Genes and common diseases, genetics in modern medicine a wright, n hastie (cambridge, 2007)

Genes and Common Diseases Genes and common diseases presents an up-to-date view of the role of genetics in modern medicine, reflecting the strengths and limitations of a genetic perspective The current shift in emphasis from the study of rare single gene disorders to common diseases brings genetics into every aspect of modern medicine, from infectious diseases to therapeutics However, it is unclear whether this increasingly genetic focus will prove useful in the face of major environmental influences in many common diseases The book takes a hard and self-critical look at what can and cannot be achieved using a genetic approach and what is known about genetic and environmental mechanisms in a variety of common diseases It seeks to clarify the goals of human genetic research by providing state-of-the art insights into known molecular mechanisms underlying common disease processes while at the same time providing a realistic overview of the expected genetic and psychological complexity Alan Wright is a Programme Leader at the MRC Human Genetics Unit in Edinburgh Nicholas Hastie is Director of the MRC Human Genetics Unit in Edinburgh Genes and Common Diseases Alan Wright Nicholas Hastie Foreword by David J Weatherall CAMBRIDGE UNIVERSITY PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521833394 © Cambridge University Press 2007 This publication is in copyright Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press First published in print format 2007 eBook (NetLibrary) ISBN-13 978-0-511-33531-0 ISBN-10 0-511-33531-8 eBook (NetLibrary) ISBN-13 ISBN-10 hardback 978-0-521-83339-4 hardback 0-521-83339-6 ISBN-13 ISBN-10 paperback 978-0-521-54100-8 paperback 0-521-54100-X Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate Contents List of Contributors Foreword page vii xiii Section 1: Introductory Principles Genes and their expression Dirk-Jan Kleinjan Epigenetic modification of chromatin 20 Donncha Dunican, Sari Pennings and Richard Meehan Population genetics and disease 44 Donald F Conrad and Jonathan K Pritchard Mapping common disease genes 59 Naomi R Wray and Peter M Visscher Population diversity, genomes and disease 80 Gianpiero L Cavalleri and David B Goldstein Study design in mapping complex disease traits 92 Harry Campbell and Igor Rudan Diseases of protein misfolding 113 Christopher M Dobson Aging and disease 132 Thomas T Perls The MHC paradigm: genetic variation and complex disease 142 Adrian P Kelly and John Trowsdale v vi Contents 10 Lessons from single gene disorders 152 23 Nicholas D Hastie 11 Environment and disease Contemporary ethico-legal issues in genetics 344 Mark I McCarthy 164 24 A J McMichael and K B G Dear 12 Type diabetes mellitus Genetics of coronary heart disease 359 Rossi Naoumova, Stuart A Cook, Paul Cook and Timothy J Aitman 176 25 Renate Gertz, Shawn Harmon and Genetics of hypertension 377 B Keavney and M Lathrop Geoffrey Pradella 26 Obstructive pulmonary disease 391 Bipen D Patel and David A Lomas Section 2: Common Medical Disorders 27 Skeletal disorders 406 Robert A Colbert 13 Developmental disorders 201 Stephen P Robertson and Andrew O M Wilkie 14 Genes, environment and cancer The polygenic basis of breast cancer 213 29 224 Paul D P Pharoah and Bruce A J Ponder 16 TP53: A master gene in normal and tumor suppression Genetics of colorectal cancer 30 233 Genetics of autoimmune disease 31 Susceptibility to infectious diseases 32 Inflammatory bowel diseases 33 302 Genetic anemias 316 W G Wood and D R Higgs 22 Genetics of chronic disease: obesity 454 Speech and language disorders 469 Common forms of visual handicap 488 Genetic and environmental influences on hearing impairment 505 Karen P Steel Jean-Pierre Hugot 21 Major psychiatric disorders in adult life Alan Wright 277 Andrew J Walley and Adrian V S Hill 20 439 Gabrielle Barnby and Anthony J Monaco 268 John I Bell and Lars Fugger 19 Molecular genetics of Alzheimer’s disease and other adult-onset dementias Amanda Elkin, Sridevi Kalidindi, Kopal Tandon and Peter McGuffin 245 Susan M Farrington and Malcolm G Dunlop 18 427 P H St George-Hyslop Pierre Hainaut 17 The genetics of common skin diseases Jonathan Rees D Timothy Bishop 15 28 34 Pharmacogenomics: clinical applications 516 Gillian Smith, Mark Chamberlain and 328 C Roland Wolf I Sadaf Farooqi and Stephen O’Rahilly Index 529 Contributors Adrian V S Hill Human Genetics University of Oxford Wellcome Trust Centre for Human Genetics Oxford, UK Adrian P Kelly Immunology Division Department of Pathology Cambridge, UK A J McMichael National Centre for Epidemiology and Population Health The Australian National University Canberra, Australia Alan Wright MRC Human Genetics Unit Western General Hospital Edinburgh, UK Amanda Elkin Neurogenetics Group Wellcome Trust Centre for Human Genetics Oxford, UK vii viii List of Contributors Andrew J Walley Christopher M Dobson Complex Human Genetics Department of Chemistry Imperial College London University of Cambridge Section of Genomic Medicine Hammersmith Hospital Cambridge, UK London, UK David B Goldstein Department of Biology (Galton Lab) Andrew O M Wilkie Weatherall Institute of University College London London, UK Molecular Medicine The John Radcliffe Hospital David A Lomas Oxford University Respiratory Medicine Unit Oxford, UK Department of Medicine University of Cambridge Anthony Monaco Cambridge Institute for Medical Research Cambridge, UK Neurogenetics Group Wellcome Trust Centre for Human Genetics Oxford, UK B Keavney Dirk-Jan Kleinjan MRC Human Genetics Unit Western General Hospital Edinburgh, UK Institute of Human Genetics University of Newcastle Newcastle, UK Donald F Conrad Department of Human Genetics Bipen D Patel Department of Public Health and Primary Care The University of Chicago Chicago IL USA Institute of Public Health Cambridge University Cambridge, UK Donncha Dunican MRC Human Genetics Unit Medical Research Council Bruce A J Ponder Western General Hospital Cancer Research UK Human Cancer Genetics Group Edingburgh, UK Department of Oncology Strangeways Research Laboratory Cambridge, UK D R Higgs MRC Molecular Haematology Unit Weatherall Institute of C Roland Wolf Molecular Medicine CR-UK