Introduction

The evolution, comparative structure and function of the eye have attracted the attention of many scientists, including Isaac Newton, who first showed that light could be split into different wavelengths, and later Charles Darwin, for whom the eye presented an interesting test of the evolutionary paradigm. Newton laid the foundations for the trichromatic theory of vision (Young, 1802), whereby different wavelengths of light are perceived by three distinct receptors within the retina, with overlapping sensitivities, now known to be the short-, medium- and long-wavelength cone opsins. The eye interacts with the environment in the most direct way, since it is constantly bombarded with electromagnetic radiation of many wavelengths and yet it specifically responds only to those in the 400–700 nm range. These wavelengths correspond closely to the solar spectrum measured below the surface of the sea, where the earliest visual systems are thought to have evolved (McIlwaine, 1996). An otherwise rare member of the carotenoid family, 11-cis retinal, an isomer of vitamin A aldehyde, has the important property of changing shape on absorbing a photon of light. This molecule combines with the different opsin apoproteins, which are members of the G-protein coupled receptor superfamily, to form the visual photopigment in all multicellular animals. In this way, light serves to generate a neural signal but at the same time renders the eye vulnerable to oxidative damage, which is a major factor in at least two of the major causes of global blindness.

Defining “environment”

The “environment”, considered in relation to health, typically refers to air pollutants, chemical residues in food, contaminated drinking water, radioactive wastes and so on. Conventionally, therefore, “environmental health” refers to research and policy in relation to the health risks posed by ambient environmental exposures. These exposures usually impinge on whole neighbourhoods, communities or populations and are therefore usually not under the control of individuals. This has important implications for prevention strategies.

Environmental risks to health from ambient physical, chemical and microbiological factors induce harm via direct physical, toxicological or microbial action. In addition to these various well-recognized human-made environmental exposures there are many important naturally occurring environmental health hazards. These include exposure to solar radiation, extreme weather conditions, and chemicals naturally present in drinking water (e.g. fluoride).

A more inclusive definition of “environment” includes the built environment and the social environment. Indeed, the influences of urban design, housing quality, material circumstances, social diets, socioeconomic conditions and social relations upon disease patterns have claimed increasing attention from researchers. Similarly, some commentators include variations in self-determined exposures (as through tobacco smoking, dietary choices and contraceptive hormone use) as part of the suite of environmental influences on health. This wider perspective becomes important, for example, in considering environmental influences on the rise of obesity in modern urban populations. This incoming tide of obesity is essentially an “environmental system” problem, reflecting fundamental, community-wide, changes in the ways of living of contemporary urban dwellers, resulting in disequilibrium between energy intake and energy output.

The coding capacity of the human genome is smaller than originally expected; it is predicted that we have 25 000–40 000 genes, only twofold more than a simple organism such as the roundworm C. elegans (Pennisi, 2003). This modest increase in gene numbers is counterbalanced by enormous gains in the potential for complex interactions through alternative splicing, and in the regulatory intricacy of elements within and between genes in chromatin (Bentley, 2004) (Chapter 1). Added to this complexity is an increasing repertoire of epigenetic mechanisms which form the basis of gene silencing and genomic imprinting, including DNA methylation, histone modification and RNA interference (RNAi). These mechanisms have profound influences on developmental gene expression and, when perturbed, cancer progression and human disease (Bjornsson et al., 2004; Meehan, 2003).

Location, location, location!

The position of a gene within a eukaryotic chromosome can be a major determinant of its transcriptional properties. In the last century it was shown that the relocation of the white gene from a euchromatic position to a heterochromatic region resulted in its variegated expression in the eye of the fruit fly (Drosophila melanogaster) (Dillon and Festenstein, 2002). This observation was an example of epigenetics, which has two closely related meanings: (1) the study of the processes involved in the unfolding development of an organism, including phenomena such as X chromosome inactivation in mammalian females, and the patterning of gene silencing; (2) any mitotically and/or meiotically heritable change in gene function that cannot be explained by changes in DNA sequence (Meehan, 2003; Waddington, 1957).

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 other forms of dermatitis, 25% for acne, and 10% for psoriasis (McCormick, Fleming and Charlton, 1996). The cumulative incidence of atopic dermatitis and other forms of eczema is perhaps 30% (Williams, 1997). Psoriasis affects 2–3% of the population (Naysmith and Rees, 2003), and skin cancer is the commonest human malignancy in Northern European populations, accounting for half of all cancer cases (Marks, 1995); (Rees, 1998).

