The load of genetic and partially genetic diseases in man. II. Some selected common multifactorial diseases: estimates of population prevalence and of detriment in terms of years of lost and impaired life

This paper presents epidemiological data on the prevalence of 26 common (i.e., having a lifetime prevalence of more than 1 per 10(4) individuals in the population) multifactorial diseases in Hungary and estimates of detriment associated with them. The detriment is expressed using 3 indicators, namely years of lost life (LL), potentially impaired life (PIL) and actually impaired life (AIL). The total prevalence of these diseases in Hungary has been estimated to be about 6500 per 10(4) individuals in the population. This estimate is in agreement with published data for other parts of the world. On the basis of clinical severity, these diseases have been split into 3 groups, namely (1) very severe (schizophrenia, multiple sclerosis, epilepsy, acute myocardial infarction and related conditions, and systemic lupus erythematosus); (2) moderately severe and/or episodal or seasonal (15 entities including Graves' disease, diabetes mellitus, gout, affective psychoses, essential hypertension, peptic ulcers, asthma, etc.); and (3) less severe than those in the first 2 groups (varicose veins, allergic rhinitis, atopic dermatitis, Scheuermann disease and adolescent idiopathic scoliosis). The essential clinical and genetic aspects of these diseases are briefly discussed. With the exception of epilepsy, none of the diseases included in our list causes mortality between ages 0 and 19. However, they are among the leading causes of death between ages 20 and 69 and thereafter. A sizeable proportion of those with essential hypertension, diabetes mellitus, rheumatoid arthritis, etc. survive to 70 years and beyond, as do those with gout, glaucoma, allergic rhinitis, psoriasis, etc. Overall, about 16% of all deaths that occur in Hungary every year (all age groups) can be attributed to these diseases. The mean number of years of PIL covers a wide range (about 20-40, 12-70 and 40-60 for groups 1, 2 and 3, respectively), the overall mean being about 24 years. However, the nature and degree of impairment and the impact on the life quality of those afflicted differ for the different diseases. Likewise, the mean number of years of AIL (for which the interval between the mean age at premature retirement and mean age at death was used as a rough index) also spans a wide range from 16 to 45, and the overall mean is about 20 years. At the population level, the diseases considered in this paper cause about 2700 years of LL, 96,000 years of PIL and about 5800 years of AIL per 10(4) individuals in the population. Relative to Mendelian diseases as a whole, these multifactorial diseases are associated with much greater detriment (LL: 1.4 X; PIL: 30 X and AIL: 3.9 X).     

Innate immunity and inflammation in ageing: a key for understanding age-related diseases

The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few – have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased chance of long life survival in a "permissive" environment with reduced pathogen load, medical care and increased quality of life.     

Free radicals in aging

Summary Aging is the progressive accumulation of changes with time that are responsible for the ever-increasing likelihood of disease and death. These irreversible changes are attributed to the aging process. This process is now the major cause of death in the developed countries. This fact is obscured by the protean nature of the contributions of this process to the events which terminate life.The aging process may be due to free radical reations. This theory is supported by: 1) studies on the origin and evolution of life; 2) the numerous studies of the effect of ionizing radiation on living systems; 3) life span experiments in which the diet was modified so as to alter endogenous free radical reaction levels; 4) the plausible explanations it provides for aging phenomena; and 5) the growing number of studies which implicate free radical reactions in the pathogenesis of specific diseases.The relationship between aging and diseases involving free radical reactions seems to be a direct one. Modulation of the normal distribution of deleterious free radical reaction-induced changes throughout the body by genetic and environmental differences between individuals results in patterns of change, in some sufficiently different from the normal aging pattern to be recognized as disease. The growing number of free radical diseases includes the two major causes of death, cancer and atherosclerosis.It is reasonable to expect on the basis of present data that a judicious selection of diets and antioxidant supplements will increase the healthy, active life span by 5–10 or more years.     

Social class differences in years of potential life lost: size,trends, and principal causes.

British social class differences in mortality are examined in terms of years of potential life lost, a measure that gives more weight to deaths that take place at younger ages. It shows wider class differences during the years of working life than those found when mortality is expressed in terms of standardised mortality ratios. Examination of the change in class differences between 1971 and 1981 for all causes of death combined and for the three categories of death which during these ages make a major contribution to total years of potential life lost shows complex changes. Inequalities in years of potential life lost have increased between 1971 and 1981, during which all the principal causes of death have shown stationary or rising rates among the manual classes. The use of years of potential life lost as a measure of population health trends focuses attention on the major contribution of violent death, which occurs mainly in younger men, to widening class differences in mortality.     

