Specific language impairment SLI

SLI is estimated to affect 2-7 of pre-primary school children and is diagnosed if significant language deficits are present despite adequate educational opportunity and normal nonverbal intelligence (Law etal., 1998). Alternative diagnoses of medical and developmental disorders such as deafness and autism must be excluded before a diagnosis of SLI is given. Features such as the orofacial dyspraxia found in the KE family would exclude a diagnosis of SLI. A continuum of language impairment...

Treatments

There are no treatments available, only two main types of prosthesis. First is the hearing aid, which amplifies incoming sounds and can be adjusted to amplify certain frequencies more than others to match the pattern of hearing loss of an individual, and to match the limited dynamic range of the damaged ear to avoid painfully loud sounds being delivered. However, there is much to be learnt about how we use the temporal and frequency cues in speech and other sounds in order to improve...

Acknowledgements

Andrew Carothers for helpful discussions. Alward, W.L., Kwon, Y.H., Kawase, K. et al. (2003). Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol, 136, 904-10. Appel, G.B., Cook, H.T., Hageman, G. et al. (2005). Membranoproliferative glomerulonephritis type II (dense deposit disease) an update. J Am Soc Nephrol, 16, 1392-403. Argraves, W. S., Greene, L. M., Cooley, M. A. and Gallagher, W. M. (2003). Fibulins...

Apparent mineralocorticoid excess AME

Though cortisol is principally a glucocorticoid, the mineralocorticoid receptor exhibits the same affinity for cortisol in vitro as it does for aldoste-rone. Since the plasma concentration of cortisol is over 100 times higher than that of aldoste-rone, the discovery that cortisol could bind to the Table 25.1. Mutations in genes causing Mendelian syndromes involving hyper- or hypo-tension Table 25.1. Mutations in genes causing Mendelian syndromes involving hyper- or hypo-tension (NKCC2)...

Twin studies and adoption studies

The first formal evidence that genetics is important in susceptibility to infectious disease was gained in the 1930s through work on twins with tuberculosis (Diehl and Von Verschuer, 1936) and twin studies have been carried out subsequently for a number of infectious diseases such as malaria (Sjoberg et al., 1992 Jepson et al., 1994), tuberculosis (Kallmann and Reisner, 1942 Comstock, 1978), leprosy (Chakravarti and Vogel, 1973) and hepatitis B (Lin et al., 1989). These studies all demonstrated...

Glucocorticoid remediable aldosteronism GRA

The last stages in the synthesis of the mineralo-corticoid aldosterone and the glucocorticoid cortisol take place in the adrenal cortex, and are catalyzed by two highly homologous enzymes which lie adjacent to each other on chromosome 8. CYP11B1 (11-beta hydroxylase) converts deoxy-cortisol to cortisol (the principal corticosteroid), a process involving 11-hydroxylation, and CYP11B2 (aldosterone synthase) converts deoxycorticoster-one to aldosterone (the principal mineralocorti-coid), a process...

Ab thalassemia

The a and b thalassemias frequently occur at high frequencies in the same geographic areas, so it is not surprising that both conditions may be found in the same patient. It may appear paradoxical but these individuals generally run a milder course this is because it is chain imbalance that damages the cell and a b thalassemia case with concomitant a thalassemia has less chain imbalance. Co-inheritance of heterozygous b or b+ thalassemia with a thalassemia (-a a or aa) results in more normal...

Why look for human obesity genes

The discovery of human obesity genes will undoubtedly lead to health benefits. Firstly some obesity syndromes are very severe, occur at a young age and are associated with other developmental and clinical manifestations. It is clear that knowledge of the underlying genetic defect in these syndromes will be of considerable clinical benefit in terms of recognising other treatable aspects of the particular syndrome and providing more informed genetic counseling. As illustrated by congenital leptin...

Genetics of human coronary heart disease

Major Risk Factors For Heart Disease

Because the classic CHD risk factors such as serum cholesterol, smoking, hypertension and diabetes mellitus are incomplete predictors of CHD, additional risk factors based on molecular genetics have been intensively investigated. The two main methods of investigation to date are genome-wide linkage studies and case-control association studies. Whole-genome association studies using ultra high-throughput genotyping have yet to report, although are expected to do so within the next 2-3 years....

Genes predisposing to exceptional longevity

It is practically intuitive to state that centenarians outlive those who are relatively predisposed to age-related fatal illnesses and that they are less likely to have environmental and genetic exposures that contribute to death at earlier ages. This selection phenomenon, called demographic selection, is exemplified by the fact that the apolipoprotein E e4 allele, associated with heart disease and Alzheimer's disease, is rare in centenarians, whereas the prevalence of an alternative allele,...

Historical perspective

Infectious disease is as old as humanity and remains a significant influence on polymorphism in the human genome. Major effects of infectious disease such as epidemics that have drastically reduced populations to a small percentage of individuals, so-called ''bottlenecks,'' such as the Black Death in Europe and the introduction of smallpox and other diseases to the Americas, have a strong selective effect. In addition, the slow continual onslaught of endemic diseases that are still with us...

Melanoma

Rates of melanoma vary widely geographically, with the major determinant of risk being skin color. The relative incidence of subtypes of melanoma differs across racial groups with one rare subtype termed ''acral lentiginous melanoma'' occurring in all racial groups (Hudson and Krige, 1993 Stevens et al., 1990 Jimbow and Kukita, 1984) but the commoner subtypes (superficial spreading melanoma, nodular melanoma and lentigo maligna) occur essentially only in white persons. For these latter subtypes...

