Common gene variants, mortality and extreme longevity in humans

Genetic factors influence variation in human life span. The fast technological advancements in genome research and the methodology for statistical analysis of complex traits provided new tools to unravel these genetic influences. Most of the genetic epidemiology and quantitative genetics is focused on the dissection of the genetic component of specific diseases rather than of human life span. Nevertheless, common variants of 22 genes have been tested for their contribution to mortality in the general population and extreme longevity in one or more studies. These studies provide indications as to the nature of biological pathways that might play a role in human ageing. Perhaps even more important at this time is the fact that they give valuable insights in the strengths and weaknesses of current strategies to identify gene variants affecting human life span and point at more powerful approaches.     

Genes and kidney disease. Candidate genes

Molecular biology techniques have provided important advances in the search for causal relationships in complex diseases supporting traditional epidemiologic studies. Genetic epidemiology allows us to detect genetic variants that could be related to the onset and progression of different diseases. In cardiovascular and renal diseases, this approach linking traditional risk factors to new described ones and those allelic variants, which contribute to the development of these manifestations permits a better understanding of individual disease susceptibility. This is usually afforded through case-control studies evaluating allelic variants of candidate genes previously associated with the disease. Even in this candidate gene search, association-based methods are more powerful than linkage studies in complex traits if we assume that some of the typed polymorphisms are causative although with subtle phenotypic effects. Some brief examples may illustrate the progress in the understanding of renal and cardiovascular diseases.     

Sudden cardiac death, genes, and arrhythmogenesis : consideration of new population and mechanistic approaches from a national heart, lung, and blood institute workshop, part I

Malignant ventricular arrhythmias are the leading mechanism of death in patients with acute and chronic cardiac pathologies. The extent to which inherited mutations and polymorphic variation in genes determining arrhythmogenic mechanisms affect these patients remains unknown, but based on recent population studies, this risk appears significant, deserving much greater investigation. This report summarizes a National Heart, Lung, and Blood Institute workshop that considered sources of genetic variation that may contribute to sudden cardiac death in common cardiac diseases. Evidence on arrhythmogenic mechanisms in recent population studies suggests a significant portion of the risk of sudden cardiac death in such broad populations may be unrelated to traditional risk factors for predisposing conditions such as atherosclerosis, hypertension, and diabetes and instead may involve unrecognized genetic and environmental interactions that influence arrhythmic susceptibility more directly. Additional population and genetic studies directed at discovering the sources of inherited molecular risk that are most directly linked to arrhythmia initiation and propagation, in addition to studies on previously well-described risk factors, would appear to have considerable potential for reducing premature cardiovascular mortality.     

Epidemiology and health services: year in review

PURPOSE OF REVIEW: Epidemiology began as the study of the occurrence of disease in populations. Initial studies focused on the presence of diseases by person, place, and time to identify risk factors for disease. The field has grown to include many subfields recognizing the contributions of multiple factors to disease susceptibility. RECENT FINDINGS: This review will focus on articles published October 2005-November 2006 relevant to genetic epidemiology, pharmacoepidemiology, and social determinants of health and health disparities. SUMMARY: Genetic epidemiology is the study of genetic contributions to disease occurrence, and of population-based genetic risks for disease. Genetics influences not only susceptibility to disease, but also the phenotype and severity of disease. Pharmacoepidemiology examines the outcomes of medication use, including clinical benefits and adverse effects. Gene-environment interactions are also included in this area. Typical topics in pharmacoepidemiology include studies of medication use, risks, benefits and genetic factors influencing the metabolism of medications. Social epidemiology is the study of social determinants of health, including psychosocial behaviors, socioeconomic status, interactions of individuals, the collective health of the community in which a person lives, and the position of the individual within society. Social epidemiology is directly relevant to studies of socioeconomic and ethnic disparities.     

Genetic modifiers of the beta-haemoglobinopathies

Identification of the molecular basis of the beta-thalassaemias and sickle cell disease (SCD) has made it clear that patients with the same beta-globin genotypes can have very variable patterns of clinical expression. Extensive biochemical and pathophysiological studies over the last 50 years have derived two major modifiers--innate ability to produce fetal haemoglobin and co-inheritance of alpha-thalassaemia, subsequently validated by family and population studies. However, these two modifiers do not explain the full clinical spectrum. Genetic studies have been successful in identifying modifiers if the loci have a major clinical effect and if the genetic variants are common. It is possible that additional modifiers could be uncovered using genetic approaches but success will depend on large sample sizes of well-characterised patients with well-defined phenotypes. Since some of the complications, such as overt stroke in SCD, are relatively rare events, intermediate end-points that contribute to the phenotype, such as Transcranial Doppler velocity (a major predictor of stroke in SCD), could be integrated within the genetic analysis. Integrating multiplex genetic testing with clinical and laboratory data to generate predictive models shows potential, but such genetic approaches also require large datasets.     