Skin disease prevalence data is predictably more limited for third world countries, but point incidence rates of skin disease are in the order of 20–30%, with a greater proportion than in first world countries being due to infectious causes (e.g. fungal disease, infestations, leprosy) (Satimia et al., 1998). Even in the absence of rigorous worldwide studies, it seems reasonable to assume that the frequency of diseases of the skin is higher than that of any other organ.

Alzheimer's disease (AD), Lewy body variant of Alzheimer disease (LBV), and the fronto-temporal dementias (FTD) are the three commonest causes of adult-onset dementia. These diseases present in mid to late adult life with progressive defects in memory and higher cognitive functions such as performing complex learned motor tasks (apraxias), reasoning etc. In the fronto-temporal dementias, the clinical syndrome can be overshadowed by behavioral disturbances (disinhibition, aggressivity etc.) and speech disturbances (aphasia), which arise from involvement of the frontal neocortex. The FTD symptom complex frequently also includes additional features such as muscle rigidity, tremor, bradykinesia (Parkinsonism), and motor neuron induced muscle weakness (amyotrophy). In contrast, the clinical features of AD and LBV (recent and immediate memory deficits, deficits in praxis, reasoning and judgement etc.) are those stemming from involvement of the temporal lobe, hippocampus, and the parietal association cortices, with lesser involvement of frontal lobes until late in the disease. LBV overlaps with AD, sharing most of the clinical and neuropathological features of AD, but being differentiated by the presence of prominent visual hallucinations, sensitivity to phenothiazine tranquilizers, and the presence of Lewy bodies (α-synuclein containing intraneuronal inclusions) in neocortical neurons. In all three diseases there is prominent loss of neurons in selected cerebral cortical regions (e.g. hippocampus and temporoparietal neocortices in AD and LBV; frontal neocortices in FTD). In AD and LBV, a second prominent neuropathological feature is the complex, extracellular, fibrillar deposits in the cortex termed senile or amyloid plaques.

The announcement of the partial completion of the Human Genome Project was accompanied by expansive claims about the impact that this remarkable achievement will have on medical practice in the near future. The media and even some of the scientific community suggested that, within the next 20 years, many of our major killers, at least those of the rich countries, will disappear. What remains of day-to-day clinical practice will be individualized, based on a knowledge of a patient's particular genetic make-up, and survival beyond 100 years will be commonplace. Indeed, the hyperbole continues unabated; as I write a British newspaper announces that, based on the results of manipulating genes in small animals, future generations of humans can look forward to lifespans of 200 years.

This news comes as something of a surprise to the majority of practicing doctors. The older generation had been brought up on the belief that most diseases are environmental in origin and that those that are not, vascular disease and cancer for example, can be lumped together as “degenerative”, that is the natural consequence of increasing age. More recent generations, who know something about the interactions between the environment and vascular pathology and are aware that cancer is the result of the acquisition of mutations of oncogenes, still believe that environmental risk factors are the major cause of illness; if we run six miles before breakfast, do not smoke, imbibe only homeopathic doses of alcohol, and survive on the same diets as our hunter-gatherer forebears, we will grow old gracefully and live to a ripe old age.

Introduction

Linguistic impairment is a core diagnostic criterion for a number of developmental disorders, such as autism and specific language impairment (SLI). Uncovering the genetic mechanisms responsible for susceptibility to language impairments will be essential to our understanding of the central deficit underlying speech and language disorders. An overlap between autistic and SLI phenotypes has been proposed based on the shared characteristic of pragmatic language impairment (PLI) in some cases. PLI describes inappropriate communication within a social context and can be observed in a subset of individuals diagnosed with both autism and SLI (Bishop and Norbury, 2002). The existence of a phenotypic overlap suggests that a shared genetic susceptibility may be responsible for some aspects of language delay. This is supported by a higher rate of autism in siblings of probands with SLI than in the general population (3%:0.17% respectively) (Tomblin et al., 2003). It has also been reported that siblings of autistic individuals have higher than expected language and communication deficits (Folstein et al., 1999). Whether these observations indicate a common genetic pathway or intermediate phenotypes common to both disorders is unclear. For example, Bishop and Norbury (2002) found a group of children with PLI also met criteria for autism, whereas another group with PLI including stereotyped language and abnormal intonation were otherwise social and communicative.

The approach taken to identify genes underlying speech and language disorders depends on the genetic model indicated by segregation analysis.

Introduction

Inflammatory bowel diseases (IBD) consist of two major disorders: Crohn's disease (CD, OMIM 266600) and ulcerative colitis (UC, OMIM 191390). They are both characterized by a chronic or relapsing inflammation of the digestive tract (for review see Shanahan, 2002; Podolsky, 2002). In UC, the inflammation is limited to the colon with continuous mucosal inflammation already affecting the rectum. On the other hand, CD may affect all the digestive tract from the mouth to the anus with discontinuous lesions. The inflammation is often transmural with potential complications including fistulas, abscesses and strictures. At late stages, granulomas with giant and epithelioid cells are encountered in biopsies or specimens in about half of CD cases.