Molecular Pharmacology Unit Ninewells Hospital & Medical School University of Oxford John Radcliffe Hospital Dundee, UK Oxford, UK List of Contributors D Timothy Bishop Jean-Pierre Hugot Cancer Research UK Department of Paediatric Clinical Centre Gastroenterology St James University Hospital INSERM University of Leeds Hopital Robert Debre´ Leeds, UK Paris, France Gabrielle Barnby Neurogenetics Group Wellcome Trust Centre for Human Genetics Oxford, UK Geoffrey Pradella AHRC Research Centre for Studies in Intellectual Property John I Bell The Churchill Hospital University of Oxford Headington Oxford, UK John Trowsdale Immunology Division and Technology Law Department of Pathology University of Edinburgh Cambridge, UK Edinburgh, UK Gianpiero L Cavalleri Jonathan K Pritchard Department of Human Genetics Department of Biology (Galton Lab) The University of Chicago University College London London, UK Chicago IL USA Gillian Smith Jonathan Rees CR-UK Molecular Pharmacology Unit Department of Dermatology Ninewells Hospital & Medical School University of Edinburgh Edinburgh, UK Dundee, UK Harry Campbell Department of Public Health Sciences University of Edinburgh Edinburgh, UK I Sadaf Farooqi CIMR Wellcome Trust/MRC Building Addenbrookes’ Hospital Cambridge, UK Karen P Steel Wellcome Trust Sanger Institute Cambridge, UK K B G Dear National Centre for Epidemiology and Population Health The Australian National University Canberra, Australia Igor Rudan Kopal Tandon School of Public Health Andrija Stampar University of Zagreb Neurogenetics Group Zagreb, Croatia Oxford, UK Wellcome Trust Centre for Human Genetics ix 494 A Wright (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 the trabecular meshwork The trabecular meshwork communicates with the blood stream via the canal of Schlemm and increased resistance in outflow through this structure may contribute to raised IOP and optic neuropathy The trabecular meshwork in POAG patients is not structurally abnormal, in contrast to the situation in PACG Since raised IOP is often absent in POAG, other factors, including disorders of the blood vessels supplying the optic nerve head, or of the retinal ganglion cells (the source of the optic nerve fibres), have been proposed to be of greater importance (Quigley, 2004) Risk factors in POAG include ones related to onset and others related to progression Age is a major risk factor, with prevalence rising steeply from 50.1% before age 30 years to 5–10% or greater in the elderly (Johnstone and Quigley, 2003) A major risk factor for both disease onset and progression is IOP, which in Europeans has a mean of 16 mm Hg and standard deviation of 2.5 mm Hg, but since the distribution is non-normal, 5–7% (rather than 2.5%) of the population has IOP greater than 21 mm Hg, which is often regarded as the upper limit of normal The risk of glaucoma rises with increasing IOP, following a shallow exponential curve with no evident threshold In addition, there is a normal diurnal variation of mm Hg that can reach even higher levels in glaucoma The higher the IOP, the greater the risk of optic nerve damage, and lowering of IOP has been shown to be beneficial in glaucoma whether or not it is elevated (Heijl et al., 2002) Other risk factors for POAG include myopia (short sight), corticosteroid use, which elevates IOP in susceptible individuals, and finally family history It has long been recognised that glaucoma clusters within families One-third to one-half of glaucoma and ocular hypertensive (raised IOP) patients have a family history of the same disorder (Williams-Lyn et al., 2000) First-degree relatives of POAG patients have a 7–10-fold increased risk compared with the general population (Tielsch et al., 1991) The mode of inheritance is multifactorial, although rare families with an autosomal dominant mode of inheritance can be found, often with onset at a young age, either in juveniles or young adults No large-scale twin or adoption studies have been reported in POAG, so that familial resemblance due to shared environmental factors is not excluded Further evidence for a genetic influence in POAG however comes from the fourfold increased risk in those of black African origin, which applies equally to Tanzanian villagers and East Baltimore residents, despite radically different environments (Buhrmann et al., 2000) Seven genes (GLC1A-G) have been mapped in POAG families showing apparently monogenic forms of glaucoma, two of which have been identified (Stone et al., 1997; Rezaie et al., 2002; Gong et al., 2004) The myocilin (MYOC) gene was the first to be identified by positional cloning, following linkage mapping of the GLC1A locus to chromosome 1q24.3-q25.2 in autosomal dominant juvenile-onset open angle glaucoma (JOAG) families (Stone et al., 1997) Over 70 diseasecausing MYOC mutations have since been identified in POAG patients with both juvenile and adult onset (Gong et al., 2004) Disease-causing MYOC mutations have been found in unselected POAG patients at a similar frequency in different ethnic groups – 4% of POAG or normal-tension glaucoma patients of White origin, 3.3% of black African origin and 4.4% of Asian origin (Gong et al., 2004) The majority of these mutations are not found in controls, but two are also present at low frequency in controls The Gln368Stop mutation is found in 2–3% of Caucasian POAG patients and about 0.3–0.4% of controls, contributing almost one-half of all White POAG mutations, although it is very rare in other ethnic groups (Stone et al., 1997; Gong et al., 2004) There has been uncertainty as to whether this variant is disease-causing or disease-modifying, since it has been found in Common forms of visual handicap unaffected controls Family studies show that the relative risk of POAG in a Gln368Stop carrier is 13.1, consistent with this being a major diseaserisk allele, although the age-of-onset tends to be later than with other POAG variants (Gong et al., 2004) The other common mutation, Arg46Stop, is found in about 1% of Asian POAG patients, but not in other ethnic groups In family studies, it confers a relative risk of 5.4 (P ¼ 0.1) for developing POAG, suggesting that it does influence POAG risk, although the numbers are small and the confidence limits wide (Gong et al., 