《宋史》人物遗传、疾病和环境对寿限的影响

将《宋史》本纪、列传人物７９３人的寿限按姓氏和阴阳类型及疾病按病因类统计分析。结果表明：⑴赵姓中因为包括了个某种“早卒”遗传病的家族,其寿限平均值较王、李、张、刘、陈等５姓的短,Ｐ＜０．０１或０．０５;而这５姓群体间的平均寿限值均无统计学上的差别,均符合中性等位基因分布的特征。⑵阴阳中和型遗传系统的平均寿限较阳型遗传系统高,Ｐ＜０．０５。⑶疾病与不良环境是寿限的限制因素,提高个体的抗性是长寿的重要     

Insights from Caenorhabditis elegans on the role of metals in neurodegenerative diseases

Neurodegeneration is characterized by the cell death or loss of structure and/or function of neurons. Many neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD) are the result of neurodegenerative processes. Metals are essential for many life processes, but they are also culpable for several neurodegenerative mechanisms. In this review, we discuss the role of metals in neurodegenerative diseases with emphasis on the utility of Caenorhabditis elegans (C. elegans) genetic models in deciphering mechanisms associated with the etiology of PD and AD.     

Mitochondrial matters of the brain: amyloid formation and Alzheimer’s disease introduction

In recent years mitochondria, as the most abundant organelles in animal and human cells, have come to the forefront of biomedical research as they are now recognized not only as the major producers of ATP needed to drive cellular functions critical for life, but they are also the instruments of cell death. Not surprisingly, therefore, mitochondria are now known to be involved in many different diseases ranging from those that affect millions worldwide to those that affect only a few, i.e., rare diseases. These diseases include in addition to cardio-myopathies and cancer also diseases that affect many other organs/tissues including the brain/nervous system, the latter diseases now commonly referred to as “neurodegenerative diseases”. Specifically, the subject of this mini-review series focuses on the role of mitochondria in Alzheimer’s disease, a major age related neurodegenerative disease that results in loss or decline of memory and other cognitive abilities. This devastating disease affects millions of Americans, and globally multi-millions with very grim predictions for the future. Although the molecular and gene-related details that underlie Alzheimer’s disease remain to be clearly elucidated, mitochondria appear to be very intimately involved. The purpose of this mini-review series is to summarize how various investigators working on this subject envision the role(s) of mitochondria in Alzheimer’s disease. The development of future therapies for this disease is likely to rely heavily on the new knowledge gained.     

Mortality from unintentional injuries in California, 1985.

In 1985 unintentional injuries were the fourth leading cause of death among California residents, causing 10,380 deaths. They were the leading cause of potential life lost, accounting for 278,109 years lost. This was more than twice the number of years lost due to heart disease and 1 1/2 times the number lost due to cancer. Motor vehicle traffic accidents were the leading cause of unintentional injury deaths, accounting for half (5,158) the deaths. The next two leading causes were poisoning (especially for men aged 25 to 44 years) and falls (especially among persons aged 75 and older). Drowning was second to motor vehicle accidents as a cause of death in children aged 1 to 14 years. California''s age-adjusted injury mortality rates in 1985 were lower in coastal and urban counties than in inland and rural counties, and these rates were generally lower in counties having organized systems of trauma care.     

Introduction. Oxidative stress in mitochondria disorders of aging

These special issues of Biological Signals and Receptors are intended to describe mitochondrial DNA damage, oxidative stress and human diseases, including neurodegenerative and neuromuscular diseases, disorders associated with aging, and ischemia-perfusion injury. Traditionally, mitochondria have been viewed as the 'powerhouse' of the cell, i.e., the site of the oxidative phosphorylation machinery involved in adenosine triphosphate (ATP) production. Consequently, much of the research conducted on mitochondria over the past 4 decades has focused on elucidating both those molecular events involved in ATP synthesis by oxidative phosphorylation and those involved in the biogenesis of the oxidative phosphorylation machinery. While monumental achievements have been made, and continue to be made, in the study of these remarkable but extremely complex processes essential for the life of most animal cells, it has been only in recent years that a large body of biological and biomedical scientists have come to recognize that mitochondria participate in other important processes. Two of these are cell death and aging which, not surprisingly, are related processes both involving, in part, the oxidative phosphorylation machinery. This new awareness has sparked a new and growing area of mitochondrial research that has become of great interest to a wide variety of scientists ranging from those involved in elucidating the role of mitochondria in cell death and aging to those interested in either suppressing or facilitating these processes as it relates to identifying new therapies or drugs for human disease.     