Common diseasecommon variant or not

One hypothesis that has become popular in recent years is that much of the genetic variation underlying complex traits is made up of common alleles (Lander, 1996 Chakravarti, 1999). This idea, often referred to as the ''common disease-common variant'' (CD-CV) hypothesis, has important implications for disease mapping, because it suggests that genome-wide association mapping should be an extremely powerful tool for identifying the variants that contribute to complex traits. An alternative model...

Familial nonspecific dementia

A small number of pedigrees have been described which segregate an autosomal dominant adult-onset disease characterized by early-onset dementia with non-specific neuropathological changes of neuronal loss, minor gliosis and some spongiform change (Gydesen et al., 1987). Completely absent are the typical findings of Alzheimer's disease (AD) or Pick's disease. Genetic linkage studies have mapped one such disease locus in one large Danish pedigree to a 12 cM region of chromosome 3 spanning the...

Infectious diseases

There is strong evidence for association of only a few infectious diseases with the MHC (Table 9.1, Figure 9.1) although infection is believed to drive MHC variation (see Chapter 18). It has been proposed that the emphasis on autoimmunity is largely because research funding for studying these diseases, prevalent in western populations, has greatly exceeded that for infections that are more usually consigned to poorer countries. In fact, the funding emphasis has shifted considerably since the...

Environmental risk factors for the development of asthma

The prevalence of asthma has increased in Western countries over the past three to four decades (Anderson et al., 1994 Burney et al., 1990 Peat etal., 1994). In 1995 6 18-21 of children under 15 years of age, and 11 of adults, in England had been diagnosed as having asthma at some point in their life (British Thoracic Society, 2003). The marked increase in asthma strongly suggests that environmental exposures must be instrumental in the development of disease. This is supported by reports in...

Mechanisms of hearing impairment

Cochlea Cross Section

Hearing depends upon the middle ear for collecting, amplifying and delivering the vibration of sound to the highly specialised cochlea, where sensory hair cells in the spiral organ of Corti detect these mechanical signals and convert them to electrical changes within the cell (auditory transduction). Depolarization of the cell allows synaptic release, triggering action potentials in cochlear neurons. Hair cells have an array of stereocilia (modified microvilli) at their upper surface, with...

Atopic dermatitis OMIM 603165

Atopic dermatitis (AD) is a clinical syndrome characterized by an itchy rash with a variety of morphological cutaneous features that change with age, in association with a positive family history and concomitant presence of other atopic diseases (atopic asthma, hay fever, and occasionally urticaria) (Williams, 1997). The atopic immunological state is characterized by a propensity to develop type 1 IgE mediated responses in response to certain antigens, but the cutaneous immuno-pathology of...

Important preliminary steps

This review argues that research investment should target research questions that are tractable with current methods and resources or which are likely to be so with appropriate investment in the foreseeable future. This requires a sober consideration of what is known about the genetic architecture of complex disease so that study designs have adequate power and a realistic chance of success. It is important not to be driven solely by technological advances or, for example, by the commercial...

Other genes for Alzheimers disease

Several large surveys of patients with familial AD have indicated that the APP, APOE, PS1 and PS2 genes account for only about half of the genetic risk factors for AD. It is therefore likely that there are several additional AD-susceptibility genes. Some of these loci will be associated with additional rare, but highly penetrant defects similar to those seen with mutations in PS1 and APP. Other genes may result in incompletely penetrant autosomal-dominant traits like those associated with PS2....

Prader Willi syndrome

The Prader-Willi syndrome (PWS) is the most common syndromal cause of human obesity with an estimated prevalence of about 1 in 25 000. It is an autosomal dominant disorder characterized by hypotonia, mental retardation, short stature, hypo-gonadotropic hypogonadism and hyperphagia (increased food intake) and obesity. Children with PWS display diminished growth, reduced lean body mass and increased fat mass - body composition abnormalities resembling those seen in growth hormone (GH) deficiency....

Current applications of pharmacogenetics

Our knowledge of pharmacogenetics can be applied in two main areas - (a) in improving the use of existing commonly prescribed drugs and (b) in the development and use of new drugs by the pharmaceutical and biotechnology industries. a) Current drugs The ability to individualize the use of currently used drugs will not only permit the identification of individuals vulnerable to drug side effects but, perhaps more importantly, will allow us to identify those patients who will or will not respond...

Genetics of monogenic and complex dyslipidemias

Disorders of lipid metabolism, both monogenic and more genetically complex, are powerful risk factors for CHD. The major circulating lipids, cholesterol, phospholipids and triglycerides, are carried in the blood by several lipoprotein particles serving the physiological task of transporting dietary and endogenously produced lipids to peripheral tissues. The major pathways of lipoprotein metabolism in humans are illustrated in (Figure 24.1). Mutations in many of the lipoproteins, receptors and...

Monogenic disorders leading to human obesity

It is well established that obesity runs in families, although the vast majority of cases do not segregate with a clear Mendelian pattern of inheritance. There are about 30 Mendelian disorders with obesity as a clinical feature but often associated with mental retardation, dysmorphic features and organ-specific developmental abnormalities (i.e. pleiotropic syndromes). A number of families with these rare pleiotropic obesity syndromes have been studied by linkage analysis and the chromosomal...

Oligopolygenic complex genetic hyperlipidemias

Familial combined hyperlipidemia (FCHL) Combined hyperlipidemia, characterized by increased serum triglyceride and or cholesterol and decreased HDL cholesterol is the most common disorder of lipid metabolism affecting 1-2 of individuals in Western societies. The term familial combined hyperlipidemia (FCHL) was coined by Goldstein et al. to describe a pattern of lipid abnormalities (Goldstein et al., 1973) in survivors of myocardial infarction who had raised blood cholesterol and triglyceride...