2004) The function of myocilin is uncertain It was originally found in trabecular meshwork cells when induced by glucocorticoids (Nguyen et al., 1998) It is widely expressed although is most abundant in the iris, ciliary body and trabecular meshwork (Aroca-Aguilar et al., 2005) It is a 55 kDa protein with a signal peptide, which may or may not be active, and an amino (N)-terminal double stranded coiled-coil leucine zipper domain, which is a protein structure well suited to protein interactions and is involved in myocilin dimerisation This is followed by a domain of unknown function and then a distinct carboxyl (C)-terminal domain similar to olfactomedin, an extracellular matrix protein of unknown function Mature myocilin forms multimers and the normal protein is secreted into the trabecular extracellular matrix (ECM) where it appears to interact with various ECM components The majority of POAG mutations occur in the olfactomedin domain, at least some of which are known to inhibit endoproteolytic cleavage of the protein into a secreted 35 kDa protein that is present in aqueous humour (Aroca-Aguilar et al., 2005) The mutant protein is retained in the endoplasmic reticulum and in transfected cells forms insoluble aggregates This may lead to loss of trabecular meshwork cells and raised IOP although the pathway between genotype and phenotype is complex A second reported POAG gene is optineurin (OPTN, GLC1E) (Rezaie et al., 2002), however, follow-up studies indicate that OPTN mutation is a rare cause of both POAG and normal tension glaucoma, probably accounting for less than 0.1% of all POAG (Wiggs et al., 2003; Alward et al., 2003) Another gene, CYP1B1, appears to be a POAG modifier gene Affected members of an autosomal dominant POAG family carrying a Gly399Val mutation in MYOC, together with an Arg368His mutation in the CYP1B1 gene (previously associated with primary congenital glaucoma, PCG), had juvenileonset open angle glaucoma The mean age at onset of POAG was 27 years (23–38 years) in CYP1B1 mutation carriers compared with 51 years (48–64 years) in non-carriers (Vincent et al., 2002) CYP1B1 is a member of the cytochrome P450 family which is thought to metabolize as yet unknown molecules critical for anterior chamber development (Stoilov et al., 1997) All of the above POAG loci were mapped or identified using single extended kindreds, in which the disease was consistent with autosomal dominant inheritance with high penetrance In the great majority of cases, POAG is not a single gene disorder but a complex trait, where multiple loci are presumed to interact with the environment and with each other to influence the cause or progression of the disease Although some preliminary genome-wide scans have been carried out in large numbers of POAG families, none has unambiguously mapped a disease-causing locus The likely genetic heterogeneity adds an extra degree of difficulty in identifying susceptibility genes 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 meshwork 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 remain unknown 495 496 A Wright Age-related 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 photoreceptors 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 region of maximal visual acuity, which contains the highest density of cone photoreceptors and 25% of all ganglion cells, the output cells from retina to brain (Hendrickson, 2005) (Figure 32.1) The importance of this region is emphasised by the fact that 40% of the primary visual cortex processes the central 1.5 mm diameter area of the fovea (Hendrickson, 2005) The macula also contains large numbers of rod photoreceptors, although these are absent from the central fovea (Figure 32.1) In the retina overall, rod photoreceptors outnumber cones by 20:1, and are exquisitely sensitive to light, but show poor spatial resolution AMD is the late stage of a condition called agerelated maculopathy (ARM), which is present in about 5% of individuals at age 60 years, rising to about 30% at age 80 (Evans, 2003) The prevalence of AMD increases from 6% at ages 65–74 years to 11% at ages 75–84 years ARM is characterized by both diffuse (basal) and focal (drusen) extracellular deposits within the macula The reason for loss of (cone and rod) photoreceptor function within the macula is usually the presence of a long-standing disease process within the adjacent retinal pigment epithelium (RPE) RPE cells have an intimate metabolic, nutritional and trophic relationship with the overlying photoreceptors, including the supply and recycling of retinoids, phagocytosis of photoreceptor outer segments and release of neurotrophic factors required for maintenance of the choroidal vasculature and photoreceptors The precise sequence of events remains uncertain but a plausible scenario would be that RPE cells and adjacent choroidal capillaries become increasingly compromised by age-associated oxidative damage, leading to exposure of modified self antigens, such as cross-linked or oxidized lipids and proteins, and activation of the alternative complement pathway The resultant auto-immune attack leads to extracellular sub-RPE deposit formation and further changes within the RPE and choroidal vasculature, including growth of immature and fragile choroidal blood vessels through the thickened sub-RPE deposits, which leak and later bleed into the central retina (choroidal neovascularization, CNV) This results in a catastrophic loss of central vision (Penfold and Provis, 2005) This model is largely based on recent genetic findings that strongly implicate the alternative complement pathway, which is discussed below Both diffuse and focal deposits in ARM lie between a structure called Bruch’s membrane and the RPE (Figure 32.1) Bruch’s membrane is a pentalaminar basement membrane consisting of the basal lamina of the RPE, an inner collagenous layer, a central elastin layer, an outer collagenous layer and the basal lamina of the underlying choroidal capillaries Blood flow through the choroidal capillaries nourishes the RPE, macula and outer retina (including the photoreceptor layer) and is one of the highest in the body (85% of ocular blood flow goes to the choroid compared with 4% to the retina) The composition of the focal sub-RPE