UC and CD are usually diagnosed in patients presenting with isolated or associated symptoms such as: diarrhea, rectal bleeding, abdominal pain, inflammatory syndromes and malabsorption. Both disorders can be complicated by under-nutrition (and failure to grow in children), osteopenia, extra-intestinal inflammation and cancer. IBD treatment is often complex and requires a combination of anti-inflammatory drugs including 5-aminosalicylates and steroids, immunosuppressant agents and biological therapies. Surgery is often mandatory and iatrogenic complications are frequent.

IBD are lifelong disorders occurring in the young adult with a peak of incidence in the third decade (for review see Mayberry and Rhodes, 1984). CD is more frequent in females (M/F sex ratio = 0.8) while UC is more frequent in males (M/F sex ratio: 1.2).

Introduction

Higher levels of blood pressure are a major risk factor for coronary heart disease (CHD), stroke, cardiac failure and renal failure. Meta-analysis of individual participant data from over 1 million people in prospective cohort studies has shown that the log risk of coronary heart disease and stroke are linearly related to the level of blood pressure throughout a range which extends well into that usually regarded as “normal,” with no evidence of a threshold below which blood pressure no longer influences risk (Lewington et al., 2002). Studies involving participants from many different countries show that high blood pressure is a risk for these conditions throughout the world, with the expected impact of high blood pressure set to increase as developing countries industrialise (Yusuf et al., 2004). Blood pressure is distributed approximately log-normally in all populations studied to date; within this distribution, cut-off criteria for levels of blood pressure which confer a level of risk requiring treatment (and thus define conventional hypertension) have changed over time, in general being revised downward as the importance of even relatively small elevations in blood pressure has been more widely appreciated. Currently, the European Hypertension Society guidelines define Grade I hypertension as a systolic pressure of 140–159 mmHg and/or a diastolic pressure of 90–99 mmHg; such a definition would result in some 40% of males and 33% of females in the UK carrying a diagnosis of hypertension (European Society of Hypertension/European Society of Cardiology Guidelines Committee, 2003).

Introduction

Epidemiological studies have shown that environmental exposures influence a person's risk of disease. For instance, migration studies show that a person's risk of cancer changes as he/she moves across environments; such changes must be due to changing exposures, as the host genome remains essentially constant (Haenszel, 1982). Studies comparing the lifestyle of persons with cancer (cases) and those without cancer (controls) have identified a number of consistent differences, assumed to be risk factors for that cancer, although the critical aspect of exposure is usually unknown or poorly measured. For instance, case-control studies show that persons with higher levels of smoking are more at risk of lung cancer, or those reporting diets higher in animal fat have a higher risk of bowel cancer but the critical combination and timing of mutagens, carcinogens, tumor promoters etc. is unknown. Instead, exposures are reported as number of packs of cigarettes per year or estimated average number of calories from fat. Chapter 11 discusses some of these issues in greater depth including the definition of the term “environment”.

Genetic studies have shown that, for some persons, susceptibility is determined at least in part by genes (Eeles et al., 2004). Family history studies indicate that for most common cancers, close relatives of cases have a risk of that same cancer which is between twice and four times that of the general population (Goldgar et al., 1994; Hemminki et al., 2004).

Introduction

The field of population genetics may be broadly defined as the study of the generation and maintenance of genetic variation within populations. Population genetic theory plays an important role in shaping our understanding of human genetic variation in general, and the genetic basis of common disease in particular. It also plays a central role in association- and linkage disequilibrium-based approaches to disease mapping, as these can only be properly understood within a population genetic framework.

One way to think about the role of population genetics in the study of complex disease is as follows. If it were possible to sequence every base pair of every person in a study population, conventional statistical methods would, arguably, be sufficient to make inferences about which sequence variants are associated with disease. Population genetics provides an analytical framework for predicting the nature of unobserved variation that lies between genotyped sites, or in unsampled individuals. Similarly, population genetic approaches are used to explore plausible models of complex disease, as there are at present few empirical data on the genetic basis of complex diseases. Lastly, population genetics allows us to measure the effect of genetic variation on health in an indirect way, by detecting selective effects that may be too subtle to observe directly in prospective data, or that may have affected humans during our evolutionary history. In short, biological properties of a species which we cannot directly observe are illuminated by population genetics.