Genetic models of breast cancer susceptibility

It is likely that the inheritance of most common cancers is polygenic. Breast cancer, like other common cancers, exhibits some degree of familial clustering, with disease being approximately twice as common in first-degree relatives of cases (Amundadottir et al., 2004 Collaborative Group on Hormonal Factors in Breast Cancer, 2001). The higher rate of most cancers in the monozygotic twins of cases than in dizygotic twins or siblings suggests that most of the familial clustering is the result of...

Is genetics important in determining susceptibility to human obesity

The recent and relatively rapid rise in the prevalence of obesity occurring over a timescale which would make conventional evolutionary explanations implausible has, understandably, led some to question the importance of genetics in the etiology of obesity. There are some obvious candidates for the causation of secular changes in obesity prevalence including the increased availability of palatable energy dense foods and the reduced requirement for physical exertion during working and domestic...

Joint effects of genes and environment

When gene expression depends on environmental potentiation, we conventionally refer to ''geneenvironment interaction. However, debate persists among biostatisticians, epidemiologists, biomedical scientists and others as to just what ''interaction'' means and whether one can recognize it, and quantify it, from empirical research data (Clayton and McKeigue, 2001). It is therefore simpler, and appropriate, to talk of ''joint effects''. These comprise situations in which, for an individual, the...

Perspectives p53 and cancer management

Over the past 15 years, many attempts have been made to translate basic knowledge of p53 protein structure and function into advances in cancer management and therapy (Table 16.2) (Seemann et al., 2004). It is not over-pessimistic to state that many of these attempts have been unsuccessful in delivering clear and ready-to-use clinical solutions. This lack of success is due to many factors, but the most important is, in my view, the widespread tendency to underestimate the complexity of the...

Posttranslational regulation signaling of DNA damage

The p53 protein is constitutively expressed in most cells and tissues as a latent factor. Due to its rapid turnover (5-20 minutes) the protein does not accumulate unless it is stabilized in response to a variety of intracellular and extracellular stimuli. Signals that activate p53 include diverse types of DNA damage (strand breaks, bulky adducts, oxidation of bases), blockade of RNA elongation, hypoxia, depletion of microtubules, ribonucleotides or growth factors, modulation of cell adhesion...

Approaches to therapeutic intervention in amyloid disease

The progress made in understanding the underlying causes of the amyloid diseases is also leading to new approaches to their prevention and treatment. For proteins whose functional state is a tightly packed globular fold, we have seen that an essential first step in fibril formation is undoubtedly the partial or complete unfolding of the native structure that otherwise protects the aggregation-prone polypeptide backbone. Thus many of the familial forms of amyloid disease are associated with...

Methodological issues in the hunt for human obesity genes

Obesity is defined as an excess of body fat, which can be measured directly using dual energy X-ray absorptiometry and isotopic dilution techniques. However, these are costly and their limited availability makes it difficult to perform such measurements in large numbers of subjects. In some studies fat mass has been measured indirectly using bioelectrical impedance or skin-fold thickness both of which correlate reasonably well within the normal range but less so in the very lean or the obese....

Environmental factors

If the long-term trend of CD demonstrates a role for the environment, epidemiological studies have failed to identify the major causative factor(s). Many environmental factors have been proposed as causative agents for IBD (Table 20.1). From these, diet, domestic hygiene and micro-organisms were the most investigated areas (Andersson et al., 2001 Bull et al., 2003 Cosnes et al., 1999 Darfeuille-Michaud et al., 1998 Ekbom et al., 1990 Ekbom et al., 1996 Gent et al., 1994 Gilat et al., 1987 Godet...

Evidence for the genetic basis of CHD

Family history of the disease is one of the strongest and most consistent risk factors for CHD. Relative risk estimates of between 1.5 and 5 have been derived from a range of family and population studies (Hawe et al., 2003 Lusis, 2003). At least a part of the risk of family history is conferred by the monogenic dyslipidaemias, including familial hypercholesterolemia (FH) (Goldstein et al., 1973), which carry a high penetrance of CHD. However, since the frequency of the FH heterozygous state,...

The MHC and disease general considerations

Tiwari and Terasaki's book published in 1985 (Tiwari and Terasaki, 1985), listed hundreds of HLA-associated diseases, even though the first demonstration of a strong association, that of HLA-B27 and ankylosing spondylitis (AS), came only a decade earlier. Meanwhile, many more associations have been added to the list but, apart from Narcolepsy, which shows an almost absolute association with DQB1*0602, none have been as strong as the association of HLA-B27 with AS (Lechler and Warrens, 2000)....

Chronic obstructive pulmonary disease COPD

COPD is defined as airflow obstruction that does not vary significantly over time. It is a heterogeneous disease which may develop from destruction of the lung parenchyma (emphysema) or inflammation of the small airways (bronchiolitis). In any affected individual there may be considerable overlap, with each of these components contributing a varying amount to airflow obstruction. Chronic bronchitis is defined by the presence of cough with sputum production that is present for three or more...

Candidate gene investigations

The literature on candidate genes investigated for association with hypertension is vast, but the results are often inconclusive. Angiotensinogen (AGT), which is amongst the most extensively studied candidate genes for hypertension, illustrates the issues. Since the first report of AGT polymorphisms associated with hypertension (Jeunemaitre et al., 1992), many similar studies have been undertaken. More than 30 published association studies are available on this candidate gene just for the...