deposits, called drusen (literally ‘‘bumps’’) is known to include over 100 different proteins, as well as a variety of lipids such as cholesterol (Crabb et al., 2002) However, one of the more abundant classes of proteins is a variety of complement components and complement regulatory proteins, including acute phase proteins, which form part of the innate immune system, the body’s first line of defence against microbial invaders The composition of the diffuse or basal sub-RPE deposits is less clear but again includes complement fragments and complement regulatory molecules as well as proteinaceous and lipid debris Common forms of visual handicap There are two major types of basal deposit Firstly, deposits that lie between RPE and its basal lamina (called basal laminar deposits), which are different in composition from drusen, accumulate strongly with age, and have a less clear relationship to AMD-associated blindness than the second type, called basal linear deposits The latter occur between the RPE basal lamina and inner collagenous layer of Bruch’s membrane, resemble drusen in composition and are strongly associated with AMD There are a number of well established risk factors for AMD The major risk factor is age Western populations have an eight- to tenfold increased risk of AMD at age 90 years compared with age 50 years (Evans, 2003) The exponential increase in age-specific prevalence of both ARM and AMD is reminiscent of many age-associated disorders A recent study of 897 elderly individuals in Iceland showed that 58% of those at least 80 years of age and all centenarians had either mild or severe forms of AMD (Geirsdottir et al., 2005) This confirms the observation that the accumulation of both diffuse and focal sub-RPE deposits with age is nearly universal, and suggests that other risk factors merely accelerate or delay the inevitable Other well-established risk factors include family history, smoking (odds ratio 2–3), raised levels of C-reactive protein, genetic variation at the APOE locus (odds ratio 0.5 for E4 allele) and ethnicity Less well established risk factors include exposure to bright light, dietary and plasma levels of antioxidants, endogeneous and exogenous oestrogens (Evans, 2003) The heritability of ARM and AMD has been investigated in two large twin studies (Hammond et al., 2002; Seddon et al., 2005) Both studies examined population based twin cohorts (UK, USA) and compared the prevalence of ARM or AMD in monozygotic (N ¼ 226, 210) compared with dizygotic (N ¼ 280, 181) twin pairs In the US study, the age range of twins was 76–86 years, and the age-corrected estimates of heritability arising from additive effects varied from 0.53 to 0.73, depending on disease grading and comparisons, while the contribution of unique environmental factors was 0.20–0.33 (Seddon et al., 2005) Shared environmental factors were not found to be statistically significant In the second study, the concordance for ARM in MZ twins was 0.37, compared with 0.19 for DZ twins, and the heritability was 0.45 (Hammond et al., 2002) Non-shared environment accounted for half (0.51) of the total variation in ARM Genetic influences in age-related macular degeneration Extracellular matrix proteins The fibulin family of secreted extracellular matrix (ECM) proteins consists of six members (fibulin1–6) which share a modular, elongated structure, including a central region with 5–11 calcium binding epidermal growth factor (cbEGF) domains and characteristic amino (N) and carboxyl (C) terminal domains (Timpl et al., 2003) The importance of the high extracellular calcium concentration ($1 mM) to fibulins and other ECM proteins is emphasised by their changed structural and functional properties in its absence (Timpl et al., 2003) The fibulins are thought to stabilise supramolecular ECM structures, such as basement membrane networks and elastic fibres, and to link such structures to cells Two members of this family have been implicated in AMD or AMD-like disorders (Stone et al., 1999; 2004) A heterozygous founder mutation in the fibulin-3 gene (EFEMP1), which changes a conserved arginine to a tryptophan residue at position 345 (Arg345Trp), was found in families with a rare autosomal dominant condition called Doyne honeycomb retinal dystrophy (DHRD, also called Malattia Leventinese) The retina in this condition shows multiple macular drusen, resembling a mosaic or honeycomb, similar to those seen in AMD, but causing severe visual loss in young adults The EFEMP1 gene is widely expressed but shows highest expression in the eye (especially 497 498 A Wright choroid/RPE), in certain capillaries and endothelial cells and in the lung (Stone et al., 1999; Giltay et al., 1999) The protein appears to be secreted from RPE cells although it does not normally localise to Bruch’s membrane or choroid, or to the drusen found in DHRD (Marmorstein et al., 2002) Curiously, while it is normally found in the interphotoreceptor matrix surrounding photoreceptors and at their synaptic terminals, in both DHRD and AMD retinas it is present as an abnormal extracellular deposit between RPE and Bruch’s membrane, in regions where there are overlying drusen The Arg345Trp mutant fibulin-3 was shown to be misfolded and to accumulate within RPE cells, rather than being secreted, suggesting that it may aggregate and compromise these cells The fivefold lower rate of secretion of mutant protein may still be sufficient to form extracellular aggregates, which could reduce cellmatrix adhesion and become the target of immune attack and drusen formation (see below) Extracellular aggregates would be expected to form on the apical or retinal side of the RPE, rather than the Bruch’s membrane or basal side, but either the mutant protein is not extruded by normal secretory mechanisms or RPE polarity is altered A variety of rare amino acid changing (missense) mutations have been found in evolutionarily conserved residues of the fibulin-5 gene (FBLN5) in 1–2% of AMD patients and no controls (Stone et al., 2004; Lotery et al., 2005) All of these FBLN5 mutations, which span the entire protein, together with a single Gln5346Arg variant in the FBLN6 gene, are associated both with a specific type of drusen, called cuticular or basal laminar drusen, and with