Host susceptibility to persistent hepatitis B virus infection

Genetic epidemiology researches such as twin studies, family-clustering of hepatitis B virus (HBV) infection studies and ethnic difference studies have provided the evidence that host genetic factors play an important role in determining the outcome of HBV infection. The opening questions include which human genes are important in infection and how to find them. Though a number of studies have sought genetic associations between HBV infection/persistence and gene polymorphisms, the candidate gene-based approach is clearly inadequate to fully explain the genetic basis of the disease. With the advent of new genetic markers and automated genotyping, genetic mapping can be conducted extremely rapid. This approach has been successful in some infectious diseases. Linkage analysis can find host genes susceptible to HBV and is of great clinical importance.     

Host susceptibility to persistent hepatitis B virus infection

Genetic epidemiology researches such as twin studies, family-clustering of hepatitis B virus (HBV) infection studies and ethnic difference studies have provided the evidence that host genetic factors play an important role in determining the outcome of HBV infection. The opening questions include which human genes are important in infection and how to find them. Though a number of studies have sought genetic associations between HBV infection/persistence and gene polymorphisms, the candidate gene-based approach is clearly inadequate to fully explain the genetic basis of the disease. With the advent of new genetic markers and automated genotyping, genetic mapping can be conducted extremely rapid. This approach has been successful in some infectious diseases. Linkage analysis can find host genes susceptible to HBV and is of great clinical importance.     

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms’ aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.     

Sudden cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, Part II

This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.     

The genetics of obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a common chronic disease and is associated with high social and economic costs. OSA is heritable, and there is evidence of both direct genetic contributions to OSA susceptibility and indirect contributions via ‘intermediate’ phenotypes such as obesity, craniofacial structure, neurological control of upper airway muscles and of sleep and circadian rhythm. Investigation of the genetics of OSA is an important research area and may lead to improved understanding of disease aetiology, pathogenesis, adverse health consequences and new preventive strategies and treatments. Genetic studies of OSA have lagged behind other chronic diseases; however recent gene discovery efforts have been successful in finding genetic loci contributing to OSA‐associated intermediate phenotypes. Nevertheless, many of the seminal questions relating to the genetic epidemiology of OSA and associated factors remain unanswered. This paper reviews the current state of knowledge of the genetics of OSA, with a focus on genomic approaches to understanding sleep apnoea.     

Molecular analysis of cardiovascular disease: some delay due to gene-environment interactions

The absence of a clear relation between genotype and phenotype has complicated molecular analyses of the susceptibility to common diseases such as cardiovascular disease. Gene-gene and gene-environment interactions may have biased genetic association studies on cardiovascular disease. In the general population, susceptibility to cardiovascular disease is probably the result of many loci with frequently occurring alleles that have relatively small effects. We hypothesize that addition of mortality analyses to genetic association studies may provide important information on the clinical relevance of molecular findings. We propose to use a parent-offspring model for this purpose: the parents contribute large follow-up and the index cases (offspring) are eliminated from the analyses to remove selection on cardiovascular disease. In particular, indirect estimation of mortality risk has high statistical power and may establish the role of common genetic variation with small effects on cardiovascular disease in the general population. Moreover, the effect of a candidate gene on excess mortality illustrates the quality of such a gene or protein as a novel target for intervention. The results of genetic association studies may have been of little clinical relevance for cardiovascular disease, but we conclude that the methodology still has possibilities for improvements and we propose to use analyses of mortality in a parent-offspring model.     

Molecular Epidemic Characteristics and Genetic Evolution of Porcine Circovirus Type 2 (PCV2) in Swine Herds of Shanghai,China

Porcine Circovirus 2 (PCV2) is a crucial swine pathogen and considered a primary causative agent of porcine circovirus-associated diseases (PCVADs), posing a serious economic threat to the swine industry across globe. The world’s biggest agricultural conglomerates have teamed up to create giant commercial pig farms across Shanghai due to the proximity of this region to more affluent lean-pork markets. Since its discovery, PCV2 has displayed extraordinary genetic diversity, and its genome is swiftly evolving through a series of mutations and recombinations. However, limited information on epidemiology, molecular characteristics, vaccine cross-protection, and the co-infection rate of PCV2 with other lethal swine diseases can adversely impact the pig production in the region. To investigate the molecular epidemic characteristics and genetic evolution of PCV2, pigs with doubtful symptoms of PCVADs were sampled from various commercial pig farms with a history of PWMS and/or PDNS across Shanghai from 2014 to 2018. Our results revealed the coexistence of multiple PCV2 genotypes (PCV2b, PCV2e, and PCV2d) among Shanghai pig herds and dominance of PCV2d among them. We also found critical amino acid substitutions in epitope regions of important capsid proteins in PCV2 isolates involved in viral replication and host immune escape. Spotted mutations may favor the prevalence and survival of various PCV2 genotypes despite availability of commercial vaccines. This study also provides insight into the co-infection status of PCV2 with major lethal swine viral diseases such as PPV and PPRSV. Collectively, these investigations will contribute to understanding the molecular epidemiology and evolution of PCV2 across the region.     