Familial adenomatous polyposis coli FAP

FAP is a highly penetrant autosomal dominant disorder, clinically characterised by the development of hundreds to thousands of adenomatous polyps of the colon and rectum. This rare syndrome has an annual incidence of around 1 7000 live births (Bisgaard et al., 1994). However malignancy is virtually inevitable if surgery is not undertaken and thus accounts for 0.2 of all colorectal neoplasia. There are a number of extra-colonic features such as multiple craniofacial and long bone osteomata,...

Introduction

Clinical practice suggests that diseases of the skin are common in most world populations. Exactly how common is, for the majority of conditions, impossible to say, as population defined studies for most skin diseases have not been carried out. In the UK, probably typical of many first world countries, about 1 6 consultations in primary care is for a skin disorder, more than for any other disease grouping (McCormick et al., 1996). Of these 1 6 consultations, 25 are for atopic dermatitis, 20 for...

The role of early environment

The well-replicated observation that babies who are small at birth grow up to have an increased risk of T2D (and other manifestations of insulin resistance, such as heart disease and high lipids) has provided new ammunition in the gene-environment debate (Barker, 1995). The conventional explanation for this association, well supported by studies of fetal deprivation in animal models (Ozanne, 2001), emphasizes the role of adverse intra-uterine environment. Under this ''thrifty phenotype''...

Environment as determinant of i genotype and ii disease

The environment assumes two important, different, roles in relation to genetic influences on disease. First, within a long evolutionary sense, various regional differences in the biological attributes of human populations have arisen as a result of natural selection pressures exerted by local environments on human biology. In this sense, environment acts as a determinant of the local human genotype. Many examples are well known in the anthropological and biomedical literature. They include (i)...

Association studies in common obesity

To date, association studies have largely been restricted to candidate genes whose dysfunction might reasonably be expected to result in obesity by virtue of their having putative effects on energy intake, energy expenditure or nutrient partitioning. Genome-wide association studies are still in the future. The interpretation of association studies always requires caution because of the possibilities of problems such as population stratification, small sample size and publication bias. Some of...

The relative contributions of genes environment and luck to how we age

The relative contribution of environmental and genetic influences to life expectancy has been a source of debate. Assessing heritability in 10 505 Swedish twin pairs reared together and apart, Ljungquist and colleagues attributed 35 of the variance in longevity to genetic influences and 65 of the variance to non-shared environmental effects (Ljungquist et al., 1998). Other twin studies indicate heritability estimates of life expectancy between 25 and 30 (Herskind et al., 1996 McGue et al.,...

Bardet Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare (prevalence < 1 100000), autosomal recessive disease characterized by obesity, mental retardation, dysmorphic extremities (syndactyly, brachydactyly or polydactyly), retinal dystrophy or pigmentary retinopathy, hypogonadism and structural abnormalities of the kidney or functional renal impairment (Katsanis et al., 2001b). Bardet-Biedl syndrome is a genetically heterogeneous disorder that is now known to map to at least eight loci 11q13 (BBS1) (Mykytyn...

Major Mendelian genes versus minor polygenes as predisposers

When genetic diseases are discussed, the usual focus is on the major single-gene disorders, such as cystic fibrosis, phenylketonuria and Huntington's chorea. In these disorders the affected individual is at very high, perhaps certain, probability of developing the disorder, no matter what. In such Figure 11.2 Joint risk of developing Alzheimer's disease as a function of apolipoprotein-E genotype and atherosclerosis score (from Hofman et at, 1997). Figure 11.2 Joint risk of developing...

Rare dominant disorders

In addition to FAP and HNPCC, there are a number of rarer syndromes that are associated with a smaller elevated risk of colorectal cancer. Each of the syndromes are characterized by benign pol-yposis of the intestine and the polyps are of unusual histology. The clinical phenotypes of these syndromes are heterogeneous, and there is some clinical overlap between them. Juvenile Polyposis syndrome is an autosomal dominant syndrome, with incomplete penetrance and manifests as diffuse hamartomatous...

The familiality of exceptional longevity

Studying Mormon pedigrees from the Utah Population Database, Kerber and colleagues investigated the impact of family history upon the longevity of 78 994 individuals who achieved at least the age of 65 years (Kerber et al., 2001). The relative risk of survival (1s) calculated for siblings of probands achieving the 97th percentile of ''excess longevity'' (for males this corresponded with an age of 95 years, and for women with an age of 97 years) was 2.30. Recurrence risks among more distant...

Mutations of the a globin genes causing a thalassemia

Deletions of one or both a globin genes on a chromosome are the commonest cause of a thalassemia (Higgs, 2001). The original duplication that gave rise to two a globin genes has been well conserved and since these blocks lie adjacent to each other, it is not uncommon for misalignment to occur between the a1 gene of one chromosome with the a2 gene of the other, during meiosis. Crossing over would then result in either a chromosome with three a genes (which has no hematological consequences on...

Heritability of intermediate traits

In simple terms, obesity can be caused by one of three things, increased energy intake, decreased energy expenditure, or increased partitioning of nutrients into fat. These can occur alone or in combination. It would be useful if we knew the extent to which each of these processes might be under genetic control in humans. One of the serious barriers to progress in this area is the enormous difficulty in getting reliable data on human food intake in the free-living situation. In contrast, energy...

Familial hypercholesterolemia and statins

Perhaps the most dramatic example of monogenic diseases leading to treatments for common disease concerns familial hypercholesterolemia (FH) and the development of statins (Goldstein et al., 2001). FH is a relatively common dominant condition affecting 1 500 of the population. Individuals with FH have high levels of cholesterol at birth and will develop atherosclerosis and vascular disease in childhood. The risk of fatal heart disease before the age of 40 years is significantly higher than...