Preventing fatal diseases increases healthcare costs: cause elimination life table approach.

OBJECTIVES: To examine whether elimination of fatal diseases will increase healthcare costs. DESIGN: Mortality data from vital statistics combined with healthcare spending in a cause elimination life table. Costs were allocated to specific diseases through the various healthcare registers. SETTING AND SUBJECTS: The population of the Netherlands, 1988. MAIN OUTCOME MEASURES: Healthcare costs of a synthetic life table cohort, expressed as life time expected costs. RESULTS: The life time expected healthcare costs for 1988 in the Netherlands were 56,600 Pounds for men and 80,900 Pounds for women. Elimination of fatal diseases--such as coronary heart disease, cancer, or chronic obstructive lung disease--increases healthcare costs. Major savings will be achieved only by elimination of non-fatal disease--such as musculoskeletal diseases and mental disorders. CONCLUSION: The aim of prevention is to spare people from avoidable misery and death not to save money on the healthcare system. In countries with low mortality, elimination of fatal diseases by successful prevention increases healthcare spending because of the medical expenses during added life years.     

Lysosomal storage of heparan sulfate causes mitochondrial defects,altered autophagy,and neuronal death in the mouse model of mucopolysaccharidosis III type C

The genetic metabolic disease mucopolysaccharidosis III type C (MPS IIIC, Sanfilippo disease type C) causes progressive neurodegeneration in infants and children, leading to dementia and death before adulthood. MPS IIIC stands out among lysosomal diseases because it is the only one caused by a deficiency not of a hydrolase but of HGSNAT (heparan--glucosaminide N-acetyltransferase), which catalyzes acetylation of glycosaminoglycan heparan sulfate (HS) prior to its hydrolysis.     

冠心病全基因组关联研究进展

近年来全基因组关联研究在世界范围内发展迅猛,研究者应用全基因组关联研究策略发现了一系列疾病的相关基因或变异,将疾病的基因组研究推向一个新的阶段。冠心病是一种由环境因素和遗传因素共同作用导致的复杂疾病,且是世界范围内死亡和致残的首要原因之一,世界各地的研究者应用此策略发现了候选基因关联研究未曾发现的多个冠心病相关易感区域。文章对近年来世界范围内针对冠心病的全基因组关联研究取得的重要进展进行简要总结,然后就现阶段全基因组关联研究所面临的挑战以及对未来研究的发展趋势进行分析阐述,为进一步探究冠心病的遗传机制提供指导。     

From Eden to a hell of uniformity? directed evolution in humans

For the first time during evolution of life on this planet, a species has acquired the ability to direct its own genetic destiny. Following 200,000 years of evolution, modern man now has the technologies not only to eradicate genetic disease but also to prolong life and enhance desired physical and mental traits. These technologies include preimplantation diagnosis, cloning, and gene therapy in the germline on native chromosomes or by adding artificial ones. At first glance, we should all be in favor of eliminating genetic diseases and enhancing genetic traits. Evolutionary considerations, however, uncover hidden dangers and suggest caution against the total embracement of such actions. The first major concern is that the genome will never be a completely reliable crystal ball for predicting human phenotypes. This is especially true for predictions concerning the performance of alleles in future generations whose populations might be subjected to different environmental and social challenges. The second, and perhaps more important, concern is that the end result of germline intervention and genetic enhancement will likely lead to the impoverishment of gene variants in the human population and deprive us of one of our most valued assets for survival in the future, our genetic diversity.     