The genetics of autoimmune endocrine disease

The common autoimmune endocrinopathies result from an interaction between environmental factors and genetic predisposition. Several chromosomal gene regions have been shown to contribute to more than one disease, supporting the clinical observation that the autoimmune endocrine diseases cluster within individuals and families. Genetic studies have implicated the major histocompatability complex (MHC)-human leucocyte antigen (HLA) genes on chromosome 6p21, although this chromosomal region does not explain all of the genetic contribution to the various disorders. Non-MHC-HLA genes, including disease-specific loci, are beginning to be identified and the publication of the draft sequence of the human genome will undoubtedly expediate future discoveries. Combined with the establishment of large cohorts of subjects with disease and the development of technology capable of performing high-throughput genotyping, genetic studies are likely to impact on the future treatment and prevention of the common autoimmune endocrine diseases.     

Risk factors of atherosclerosis: A review of genetic epidemiology data from a Serbian population

Determining common risk factors for the onset and progression of atherosclerosis and cardiovascular diseases, which are known to be multi-factorial and polygenic diseases, represents a challenge for medicine in the future. In recent years, there have been breakthroughs in the determination of pathogenesis, risk estimating methodologies, modifications of genetic risk in prophylaxis and in establishing new therapeutic targets in pharmacology. The role of genetic epidemiology is to provide necessary data about genetic characteristics of different populations, as well as gene-gene and gene-environment interactions, that lead to the development of diseases. The aim is to define high-risk haplotypes and primary targets for a new generation of pharmaceutical products and tools designed for the diagnosis and therapy of these disorders. The present review provides examples from the authors' genetic epidemiology studies regarding the association of candidate genes with risk factors of atherosclerosis, such as dyslipidemias, hypertension and diabetes mellitus, in a Serbian population, along with basic assumptions that come with this type of research. The main results of these studies are discussed, as well as problems that should be taken into consideration in future evaluations of disease risk in a population.     

小核糖核酸病毒感染与人兽共患病的关系北大核心CSCD

小核糖核酸病毒作为重要的感染性病原体,其在基因突变和重组的驱动下表现出高度的遗传变异性,可感染从低等脊椎动物到哺乳动物等多种宿主,包括人类、非人灵长类动物、啮齿动物、蝙蝠、鸟类等。近年来,由新发病毒引起的人兽共患病受到公共卫生领域的广泛关注。鉴于小核糖核酸病毒种类的高度多样性,许多新发现的病毒属于小核糖核酸病毒科(Picornaviridae)的家族成员。目前,与人类疾病相关的小核糖核酸病毒在人群中的流行情况及其遗传多样性特征已有一定的研究基础。本文围绕小核糖核酸病毒的分子生物学特征、分类学以及可能引起人兽共患病的病毒属等进行综述,为进一步开展小核糖核酸病毒感染的预防控制和科学研究提供借鉴。     

Identifying the susceptibility genes for coronary artery disease: from hyperbole through doubt to cautious optimism

The genetic basis of coronary artery disease (CAD) is complex, and the fact that an alarmingly high proportion of reported associations between genetic variants and CAD are not replicated has generated uncertainty as to whether molecular genetics is ever going to deliver on the promises delivered in the late 1990s. However, during 2007, the first generation of large-scale genome-wide association studies using high-density, single nucleotide polymorphism genotyping arrays have revealed genetic variants that are robustly associated with CAD and CAD-related traits such as type 2 diabetes and obesity. In particular, a robust susceptibility locus for CAD has been identified on chromosome 9p21. Also, evidence has been obtained that multiple rare alleles with fairly strong phenotypic effects may contribute to the genetic heritability of CAD, in addition to common variants with a modest impact on risk. Furthermore, new mechanistic connections have been discovered between different common complex diseases including CAD. This review focuses on the challenges and recent advances of molecular genetics in dissecting the molecular pathophysiology of atherothrombosis and defining novel targets for treatment.     