Other environmental risk factors that may predispose smokers to COPD

In addition to cigarette smoking a number of environmental factors have been identified which Table 26.4. Environmental risk factors associated with the development of COPD Childhood respiratory tract infections Exposure to passive smoke in childhood Latent viral infection Ocupation exposures Cadmium worker Coal miners Gold miners and other underground tunnel workers Indoor pollution Kerosene heaters Nitrogen dioxide Particulates from burning biomass fuels Nutritional Factors Low dietary intake...

Study design

For case-control studies, practical and efficient study designs for the investigation of the joint effects of genes and environment are required. Case selection is usually straightforward, with the availability of Cancer Registries or, other population-based resources, listing diagnoses by geographical region and date. Access to such lists varies, depending on Data Protection rules etc. However, often, for case recruitment into epidemiological studies, the only notable concern is the timing of...

Osteoporosis

The most common disease of bone, osteoporosis, is characterized by low bone mineral density (BMD), deterioration of bone architecture, and enhanced fragility with increased risk of fracture. Osteoporosis is defined as BMD more than 2.5 standard deviations below the mean established for young adults, while a less severe reduction in BMD ( 1 to 2.5 standard deviations) is referred to as osteopenia. Based on this definition, it is estimated that osteoporosis affects 50 of women 80 years of age or...

Insights from rodent models

The use of rodent models to dissect the complex genetic etiology of atherosclerosis offers a powerful alternative to human studies because experimental parameters, such as environment, breeding scheme, and detailed phenotyping, can be more easily controlled. Over the last two decades, linkage and gene targeting studies in rodents have provided profound genetic insights into the patho-genesis of dyslipidemia and atherosclerosis (Allayee et al., 2003 Glass et al., 2001 Lusis, 2000 Mehrabian et...

Novel human monogenic obesity syndromes

In the past eight years several human disorders of energy balance that arise from genetic defects have been described. All of these are in molecules identical or similar to those known to cause obesity in genetic and experimental syndromes of obesity in rodents (Leibel et al., 1997) and all have been identified using a candidate gene approach (Figure 22.2). These mutations all result in morbid obesity in childhood without the developmental pleiotropic features characteristic of the recognized...

Genetics of blood pressure and essential hypertension

A number of genome-wide genetic linkage studies of hypertension in affected relative pairs (Caulfield et al., 2003 Kardia et al., 2003 Rao et al., 2003 von Wowern et al., 2003), quantitative levels of blood pressure (de Lange et al., 2004 James et al., 2003) or other study designs have been undertaken in an attempt to localize genes with substantial effects. Candidate gene investigations comparing case control allele frequencies have also been widely applied in studies of hypertension. Two...

Technical terms

De novo - Occurring for the first time uniquely in one individual, i.e. not inherited. FISH - Fluorescent in situ hybridization, a nucleic acid probe is labelled and hybridized to immobilized chromosome spreads where it binds to homologous sequences. In silico analysis - Computer-based characterization of a gene using publicly available databases. Non-parametric linkage analysis - Linkage analysis that relies on some specification of the components of a genetic model but not usually pene-trance...

Penetrance expressivity and genetic modifiers

One of the major benefits expected to derive from genetic studies of common disease, will be the ability to identify individuals at highest risk of developing a particular disease through genetic profiling. For example, from a rigorous theoretical analysis, it has been calculated that it should be possible to identify the 10 of women who have a 20-30 risk of breast cancer, compared with a 5 risk for women across the whole population (Pharoah et al., 2002 Chapter 15, this volume). This will...

Genes and environment

Some cases of hearing impairment result primarily from a single gene mutation inherited in a Mendelian fashion, and other cases are the consequence of a known environmental insult such as meningitis or cisplatin administration. However, in many (maybe most) cases, both the genome of an individual and the environment interact to lead to deafness. For example, not all cases of meningitis lead to hearing loss, and people working in the same noisy environment do not all develop the same degree of...

Noninsulindependent Type II diabetes mellitus

The incidence of non-insulin-dependent (i.e. Type II) diabetes mellitus (NIDDM) is increasing in adult urban populations around the world. The approximately 3 of adults currently affected by NIDDM will become an estimated 5 by 2025 (World Health Organization, 1998), as populations age and urbanize, and as obesity becomes more prevalent. NIDDM is a serious metabolic disorder which damages kidneys, heart, blood vessels and retina. The disorder results from ''insulin resistance'' - a reduction in...

Agerelated macular degeneration

The most common cause of blindness in westernized countries is a disorder of the central retina called age-related macular degeneration (AMD). This accounts for about one-half of all blind registrations in Western countries and is increasingly recognised in less developed countries. It results from loss of the light-sensitive photo-receptors within a specialized region of the central retina known as the macula (Figure 32.1). The macula is 5-6 mm in diameter and centred around the fovea, the...

Conclusion

Studies thus far indicate that exceptional longevity is strongly familial and suggest that a significant component of that familiality is genetic. Once thought to be much too complex a puzzle of environmental, behavioral, genetic and stochastic factors, exceptional longevity and likely associated exceptional survival phenotypes appear to be associated with a number of discernable and influential factors. From age 20 to extreme old age, the siblings of centenarians appear to maintain half the...