Molecular mechanism and therapy application of necrosis during myocardial injury

Necrosis is an ancient topic which gains new attraction in the research area these years. There is no doubt that some necrosis can be regulated by genetic manipulation other than an accidental cell death resulting from physical or chemical stimuli. Recent advances in the molecular mechanism underlying the programmed necrosis show a fine regulation network which indicates new therapy targets in human diseases. Heart diseases seriously endanger our health and have high fatality rates in the patients. Cell death of cardiac myocytes is believed to be critical in the pathogenesis of heart diseases. Although necrosis is likely to play a more important role in cardiac cell death than apoptosis, apoptosis has been paid much attention in the past 30 years because it used to be considered as the only form of programmed cell death. However, recent findings of programmed necrosis and the related signalling pathways have broadened our horizon in the field of programmed cell death and promote new pharmacological application in the treatment of heart diseases. In this review, we summarize the advanced progress in these signalling pathways and discuss the pathos‐physiological relevance and therapeutic implication of targeting necrosis in heart diseases treatment.     

Burden of disease and productivity impact of Streptococcus suis infection in Thailand

BackgroundStreptoccocus suis (S.suis) infection is a neglected zoonosis disease in humans mainly affects men of working age. We estimated the health and economic burden of S.suis infection in Thailand in terms of years of life lost, quality-adjusted life years (QALYs) lost, and productivity-adjusted life years (PALYs) lost which is a novel measure that adjusts years of life lived for productivity loss attributable to disease.MethodsA decision-analytic Markov model was developed to simulate the impact of S. suis infection and its major complications: death, meningitis and infective endocarditis among Thai people in 2019 with starting age of 51 years. Transition probabilities, and inputs pertaining to costs, utilities and productivity impairment associated with long-term complications were derived from published sources. A lifetime time horizon with follow-up until death or age 100 years was adopted. The simulation was repeated assuming that the cohort had not been infected with S.suis. The differences between the two set of model outputs in years of life, QALYs, and PALYs lived reflected the impact of S.suis infection. An annual discount rate of 3% was applied to both costs and outcomes. One-way sensitivity analyses and Monte Carlo simulation modeling technique using 10,000 iterations were performed to assess the impact of uncertainty in the model.Key resultsThis cohort incurred 769 (95% uncertainty interval [UI]: 695 to 841) years of life lost (14% of predicted years of life lived if infection had not occurred), 826 (95% UI: 588 to 1,098) QALYs lost (21%) and 793 (95%UI: 717 to 867) PALYs (15%) lost. These equated to an average of 2.46 years of life, 2.64 QALYs and 2.54 PALYs lost per person. The loss in PALYs was associated with a loss of 346 (95% UI: 240 to 461) million Thai baht (US$11.3 million) in GDP, which equated to 1.1 million Thai baht (US$ 36,033) lost per person.ConclusionsS.suis infection imposes a significant economic burden both in terms of health and productivity. Further research to investigate the effectiveness of public health awareness programs and disease control interventions should be mandated to provide a clearer picture for decision making in public health strategies and resource allocations.     

陆地棉品种和骨干品系黄萎病抗性鉴定

选育和推广抗病品种是防治陆地棉黄萎病的主要措施,为了早日实现多类型、多区域大面积抗病品种的应用,本研究选取107份遗传背景差异较大的种质,利用河北省农林科学院棉花研究所小安舍试验站黄萎病病圃进行了3年黄萎病抗性重复鉴定。鉴定得到抗病品系8个,占7.5%;耐病品种(系)20个,占18.7%。本研究表明,当前被作为育种亲本的抗病品系还太少,需要深入开展抗病遗传机制,以及与其他经济性状协同改良的关系,为陆地棉抗病育种提供理论指导;达到抗病或接近抗病水平的大部分品种(系)来自于海陆野远缘后代,具有外源基因血统,证明了远缘杂交是陆地棉黄萎病抗性改良的有效手段。     