Osteoporosis as an Hereditary Disease

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that bone mineral density (BMD) and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover have a significant heritable component. Osteoporotic fractures also have a genetic component but heritability reduces dramatically with increasing age. Many different genetic variants contribute to the regulation of these phenotypes; most are common variants of small effect size, but there is evidence that rare variants of large effect size also contribute in some individuals. Genome wide association studies have recently been successfully employed to identifying genes that predispose to osteoporosis, although some of these had already been identified through the study of rare bone diseases. Although there has been extensive progress in understanding the genetic basis of osteoporosis over the past 10 years, most of the genetic variants that regulate bone mass remained to be discovered.     

Mechanisms of disease: the genetic epidemiology of gallbladder stones

Cholelithiasis is one of the most prevalent and most expensive gastroenterologic diseases. It belongs to the group of complex metabolic disorders that affect humans, and its critical pathogenic mechanisms are not well defined. As a result, primary or secondary prevention strategies are sparse, and the only effective treatment is cholecystectomy. Here we provide an update on the molecular pathogenesis of gallbladder stones, evidence supporting the hypothesis that genetic factors are key elements predisposing to gallstones, and progress in human genetic studies of cholesterol stones. Data from recent identical twin, family and linkage studies provide conclusive evidence for a strong genetic component to gallstone disease. Furthermore, epidemiologic studies in at-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. By contrast, monogenic subtypes of cholelithiasis, such as ATP-binding-cassette transporter deficiencies, appear to be rare. The summary of human association studies illustrates that distinct common gene variants might contribute to gallstone formation in different ethnic groups. The characterization of lithogenic genes in knockout and transgenic mice and the identification of many gallstone-susceptibility loci in inbred mice provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal novel molecular targets for prevention and medical therapies.     

Genetic Testing in Inherited Arrhythmias: Approach,Limitations, and Challenges

Genetic testing is playing an ever-expanding role in cardiovascular care and is becoming part of the “toolkit” for the cardiovascular clinician. In patients with inherited arrhythmias, genetic testing can confirm a suspected diagnosis, establish a diagnosis in unexplained cases, and help facilitate cascade family screening. Many inherited arrhythmia syndromes are monogenic diseases arising from a single pathogenic variant involved in the structure and function of cardiac ion channels or structural proteins. As such, “arrhythmia gene panels” will often cast a wide net for such heritable diseases. However, challenges may arise when genetic testing results are ambiguous, or when genetic testing results (genotype) and clinical phenotypes do not match. In cases of “genotype-phenotype matching,” genetic results complement the clinical phenotype and genetic testing can be used in diagnosis, family screening, and occasionally prognostication. It becomes more challenging when genetic results are negative or noncontributory and “contradict” the clinical phenotype. “Genotype mismatches” can also occur when genotype-positive patients have no clinical phenotype, or when genetic testing results point towards a completely different disease than the clinical phenotype. We discuss an approach to genetic testing and review the challenges that may arise when interpreting genetic testing results. Genetic testing has opened a wealth of opportunities in the diagnosis, management, and cascade screening of inherited arrhythmia syndromes, but has also opened a “Pandora’s box” of challenges. Genetic results should be interpreted with caution and in a multidisciplinary clinic, with support from genetic counsellors and an expert with a focused interest in cardiovascular genetics.     

Sex-specific genetic effects influence variation in body composition

Aims/hypothesis  Despite well-known sex differences in body composition it is not known whether sex-specific genetic or environmental effects contribute to these differences. Methods  We assessed body composition in 2,506 individuals, from a young Dutch genetic isolate participating in the Erasmus Rucphen Family study, by dual-energy X-ray absorptiometry and anthropometry. We used variance decomposition procedures to partition variation of body composition into genetic and environmental components common to both sexes and to men and women separately and calculated the correlation between genetic components in men and women. Results  After accounting for age, sex and inbreeding, heritability ranged from 0.39 for fat mass index to 0.84 for height. We found sex-specific genetic effects for fat percentage (fat%), lean mass, lean mass index (LMI) and fat distribution, but not for BMI and height. Genetic correlations between sexes were significantly different from 1 for fat%, lean mass, LMI, android fat, android:gynoid fat ratio and WHR, indicating that there are sex-specific genes contributing to variation of these traits. Genetic variance was significantly higher in women for the waist, hip and thigh circumference and WHR, implying that genes account for more variance of fat distribution in women than in men. Environmental variance was significantly higher in men for the android:gynoid fat ratio. Conclusions/interpretation  Sex-specific genetic effects underlie sexual dimorphism in several body composition traits. The findings are relevant for studies on the relationship of body composition with common diseases like cardiovascular disease and type 2 diabetes and for genetic association studies. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.