Proopiomelanocortin deficiency

The first-order neuronal targets of leptin action in the brain are anorectic (reducing food intake) pro-opiomelanocortin (POMC) and orexigenic (increasing food intake) neuropeptide-Y Agouti-related protein (NPY AgRP) neurons in the hypothalamic arcuate nucleus, where the signalling isoform of the leptin receptor is highly expressed (Schwartz et al., 2000). Forty percent of POMC neurons in the arcuate nucleus express the mRNA for the long form of the leptin receptor and POMC expression is...

A model for human hearing impairment

Age-related hearing loss is an extremely common human disease, so what have we learnt so far that might suggest the causes Does the common disease common variant model look the most likely model If we look firstly at childhood deafness, despite the large number of genes that have been identified, most families with a deaf child still have no molecular diagnosis. The gene most commonly involved in severe or profound childhood deafness is GJB2, encoding the connexin 26 molecule, a component of...

Is achieving extreme old age worthwhile the centenarian phenotype

Average life expectancy has markedly increased over the past century. In 1900 average life expectancy was 46 years and in the United States it is currently almost 79 years. The age 85+ group is the fastest growing segment of our population and within that group, the number of centenarians is growing even faster. Whether mortality declines have been accompanied by health improvements among the elderly has been a matter of debate. Some authors have suggested that mortality declines have led to...

Primary open angle glaucoma

POAG is a slowly progressive disorder of unknown cause in which optic neuropathy develops in the context of abnormalities of the central field of vision, with or without raised IOP. The fluid bathing the anterior chamber of the eye (Figure 32.1), which lies between the cornea and iris lens, is called the aqueous humor. It is continuously secreted by epithelial cells of the ciliary body and drains into the ''filtration angle'' between the cornea and iris, which contains a porous structure called...

Skin cancers

There are two main types of skin cancer melanoma, arising from the neural crest derived melanocytes and basal cell carcinoma and squa-mous cell carcinoma derived from keratinocytes (the latter two referred to as non-melanoma skin cancer, NMSC) (Rees, 2002b). This broad distinction into two types is useful NMSC is extremely common and case-fatality extremely low (< 0.5 ) melanoma by contrast is less common but with a case fatality of -20 (Rees, 1998). Melanomas usually present as pigmented...

Role of genetics in deafness in the population

Many reports of clinical populations of children with permanent hearing impairment have been published, usually suggesting between a third and a half of children have a genetic etiology (e.g. Fortnum et al., 2002 Morzaria et al., 2004). However, the criteria for ascribing a genetic aetiology often are not clear many authors assume a genetic causation in the absence of any other clear cause, while others report syndromic deafness as a separate category even when it is highly likely to be due to...

Equality of access and discrimination

In his recent book entitled Our posthuman future, Francis Fukuyama puts forward the fairly uncon-troversial position that the basis upon which groups of people have historically been denied access, dignity and equal rights is through discrimination and prejudice (Fukuyama, 2002). In the nineteenth and early twentieth centuries, this manifested itself in assumptions that women were less rational, emotional, and therefore unsuited to professions or politics, and that immigrants from eastern and...

Craniometaphyseal dysplasia

Craniometaphyseal dysplasia (CMD) is characterized by metaphyseal dysplasia with sclerosis and hyperostosis of cranial bones. CMD is usually autosomal dominant, although autosomal recessive inheritance has been reported. The long bones have broadened metaphyses and develop an ''Erlenmeyer flask'' appearance. Hyperostosis of calvarial and facial bones leads to nasal obstruction, compression of the cranial nerves, and hypertelorism. Much of the disability associated with CMD is due to facial...

Familial expansile osteolysis

Familial expansile osteolysis (FEO) is characterized by focal regions of increased bone remodeling resembling those seen in adult PDB. There is increased activity of osteoclasts and osteoblasts leading to expansion, deformity and increased risk of fracture. Although PDB and FEO have histologic and phenotypic similarities, they are sufficiently different to be considered separate diseases. FEO begins in the second decade, tends to be more severe, and the bone lesions are predominantly...

Environmental effects

The environment plays a major role in determining the onset and course of most autoimmune diseases. These effects contribute up to 40 of the susceptibility (Janeway et al., 2001). Most environmental factors remain to be determined although there has been no shortage of candidates. One reason why they may be so difficult to identify is that the disease symptoms may develop many years after the triggering events in the environment. Top of the list of candidates for the environmental triggers are...

Environmental causes of deafness

It is well established that exposure to certain environmental factors will lead to hearing loss (e.g. Fransen et al., 2003). Excessive noise exposure is the most obvious cause of hearing loss. However, infections such as prenatal rubella or meningitis can lead to deafness. Certain drugs also have ototoxic effects, including aminoglyco-side antibiotics, cisplatin and diuretic agents. In some cases it is clear that one of these factors is the immediate cause of deafness, such as hearing...

Geneenvironment interaction

The increase in the prevalence of obesity in the last 30 years suggests the importance of changing environmental factors in particular the increasing availability of energy-dense, high-fat foods and a reduction in physical activity. Further evidence for the critical role of environmental factors in the development of obesity comes from migrant studies and the ''westernisation'' of diet and lifestyles in developing countries. A marked change in BMI is frequently witnessed in migrant studies,...

Frontotemporal lobe dementia FTD

Fronto-temporal dementia is a pleomorphic neuro-degenerative illness which typically begins before the age of 65 years. In a minority of cases, the disease is inherited as an autosomal-dominant trait (Lynch et al., 1994 Wszolek et al., 1992). The disease often begins with personality and behavioral changes including disinhibition manifest by alcoholism, hyper-religiosity, hypersexuality, hyperphagia (elements of the Kluver-Bucy syndrome) and stealing. As the disease progressed in these...