RPE detachments, which are together present in about 20% of AMD subjects (Stone et al., 2004) The FBLN5 gene is expressed widely, including RPE cells and the elastic lamina of arteries, and its binding to both integrins and tropoelastin suggests that it connects extracellular elastin fibres to cells (Argraves et al., 2003) Fibulin5 has a single RGD (Arginine-Glycine-Aspartate) motif in the N-terminal domain which promotes cell adhesion by interaction with avb3, avb5 and a9b1 integrins (Nakamura et al., 2002) Fibulin-5 also interacts both with fibrillin-1, another component of elastic fibres (Freeman et al., 2005) and with extracellular superoxide dismutase (SOD3), which in fibulin-5 deficient mice results in an increase in vascular superoxide formation, which could promote aggregation of ECM proteins (Nguyen et al., 2004) Homozygous deficiency of fibulin-5 in mice and humans is associated with defective elastogenesis and the condition cutis laxa, with loose skin, diverticulosis, pulmonary emphysema and vascular abnormalities (Timpl et al., 2003; Argraves et al., 2003) In contrast, the mutations in the FBLN5 gene associated with AMD were heterozygous and suggested a gain-of-function phenotype Although the disease mechanism remains to be fully elucidated, it was suggested that, similar to DHRD, impaired RPE secretion of mutant proteins could lead to haploinsufficiency and impaired adhesion between elastin, a major component of Bruch’s membrane, and RPE cells, either directly or indirectly via integrin-mediated cell attachment (Stone et al., 2004) Two other rare autosomal dominant forms of macular degeneration with sub-RPE deposits and clinical features resembling AMD result from mutations affecting the ECM proteins TIMP-3 and C1QTNF5 respectively (Weber et al., 1994; Hayward et al., 2003) Mutations in the tissue inhibitor of metalloproteinases or TIMP3 gene give rise to Sorsby fundus dystrophy, which is associated with sub-RPE deposits and macular degeneration resembling AMD TIMP3 is involved in ECM remodeling and has been shown to inhibit matrix metalloproteinases, to bind fibulin-3 and to competitively inhibit binding of vascular endothelial growth factor (VEGF) to one of its receptors (VEGFR2 or KDR) (Qi et al., 2003; Klenotic et al., 2004) VEGF is a potent enhancer of angiogenesis and vascular permeability which is implicated in the choroidal neovascularisation of AMD It remains unclear whether some or all of these mechanisms are operative in the sub-RPE deposit Common forms of visual handicap formation or neovascularisation seen in Sorsby fundus dystrophy Similarly, the precise disease mechanism is unclear in late-onset retinal macular degeneration (L-ORMD), which closely resembles Sorsby fundus dystrophy and the common neovascular or ‘‘wet’’ form of AMD (Ayyagari et al., 2000; Hayward et al., 2003) This disorder is caused by a founder mutation in the short-chain collagen gene C1QTNF5, which leads to formation of high molecular weight aggregates and failure of C1QTNF5 protein secretion by RPE cells into the ECM (Hayward et al., 2003; Shu et al., 2006) The innate immune system: complement factor H Three studies reported a strong association between AMD and a polymorphism within the CFH gene encoding complement factor H (CFH) (Klein et al., 2005; Edwards et al., 2005; Haines et al., 2005) In each report, an association was found between a common CFH amino acid substitution changing a conserved tyrosine to histidine residue (Tyr402His) within the seventh short consensus repeat (SCR) module of CFH CFH is a modular protein with 20 SCR domains showing different binding specificities, which down-regulates the alternative complement activation pathway A single copy of the Tyr402His allele was associated with a two- to three fold increased risk of AMD compared with unaffected controls, while two copies were associated with a 6–7 fold increased risk of AMD in case-control studies Two of the three studies identified the CFH variant in the course of following up a linkage signal on chromosome 1q31, which was found in several whole genome scans of affected sib pairs with AMD (Fisher et al., 2005) These studies carried out case-control association studies using single nucleotide polymorphism (SNP) markers spanning the region (Haines et al., 2005; Edwards et al., 2005) The third study carried out a whole genome scan in 96 AMD cases and 50 controls using 103,611 SNPs, with an average density of SNP every 30 kilobases (kb) (Klein et al., 2005) In the latter study, a remarkable result was obtained in which only two SNPs showed statistically significant associations with AMD (P54.8 Â 10À7) after using a conservative Bonferroni correction for multiple testing One of these SNPs was excluded, leaving a single associated SNP located within an intron of the CFH gene Both SNPs lay within a 500 kb block of strong linkage disequilibrium within the study sample, which is about tenfold larger than is typical for the human genome This block contains the entire Regulator of Complement Activation (RCA) gene cluster, which includes seven complement regulatory genes, CFH, FHL1 and FHR1–5 The authors subdivided this region further, using data from the normal population, and identified a high risk SNP-haplotype spanning only the CFH gene, which conferred either a 4.6-fold or 7.4-fold increased risk of AMD in heterozygotes and homozygotes respectively The entire CFH gene was then sequenced in 93 controls to identify all common variants This identified 50 variant sites, three of which were predicted to change the amino acid sequence of the protein (non-synonymous substitutions), including the Tyr402His substitution within exon (SCR module 7), which was present in 97% of the high risk haplotypes and showed the strongest association with AMD (Klein et al., 2005) In an independent data set, the AMD risk for Tyr402His (CC) homozygotes, who represented 12% of this population, increased from about 20% in the general population to 54% (2.4-fold increase): in CT heterozygotes it was only marginally increased (22%), while in low risk (TT) homozygotes it was more than halved (9%) (data from Zareparsi et al., 2005) Strong supporting evidence also implicates the CFH gene in AMD Firstly, CFH protein is present in