. The LOD score was significant for interleukin-4 receptor (p = 0.04). CONCLUSIONS: In this small group of sib-pairs with inflammatory bowel disease a modestly increased allele-sharing was found for some inflammatory related genes. Different results per family may suggest genetic heterogeneity. This method can be useful as a first step to further evaluation of specific candidate genes which may play a pathogenetic role in individual families.     

A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with approximately 50% of familial cases being heterozygous for mutations in the receptor tyrosine kinase RET. Even when identified, the penetrance of RET mutations is only 50-70%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe RET mutations (group I); and the six remaining families, five of which are RET-linked families with no sequence alterations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes.     

Sarcoidosis and granuloma genes: a family-based study in African-Americans.

The evidence for a genetic component in the aetiology of sarcoidosis includes familial aggregation, associations with genetic polymorphisms, and linkage to the major histocompatibility complex class region on chromosome 6p. Unfortunately, the majority of genetic associations with sarcoidosis have not been consistently replicated. In the present study, using a family-based study design, which controls for population stratification, the authors attempted to replicate previously reported associations between sarcoidosis and three attractive candidate genes studied primarily in case-control samples. In 225 nuclear families, ascertained through African Americans with a history of sarcoidosis, no evidence was found for an association between sarcoidosis susceptibility and polymorphisms in the angiotensin converting enzyme, vitamin D receptor and tumour necrosis factor-alpha genes. Further analyses of chronic and acute disease phenotypes failed to reveal any notable associations. Assuming an underlying inheritance model with an additive allelic effect on disease risk, the current study had approximately 80-90% statistical power to detect a 3-fold increased risk associated with the putative risk allele of the polymorphisms under study. The present authors conclude that in African-Americans, the angiotensin converting enzyme, vitamin D receptor, and tumour necrosis factor-alpha genes are not significant risk factors for sarcoidosis susceptibility.     

Essential hypertension and histocompatibility antigens. A linkage study

It is well established that genetic and environmental factors are involved in the etiology of essential hypertension. The presence of genes predisposing to essential hypertension in the human leukocyte antigen (HLA) complex is controversial because studies of an association between HLA antigens and essential hypertension have failed to yield consistent results. Our aim in the present study was to further investigate this issue through the method of linkage analysis. Analysis of 96 hypertensive siblings distributed in 31 families indicated a significant distortion (p = 0.0009) of the normal segregation pattern of inheritance of HLA haplotypes. Thus, our data indicate that at least one of the genes responsible for genetic predisposition to essential hypertension is located very near or within the HLA complex.     

IBD and genetics: new developments

BACKGROUND: Inflammatory bowel disease (IBD) is a complex disorder with an aetiology that is only partly understood. Apart from environmental factors, inheritance contributes to IBD. REVIEW: Family studies show an increased risk among family members of a patient with IBD, particularly among first-degree relatives. In twin studies, concordance for disease type and localization is observed. In genetically isolated groups there is a higher prevalence of IBD. For instance. Ashkenazi Jews carry the highest risk. Further evidence comes from animal species that spontaneously develop IBD. Unlike Mendelian inheritance, in complex genetic diseases like IBD, genes are expected to be low penetrant and therefore less prone to selection, which results in higher expected gene frequencies. NOD2/CARD15, the first gene associated with IBD, is a polymorphic gene involved in the innate immune system. The gene has over 60 variations. Three of these play a role in 27% of patients with CD, with a predilection for patients with ileal disease. CONCLUSION: Genetics plays an important role in unravelling the pathogenesis of IBD leading to possible new therapeutic approaches.