Number of genetic variants contributing to genetic etiology implications for study strategy

Many late-onset diseases result from the cumulative breakdown of numerous quantitatively varying physiological systems. For example, high blood pressure can follow from abnormalities in cardiac output, blood vessel architecture, renal function, fat distribution, endothelial function and central nervous system integration, or failure of diverse homeostatic mechanisms, including baro-receptors, natriuretic peptides, renin-angiotensin-aldosterone, kinin-kallikrein, adrenergic receptors and local...

Pagets disease of bone

Paget's disease of bone (PDB) is one of the most common chronic skeletal diseases affecting up to 3 of many White populations over the age of 60 years. Its ethnic and geographic distribution is variable, with a high prevalence in Whites from the United Kingdom, Australia, North America and Western Europe. PDB is characterized by focal areas of increased bone resorption and formation, leading to deformity and or enlargement. The axial skeleton (pelvis, lumbar and thoracic spine, and sacrum) is...

Modifiers of deafness genes

Several modifier genes have been localised that modify the phenotype of carriers of known deafness genes. In humans, a dominant modifier has been reported to suppress deafness in people homozygous for the DFNB26 recessive deafness locus (Riazuddin et al., 2000). Two modifiers have been proposed to influence the hearing loss observed in carriers of the A1555G mitochondrial mutation associated with progressive hearing loss, a locus on chromosome 8 near D8S277 and a locus on chromosome 6 near the...

Matrix attachment sites

Matrix or scaffold attachment sites (MAR SARs), are DNA sequences isolated as fragments that remain attached to nuclear structures after stringent extraction with high salt or detergent. They are usually A T rich and are thought to be the sequences where DNA attaches to the nuclear matrix, thus forming the looped structures of the chromosome that were once thought to demarcate separate gene domains. In some cases, MARs have been shown to coincide with transcriptional enhancers and insulators,...

Obesity a major public health threat

Obesity is broadly defined as a condition in which body fat stores have increased to the extent that health may be adversely affected. Obesity is associated with substantially increased mortality from cardiovascular and cerebrovascular disease, diabetes and certain cancers (Kopelman, 2000) (Figure 22.1). It also results in morbidity from musculoskeletal, gastrointestinal, psychiatric and reproductive diseases and is associated with lowered quality of life, self-esteem and socioeconomic...

Mutations of the J globin gene causing b thalassemia

Screening for heterozygous b thalassemia is initially based on the decrease in red cell indices (mean cell volume 70fl in contrast to a normal value of 90fl, and mean cell hemoglobin 20pg versus 30pg). Confirmation is obtained by measuring the proportion of the minor adult hemoglobin, HbA2 (a2S2) which is increased from a normal level of 2.0-3.0 to 3.5-5.5 . In contrast to the a gene cluster, mutations causing b thalassemia are rarely gene deletions but typically point mutations affecting...

Response to leptin therapy

Recently we reported the dramatic and beneficial effects of daily subcutaneous injections of leptin reducing body weight and fat mass in three congenitally leptin-deficient children (Farooqi et al., 1999 2002). The major effect of leptin was on appetite with normalisation of hyperphagia. Leptin therapy reduced energy intake during an 18MJ ad libitum test meal by up to 84 (Farooqi et al., 2002). We were unable to demonstrate a major effect of leptin on basal metabolic rate or free-living energy...

Scope of chapter

Even most full time dermatologists will not see at first hand the majority of skin diseases. Most individual disease entities are rare. Some of these rare disorders, such as epidermolysis bullosa and cancer syndromes such as Gorlin's syndrome or familial melanoma have attracted considerable attention from human geneticists over the last ten years. Many such disorders present with a striking collection of physical signs, rely almost entirely on clinical skills for diagnosis, and are highly...

Protein misfolding and its consequences for disease

Amyloidois Images

Folding and unfolding are the ultimate ways of generating and abolishing specific cellular activities, and unfolding is also the precursor to the ready degradation of a protein (Matouschek, 2003). Moreover, it is increasingly apparent that some events in the cell, such as translocation across membranes, can require proteins to be in unfolded or partially folded states. Processes as apparently diverse as trafficking, secretion, the immune response and the regulation of the cell cycle are in fact...

Type 2 diabetes the next global epidemic Definitions

In contrast to type 1 diabetes, which is known to result from autoimmune destruction of the insulin-secreting beta-cells of the pancreas, leading to lifelong dependence on exogenous insulin, the etiology of type 2 diabetes is poorly understood (Kahn, 2003). Whilst type 1 diabetes is typically diagnosed in childhood or early adulthood, type 2 diabetes classically presents in later life. These clinical distinctions lie behind previous disease classifications in which type 2 diabetes was known...

The fundamental origins of amyloid disease

Despite our increasing knowledge of the general principles that underlie protein misfolding diseases, the manner in which improperly folded proteins and aggregated proteins can generate pathological behavior is not yet understood in detail. In the case of systemic disease, the sheer mass of protein that can be deposited may physically disrupt the functioning of specific organs (Pepys, 1995). In other cases it may be that the loss of functional protein results in the failure of some crucial...

Albright hereditary osteodystrophy

Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder due to germline mutations in GNAS1 that decrease expression or function of the heterotrimeric GTP binding protein, G alpha s. Maternal transmission of GNAS1 mutations leads to AHO (characterized by short stature, obesity, skeletal defects, and impaired olfaction) plus resistance to several hormones (e.g. parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal...