choroidal blood vessels and in an area bordering RPE cells adjacent to Bruch’s membrane (Klein et al., 2005) Secondly, CFH is a key regulator of the alternative complement activation pathway, suggesting that risk alleles such as 402His may be less effective than 402Tyr in down-regulating the complement pathway, which could lead to 499 500 A Wright inappropriate activation and autoimmune damage to host tissues such as RPE and the choroidal vasculature CFH is secreted in large amounts by the liver into the plasma which coats host cells and ECM surfaces The alternative complement activation pathway normally shows continuous low level activation, by conversion of C3 to C3b by the C3 convertase (C3bBb) If C3b is formed in sufficient quantities, it leads to amplification of a destructive cascade with opsonization and phagocytosis of cells and lysis of target cells by formation of the terminal C5b-9 membrane attack complex (MAC) (Rodriguez de Cordoba et al., 2004) This is therefore tightly controlled, both at the level of the cell membrane, by means of a group of membrane proteins (DAF, MCP, CR1, CD59), and by fluid phase regulators, particularly plasma CFH, which is continuously required to suppress C3b formation CFH acts by promoting the decay of the C3 convertase (C3bBb) and by acting as a cofactor in the proteolytic inactivation of C3b by factor I CFH is also synthesised outside the liver by tissues such as RPE and vascular endothelium, which appears to boost the local protection of tissues lacking membrane bound complement regulators The binding of CFH to host as opposed to activator (e.g pathogen) cell surfaces is complex and involves binding of at least three SCR modules (SCR3, SCR13, SCR20) to host polyanionic heparin or sialic acid molecules, as well as other SCRs, using binding patterns that are unique to different activators (Pangburn et al., 2000) Several common pathogens have developed receptors capable of binding CFH to escape detection, including Streptococcus pyogenes and pneumoniae, which bind SCR7, containing the Tyr402His variant (Rodriguez de Cordoba et al., 2004) It is possible that this variant, which is predicted to alter the function of SCR7 (Rodriguez de Cordoba et al., 2004), reduces the inhibitory effects of CFH on complement activation, perhaps as a result of natural selection to enhance complement lysis of such pathogens A scenario in which both residues (402Tyr and 402His) have a selective advantage in the face of different microbial infections could lead to a balanced polymorphism, with maintenance of both alleles at high frequency The penalty could be a less stringent inhibition of complementmediated attack in later life, when synthesis of CFH by liver or RPE declines Homozygous loss-of-function mutations in the CFH gene lead to the rare condition type II membranoproliferative glomerulonephritis, which is associated with childhood onset of renal failure, electron-dense deposits under the renal glomerular basement membrane and, in 10% of patients, early-onset AMD with typical macular drusen and visual loss (Appel et al., 2005) The glomerular podocytes lack membrane-bound complement regulators and so rely heavily on CFH to prevent complement activation The glomerular capillary tuft-basal lamina-podocyte resembles the choroidal capillary–Bruch’s membrane–RPE interface in its very high blood flow, the presence of fenestrated capillaries and the intimate contact between blood and the basal laminae of both RPE and podocytes (Appel et al., 2005) This anatomical arrangement allows fast passage of fluids and large molecules (570 kD in size, including protein-bound vitamin A), into and out of the retina, but perhaps contributes to the vulnerability of both sites to inflammatory attack and complement-mediated damage (Marshall et al., 1998) Many intriguing questions remain regarding the molecular pathology of AMD One possible model emerging from the recent CFH findings is that, during ageing, RPE cells become increasingly detached from their basal lamina, which is aggravated by immune deposits Bruch’s membrane shows a linear increase in thickness with age, which is most marked in the macula, as a result of the build up of membrane, protein and lipid debris (Marshall et al., 1998) Loss of cell adhesion can have wide ranging consequences, including altered signal transduction and changes in gene expression, differentiation, polarity, cell survival and apoptosis (Yamada and Geiger, 1997) Reduced expression of CFH and its shorter isoform, FHL1, both of which are synthesised by RPE cells (Hageman et al., 2005) could follow, leading to Common forms of visual handicap increased complement activation, drusen formation and a vicious cycle of sub-RPE deposit formation and complement-mediated damage Why is the macula the preferred site of such damage? The density of metabolically active photoreceptors associated with each RPE cell is highest in this region, the choroidal blood flow and pO2 are also higher than elsewhere in the retina and the central retina is most exposed to light and oxidative damage In short, RPE cells in the macula may have the greatest exposure to a variety of oxidative, inflammatory, physical and other stresses throughout life, making them highly vulnerable to agerelated damage The number of individuals over the age of 60 years is expected to triple from about 600 million in 2000 to billion by 2050 so that, in the developed world, they are predicted to constitute about onethird of the population (United Nations, 2001) The burden of age-related blindness is therefore set to increase accordingly This will impose a substantial burden on our health care systems, emphasising the need for urgency in developing improved methods of prevention and care These are likely to be informed by the results of genetic studies of such conditions, which are already clarifying our understanding of disease pathogenesis Acknowledgements I would like to thank Dr Andrew Carothers for helpful discussions REFERENCES 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: physiological and disease perspectives EMBO Rep, 4, 1127–31 Aroca-Aguilar, J D., Sanchez-Sanchez, F., Ghosh, S., Coca-Prados, M and Escribano, J (2005) Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids Arg226 and Ile227 J Biol Chem, 280, 21043–51 Ayyagari, R., Griesinger, I B., Bingham, E et al (2000) Autosomal dominant hemorrhagic macular dystrophy not associated with the TIMP3 gene Arch Ophthalmol, 118, 85–92 Buhrmann, R R., Quigley, H A., Barron, Y et al (2000) Prevalence of glaucoma in a rural East African population Invest Ophthalmol Vis Sci, 41, 40–8 Congdon, N G and Taylor, H R (2003) Age-related cataract In Johnson, G J., Minassian, D C., Weale, R A and West, S K (eds.), The epidemiology of eye disease, pp.105–19 London: Arnold Conley, Y P., Erturk, D., Keverline, A et al (2000) A juvenile-onset, progressive cataract locus on chromosome 3q21-q22 is associated with a missense mutation in the beaded filament structural protein-2 Am J Hum Genet, 66, 1426–31 Crabb, J W., Miyagi, M., Gu, X et al (2002) Drusen proteome analysis: an approach to the etiology of agerelated macular degeneration Proc Natl Acad Sci USA, 99, 14682–7 Delaye, M and Tardieu, A (1983) Short-range order of crystallin proteins accounts for eye lens transparency Nature, 302, 415–17 Edwards, A O., Ritter, R., 3rd, Abel, K J et al (2005) Complement factor H polymorphism and age-related macular degeneration Science, 308, 421–4 Evans, J (2003) Age-related macular degeneration In Johnson, G J., Minassian, D C., Weale, R A and West, S K (eds.), The epidemiology of eye disease, pp 356–69 London: Arnold Fisher, S A., Abecasis, G R., Yashar, B M et al (2005) Meta-analysis of genome scans of age-related macular degeneration Hum Mol Genet, 14, 2257–64 Francis, P., Berry, V., Bhattacharya, S and Moore, A (2000) Congenital progressive polymorphic cataract caused by a mutation in the major intrinsic protein of the lens, MIP (AQP0) Br J Ophthalmol, 84, 1376–9 Freeman, L J., Lomas, A., Hodson, N et al (2005) Fibulin5 interacts with fibrillin-1 molecules and microfibrils Biochem J, 388, 1–5 501 502 A Wright Geirsdottir, A., Stefansson, E., Jonasson, F et al (2005) Do all individuals with a family history of age-related maculopathy (ARM) develop age-related macular degeneration (AMD) if they live to be 100 years old? 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increase with each decade of life, until 40% of the 71À80 years age group and 80% of the 80ỵ age group have a hearing loss of 35 dB or more (Davis, 1989; Davis and Moorjani, 2002) In total, approximately 20% of all adults over 18 in the UK suffer some form of hearing impairment (25 dB or greater hearing loss in at least one ear), and the proportions for other countries are very similar (Davis and Moorjani, 2002) The increase at various impairment levels is illustrated in Figure 33.1 However, thresholds are a crude reflection of the impairment, because it is not just the amplitude but the clarity of hearing that is affected Our ability to distinguish speech sounds, to focus on specific sound sources such as one speaker in a noisy room, and to localize sounds in the environment all require accurate frequency and temporal discrimination, features that are disproportionately affected by hearing impairment Much hearing loss with age affects sensitivity to high frequencies first, although some types of hearing loss have a more even effect across the frequency spectrum Figure 33.3 illustrates typical hearing levels in age-related progressive hearing loss (Rosenhall, 2002) Mechanisms of hearing impairment 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 extracellular Figure 33.1 Prevalence of hearing loss (HL) with age, for different severities in decibels (db) 505 506 K P Steel Figure 33.2 Anatomy of the cochlea Cross section through the cochlear canal showing the organ of Corti (OC) on the floor of the endolymph (el) filled cochlear duct with the stria vascularis (SV) on the lateral wall and perilymph (pl) filled scala vestibuli and scala tympani (upper figures) Cross section of cochlear duct (scala media) showing the tectorial membrane (tm), inner hair cells (ihc), pillar cells (p); outer hair cells (ohc), Dieter’s (d), Hensen’s (h) and Claudius’ (c) cells, outer sulcus (os), inner sulcus (is), spiral ligament (sl), spiral limbus (slm), interdental cells (i), marginal (m), basal (b) and intermediate (i) cells (lower figure) links between them When the stereocilia (or hair) bundle is deflected by incoming vibration, one type of link, the tip link, mechanically opens the transduction channel allowing rapid influx of cations into the cell Hair cell function depends upon precise control of the environment, and specialized supporting cells within the organ of Corti and cellular structures around the cochlear duct serve this function For example, the stria vascularis on the lateral wall pumps out potassium into the fluid bathing the tops of the hair cells, generating a high potassium concentration and a high resting potential, the endocochlear potential, which are both essential for hair cell function (Figure 33.2) It is frequently stated that age-related hearing loss is due to degeneration of the sensory hair cells in the organ of Corti of the cochlea However, there is no evidence for this contention from animal studies Rather, it appears that hair cell degeneration is a correlate or a consequence of some primary dysfunction, either of hair cells or of some other part of the auditory system Genetic/environmental influences on hearing impairment Figure 33.3 Typical audiograms of 70À80 years old, sensory type Hearing loss (HL) is shown in decibels (db) These sensory hair cells seem to be particularly sensitive to any disturbance of their homeostasis, resulting in their degeneration However, findings in animal models suggest that hearing impairment correlates with hair cell function rather than with hair cell death, as there can be plenty of surviving but dysfunctional hair cells in a mouse with a Tmc1 or a Cdh23 mutation, or in a mouse with a mutation affecting cochlear homeostasis Even with noise-induced damage, cochlear responses correlate better with stereocilia bundle damage than with hair cell death (e.g Holme and Steel, 2004) Mature mammalian hair cells in the cochlea never regenerate, so hair cell loss accumulates with age and this can be observed in human temporal bone specimens from people with hearing impairment However, donated human inner ears