Ziele und Grenzen der Quantifizierung genetischer Risiken

This present article deals with the question of how meaningful statistical risk assessments in genetic counseling may be for the decision-making process of individuals who ask for genetic advice. Even in some Mendelian diseases and generally in the case of multifactorial diseases it is not satisfactory to provide an a priori risk for all affected families. The question of whether a given person or his or her future children may develop the disease in question with severe, possibly untreatable symptoms may largely depend on individual circumstances. Accordingly, the inclusion of such circumstances in the assessment of an individual’s a posteriori risk may largely deviate upwards or downwards from this a priori risk. Currently, the lack of such data often prevents the quantification of an individual a posteriori risk; it is, however, obvious that individual risk assessment will play an increasing role in future genetic counseling. Besides a better understanding of individual environmental influences our growing insight into the impact of epigenetic changes will enforce a re-evaluation of individual risks. Epigenetic changes acquired during fetal development or early childhood may lead to lasting physiological changes and, accordingly, may significantly affect the risk of an individual to develop a certain disease during his or her later life. Due to the complexity of genetic and epigenetic networks it is as inappropriate to categorize mutated genes or alleles which increase the risk for a certain disease as “bad” or “sick” genes as it is to consider genes with apparently health-promoting properties as “good” or “healthy” genes. Such rhetoric may foster feelings of either guilt or superiority in individuals and may have an even more politically dangerous impact by encouraging neo-eugenic thinking. In contrast, the goal of non-directive genetic counseling is to provide individuals seeking advice with reliable information which helps them arrive at a personal decision. Given their personal circumstances this decision should be ethically acceptable and realistically allow them to cope with their problem in their future lives. As seen in cases of Mendelian diseases, such as sickle cell anemia or thalassemias, heterozygous carriers may have selective advantages, in this particular case a natural resistance against Malaria tropica. This example demonstrates that a genetic burden may not have only disadvantages but also advantages for the health of a whole population. This consideration may hold for many alleles which have been present in the gene pool of a population for many generations, although they contribute to a genetic predisposition for a multifactorial disease. In debates about the heritability of a given trait, the heritability coefficient has often been used as an argument for and against the predominant impact of genes on the trait in question. The authors wish to remind their readers that this coefficient reflects the genetic variation measured in a given population divided by the variation of all possible parameters which affect the phenotypic trait. It neither gives an answer about the absolute influence of genes and other factors on this trait nor does it provide information about how unforeseen changes in the environment may affect the heritability of the trait in the future. Contrary to a common misunderstanding in public discussion this coefficient does not allow any conclusion on the interaction of genetic, epigenetic and environmental factors involved in the development of the trait in question in an individual. Finally, in the closing section the authors highlight the opportunities of risk-adapted disease prevention.     

Multiple causes of death and the epidemiological transition in American Samoa

Abstract

Multiple‐cause mortality data were used to examine changing patterns of mortality between 1950 and 1979 in American Samoa. This period coincided with a transition from infectious to chronic diseases as the primary causes of death. The available data indicate that as mortality rates from infections declined, the first chronic disease to increase in frequency was cancer. The absence of a lag period suggests that increased cancer mortality may be a consequence of life extension in the presence of modernization. In contrast, mortality rates from cardiovascular diseases tended to increase only after a lag period. As mortality from infections declined, ischemic heart disease replaced infections as the leading cause of death, in either a total‐mentions or an underlying‐cause model of mortality. The transition to degenerative disease mortality in American Samoa was neither as rapid nor as simple as a tabulation by underlying cause of death indicates. Patterns of change were interrelated.     

Protein misfolding in the late‐onset neurodegenerative diseases: Common themes and the unique case of amyotrophic lateral sclerosis

Enormous strides have been made in the last 100 years to extend human life expectancy and to combat the major infectious diseases. Today, the major challenges for medical science are age‐related diseases, including cancer, heart disease, lung disease, renal disease, and late‐onset neurodegenerative disease. Of these, only the neurodegenerative diseases represent a class of disease so poorly understood that no general strategies for prevention or treatment exist. These diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, the transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis (ALS), are generally fatal and incurable. The first section of this review summarizes the diversity and common features of the late‐onset neurodegenerative diseases, with a particular focus on protein misfolding and aggregation—a recurring theme in the molecular pathology. The second section focuses on the particular case of ALS, a late‐onset neurodegenerative disease characterized by the death of central nervous system motor neurons, leading to paralysis and patient death. Of the 10% of ALS cases that show familial inheritance (familial ALS), the largest subset is caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). The unusual kinetic stability of SOD1 has provided a unique opportunity for detailed structural characterization of conformational states potentially involved in SOD1‐associated ALS. This review discusses past studies exploring the stability, folding, and misfolding behavior of SOD1, as well as the therapeutic possibilities of using detailed knowledge of misfolding pathways to target the molecular mechanisms underlying ALS and other neurodegenerative diseases. Proteins 2013; 81:1285–1303. © 2013 Wiley Periodicals, Inc.