Asthma

Asthma is an inflammatory condition of the airways which results in bronchial reactivity to a variety of stimuli with consequent narrowing of the airways. This results in airflow obstruction which is usually reversible (National Heart, Lung, and Blood Institute, 1992 Department of Health and Social Services, 2003). The cardinal features of airway inflammation, bronchial hyper-reactivity and reversible airflow obstruction give rise to the symptoms of wheeze, breathlessness, cough and chest...

Diseases of genomic imprinting

Mammals possess an epigenetic system thought to be important for fetus-mother nutrient transfer and normal development, termed genomic imprinting (Constancia et al., 2002 Ferguson-Smith et al., 2003b Ferguson-Smith et al., 2004 Reik et al., 2003 Walter and Paulsen, 2003). Epigenetic guidelines are imprints laid down in germ cells (in most cases by DNA methyltransferases) governing how genes are expressed depending on their parental origin, be it maternal or paternal (Bjornsson et al., 2004...

Glaucoma

Glaucoma is a diverse group of progressive optic nerve disorders (neuropathies) which accounts for 12 of global blindness, second only to cataract (Resnikoff etal., 2004). In Western countries, where cataract-related blindness is substantially less common (about 5 of blindness), glaucoma is also the second most common cause, accounting for 18 of all blindness (Resnikoff etal., 2004). The diagnosis of adult-onset glaucoma is primarily based on characteristic structural abnormalities of the optic...

Leptin receptor deficiency

The signalling form of the leptin receptor is deleted in db db mice (and disrupted in the fatty Zucker and Koletsky rat models) which are consequently unresponsive to endogenous or exogenous leptin (Tartaglia, 1997). In rodents, the phenotype is comparable to ob ob, with earlier development of hyperglycemia on some backgrounds. A mutation in the leptin receptor has been reported in several obese subjects from a consanguineous family of Kabilian origin (Clement et al., 1998). Affected...

Lessons from maturity onset diabetes of the young MODY

As mentioned earlier, a small proportion (around 1 ) of families with diabetes are clearly segregating an autosomal dominant form of early-onset T2D (Frayling et al., 2001). The term ''maturity onset diabetes of the young'' (MODY) was coined to describe these key clinical features, at a time when most diabetes seen before late middle age was autoimmune (that is, type 1, or juvenile-onset diabetes as it was then known). Most people with MODY were not particularly obese, suggesting that the...

Osteoporosispseudoglioma syndrome

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive condition characterized by juvenile-onset osteoporosis with increased fracture risk and skeletal deformities. Children with OPPG are frequently blind at birth due to vitreous opacities. Inactivating mutations in LRP5 have recently been shown to cause this disorder in homozygous individuals (Gong et al., 2001), while heterozygous carriers exhibit intermediate reductions in bone mass and have an increased fracture risk (Gong...

Primary angle closure glaucoma

Little is known about the molecular basis of the disease in this, the commonest, form of glaucoma in East or South East Asian populations. It results from permanent closure of the filtration angle as a result of iris apposition to the trabecular mesh-work. It tends to occur in short hypermetropic (long-sighted) eyes with an anteriorly placed lens. The prevalence increases with age and in the presence of a family history and females are more often affected than males, but specific causal factors...

Review of evidence for a genetic effect

Given the large commitment of time and resources required to investigate the genetic basis of complex disease, it is important first to show a clear influence of genetic factors on variation in a complex trait or on disease frequency. In complex disease, a family history is an unreliable guide, as it is often not present, either because the genetic influence is weak or because a polygenic etiology results in disease risk declining exponentially with decreasing relationship to an affected family...

Thalassemia due to mutations in transacting factors

Although the vast majority of b thalassemia mutations are linked to the b cluster on chromosome 11, there are two rare conditions in which mutations in trans-acting factors cause mild forms of b thalassemia. In one family, a mutation affecting the key erythroid transcription factor GATA-1 has been shown to cause thrombocytopenia and b thalassemia (Yu et al., 2002). It has been suggested that differences in the types of GATA-1 binding sites present in the a and b clusters may explain why this...

Genetic and environmental contributions to CHD pathogenesis

The significant changes in CHD incidence and mortality over the past 20 years can be attributed at least in part to variation in known environmental risk factors (Table 24.1). Frequency of cigarette smoking, efficacy of primary and in-hospital coronary care, treatment of plasma lipids, and the prevalence of obesity and type 2 diabetes (T2DM) have changed significantly over the past 20 years and also vary markedly between populations. These environmental factors explain, at least in part, the...

Congenital leptin deficiency

Mice Leptin Deficiency

The role of leptin was first discovered in studies of severely obese ob ob mice, which harbour mutations in the ob gene resulting in a complete lack of its protein product leptin which is derived from adipose tissue (Zhang et al., 1994). Administration of recombinant leptin reduces the food intake and body weight of leptin-deficient ob ob mice and corrects all their neuroendocrine and metabolic abnormalities (Halaas et al., 1995). Figure 22.2 Neuronal pathways involved in the regulation of body...

Realistic estimation of study power

Power is governed by the proportion of phenotypic variance in the population that is explained by the genetic variant. Since this is typically low in complex disease, there is a need to achieve large sample sizes in almost all study designs. There is thus an increasing need to channel research funding and effort to large national or international collaborations between government, pharmaceutical industry, medical research charities and universities to achieve sufficient sample size. Lack of...

Beyond oligogenic disease

It remains to be seen if the application of similar approaches to define the genetic determinants of other developmental disorders will be as successful as for HSCR. Complicating issues may include identifying and controlling for environmental modifiers of the phenotype as well as developing methodologies to overcome combinatorial heterogeneity between contributing loci. Similar reliance upon studies utilizing inbred strains of mice may also be problematic with models that incorporate multiple...