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 increased prevalence of frailty among older survivors because treatment of existing diseases simply postpones death to older ages (Gruenberg, 1977; Kramer, 1983; Olshansky and Ault, 1986), while others suggest that mortality declines have led to a compression of morbidity (Fries, 1980). Early US evidence from the 1970s was generally consistent with the idea that health among the elderly had deteriorated (Crimmins and Ingegneri, 1993; Verbrugge, 1984), while more recent evidence provides a somewhat more optimistic view (Freedman and Soldo, 1994; Manton et al., 1997). Changes in disability prevalence over time, however, have varied by type and severity and by the data source used for trend analyses (Waidmann and Manton, 1998).

Centenarians studied by Hitt et al. appear to fit the pattern of postponement of disability to very advanced ages. In a population-based sample, it was observed that 90% of centenarians were independently functioning at age 92 (Hitt et al., 1999).

Introduction

Colorectal cancer is a major public health problem in the developed world and is becoming increasingly prevalent in developing countries. The current annual world incidence is around 950 000 cases (Globocan, 2000). It is the most common cause of early cancer death in the non-smoking population. Recent developments have led to the isolation of a number of moderate- to high-risk cancer susceptibility genes for the disease. Identifying people with high-risk alleles offers real opportunities for application of preventive measures. Intensive surveillance to detect early cancer, or even prevent cancer by polyp removal, can be targeted by genotype information. Surgical intervention and chemoprevention guided by genetic information are also likely to be part of future armaments used to combat the disease. The last ten years has seen a number of exciting developments in understanding key molecular events involved in colorectal cancer susceptibility, which are beginning to provide new insight into the fundamental basis of the disease. In this chapter we will describe the major advances and how they are impacting diagnosis and clinical management of colorectal cancer.

Colorectal cancer epidemiology

The multifactorial etiology of colorectal cancer involves environmental factors as well as genetic susceptibility (see Chapter 14). There are large differences in global prevalence of the disease, which is generally four times higher in developed countries than in developing countries (IARC, WHO, 1997). Incidence rates also vary according to ethnicity (American Cancer Society, 2002), however the observed variation between countries is primarily due to the role of environmental factors.

Introduction

It has been estimated that there are on the order of 6000 single gene disorders, most inherited as X-linked recessive, autosomal dominant or autosomal recessive Mendelian conditions (McKusick, 1998). In total, approximately 1% of the population is born with or will develop a disease through carrying such single gene mutations.

Even before the completion of the Human Genome sequence (International Human Genome Sequencing Consortium, 2001; Venter et al., 2001), heroic positional cloning efforts had successfully identified the genes mutated in 1000 or so of these disorders. Since the genome sequence has been available, the remainder are being picked off at an astonishing rate, the limiting factor now being the small number of affected individuals in some of the most rare conditions.

Identification of the genes mutated in Mendelian disorders has led to profound insights into disease mechanisms and, in some instances, has already had a clinical impact. Perhaps the most dramatic examples are phenylketonuria and bowel cancer, where identification of the underlying genetic cause has led to cures through nutritional and surgical intervention, respectively. In a number of cases, identification of the genes has enabled prenatal diagnosis with the offer of termination of pregnancy. Finally, in a few conditions the genetic breakthroughs have led to novel therapies, either pharmacological or immunological. Another enormous bonus is the profound impact that knowledge of these genes and their products has had on our understanding of basic biological processes.

Introduction

Recent years have witnessed major advances in our understanding of the genetic basis for many skeletal disorders. In several instances, particularly with the less common Mendelian diseases, the responsible gene has been mapped, mutations identified, and their functional significance determined, contributing significantly to our understanding of the molecular basis for pathogenesis. For more common disorders where susceptibility is complex, a complete picture of the responsible genetic polymorphisms and how they influence pathogenesis has been more difficult to achieve. In this chapter we focus on our current understanding of the genetic basis and pathogenic mechanisms for disorders of bone homeostasis. For readers interested in the genetic basis of developmental disorders of the skeleton, we recommend a recent review (Kornak and Mundlos, 2003).

Bone resorption and bone formation are ongoing processes in both the developing and mature skeleton. Even during growth, where the balance favors bone formation, bone resorption is necessary to remove calcified cartilage prior to the formation of mature bone. In the adult skeleton, there continues to be a dynamic balance between these processes that serves both metabolic and mechanical needs of the individual. Although bone mass continues to increase during childhood, it peaks between the ages of 25 and 35 years, and then begins a steady decline that becomes most prominent after age 50 years when bone formation does not fully compensate bone loss. The delicate balance between bone formation and bone resorption is maintained largely by the coordinated actions of two cell types, osteoblasts and osteoclasts.