generally represent the end-stage of a long disease process Schuknecht and Gacek (1993) proposed several different fundamental types of hearing loss based on observations of many temporal bones and audiograms of people with progressive hearing loss with age (also known as presbyacusis) The most common type was sensory presbyacusis, characterised by the steeply sloping audiogram with poor thresholds at high frequencies, as illustrated in Figure 33.3, with associated hair cell loss at the basal end of the cochlear duct (the region normally involved in high frequency detection) The second type was strial presbyacusis, with more equal hearing loss across the frequency range and atrophy of the stria vascularis, a structure on the lateral wall of the cochlear duct that pumps high levels of potassium into the fluid bathing the upper surface of the hair cells and generates a high resting potential in this fluid A third type, neural presbyacusis, was rare but showed loss of cochlear neurons leading to limited threshold increases but difficulty in speech discrimination This is a useful first step in grouping pathological mechanisms However, as we discover more of the genes underlying hearing impairment (see later), and understand more about their involvement in the pathological process, it is becoming clear that there are dozens, maybe hundreds, of different ways that hearing can be compromised Furthermore, other parts of the auditory system can be involved in progressive hearing loss, such as the middle ear (Browning and Gatehouse, 1992; Rosowski et al., 2003) Cognitive decline with age may interact with hearing impairment to exacerbate the functional disability in the elderly population, but the vast majority of cases of hearing loss are the result of a pathological process affecting the inner or middle ear (mainly the inner ear) rather than an effect of the central auditory system alone 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 programming of hearing aids to facilitate use of 507 508 K P Steel these cues The threshold for provision of a hearing aid is often considered to be around 25 dB hearing level, although many people are not fitted with an aid until their hearing is much worse than this (Davis and Moorjani, 2002) Second is the cochlear implant, which involves surgery to place an extended array of electrodes within the cochlear duct and a subcutaneous receiver for detecting the coded stimulation and transmitting to the electrode array This is normally considered only for people who have such a profound hearing impairment that they are not helped by hearing aids For example, the vast majority of children fitted with a cochlear implant have hearing loss of 95 dB or more (Fortnum et al., 2002) Both prosthetic approaches require time to adjust, and in the case of cochlear implants, a considerable period of rehabilitation is needed to maximise benefit Neither prosthetic approach is ideal, so there is a need for other approaches to minimise the effects of hearing impairment Understanding the molecular basis of hearing impairment should allow the development of treatments to stop or slow down progression of hearing loss, if not to restore hearing Some preliminary work in animal models suggests that biological agents may be useful, at least if applied at around the time of a damaging stimulus (e.g Wang et al., 2003; Zhai et al., 2004) Treatments might involve some way of triggering regeneration of lost hair cells and their supporting cells, because these cells not regenerate once they die Alternatively, a drug-based approach might allow some degree of transcriptional control, such as upregulating alternative genes to replace dysfunctional elements of the hearing process (e.g Steel, 2000) Slowing down or stopping the advance of a progressive hearing loss seems to be a much more tractable biological problem than developing a treatment to correct an early developmental defect, and most deafness in the human population is progressive, even during early childhood (Fortnum et al., 2001; Johansen et al., 2004) The limited options currently available for hearing-impaired people together with the large numbers of affected individuals argues for further research towards understanding the molecular basis of the disease process 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 aminoglycoside 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 impairment that develops over the few days after exposure to an ototoxic drug or after meningitis, but often it is not so obvious For example, although many studies of noise exposure in animals have shown the deleterious effects of noise on auditory function, such experiments are impossible in humans so we are left trying to piece together a history of noise exposure long after the event The National Study of Hearing in the UK found a small but significant effect of relatively high reported noise exposure on hearing levels, but not for moderate noise exposures, and the effects were very small compared with the effects of age (Davis, 1989) Animal studies have revealed some factors that moderate or potentiate noise-induced hearing loss For example, exposure to certain drugs and chemicals like toluene and styrene or concomitant hyperthermia potentiate noise-induced hearing loss (Davis et al., 2002; Fechter, 2004) Surprisingly, exposure to a stressful stimulus, such as heat stress, restraint stress or moderate noise levels, during the few days prior to the damaging noise exposure can reduce the amount of noise-induced damage (e.g Yoshida et al., 1999; Yoshida and Liberman, 2000) This phenomenon is known as conditioning or toughening ... cisregulatory elements of a gene are modular proteins with distinct domains, including ones for DNA binding and transcriptional activation (‘‘transactivation’’) The DNA binding domain targets the activator... chromatin 20 Donncha Dunican, Sari Pennings and Richard Meehan Population genetics and disease 44 Donald F Conrad and Jonathan K Pritchard Mapping common disease genes 59 Naomi R Wray and Peter M Visscher... Pierre Hainaut Naomi R Wray Queensland Institute of Medical Research PO Royal Brisbane Hospital Brisbane, Australia International Agency for Research on Cancer Lyon, France Renate Gertz Generation