This chapter is about the genetic diagnosis of two of the common- CHROMOSOME 19 est diseases that afflict people, one a swift and merciless killer,...
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Pick a disease talked about in the chapter "Prevention". Talk about genes responsible for the disease. Discuss what factor contribute to early onset and/or progression of the disease. Can it be prevented based on the information learned in the chapter. If yes, how? Finally, talk about how the disease can be diagnosed/ predicted using molecular biology techniques. 

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This chapter is about the genetic diagnosis of two of the common- CHROMOSOME 19 est diseases that afflict people, one a swift and merciless killer, the other a slow and relentless thief of memory: coronary heart disease and Alzheimer's disease. I believe we are in danger of being too 8 8 squeamish and too cautious in using knowledge about the genes that influence both diseases, and we therefore stand at risk of com- mitting the moral error of denying people access to life-saving research. There is a family of genes called the apolipoprotein genes, or APO Prevention genes. They come in four basic varieties, called A, B, C and - strangely - E, though there are various different versions of each on different chromosomes. The one that interests us most is APOE, which happens to lie here on chromosome 19. To understand APOE's job requires a digression into the habits of cholesterol and triglyceride fats. When you eat a plate of bacon and eggs, you absorb much fat Ninety-nine per cent of people don't have an inkling and with it cholesterol, the fat-soluble molecule from which so many about how fast this revolution is coming. hormones are made (see the chapter on chromosome 10). The liver Steve Fodor, president of Affywetrix digests this stuff and feeds it into the bloodstream for delivery to other tissues. Being insoluble in water, both triglyceride fats and cholesterol have to be carried through the blood by proteins called The improvement of any medical technology confronts our species lipoproteins. At the beginning of the journey, laden with both choles- with a moral dilemma. If the technology can save lives, then not to terol and fats, the delivery truck is called VLDL, for very-low- develop it and use it is morally culpable, even if there are attendant density lipoprotein. As it drops off some of its triglycerides, it risks. In the Stone Age, we had no option but to watch our relatives becomes low-density lipoprotein, or LDL ('bad cholesterol"). die of smallpox. After Jenner had perfected vaccination we were Finally, after delivering its cholesterol, it becomes high-density lipo- derelict in our duty if we did so. In the nineteenth century, we had protein, HDL (good cholesterol') and returns to the liver for a no alternative to watching our parents succumb to tuberculosis new consignment. After Fleming found penicillin we were guilty of neglect if we failed The job of APOE's protein (called apo-epsilon) is to effect an to take a dying tubercular patient to the doctor. And what applies introduction between VLDL and a receptor on a cell that needs on the individual level applies with even greater force on the level some triglycerides; APOB's job (or rather apo-beta's) is to do the of countries and peoples. Rich countries can no longer ignore the same for the cholesterol drop-off. It is easy to see therefore that epidemics of diarrhoea that claim the lives of countless children in APOE and APOB are prime candidates for involvement in heart poor countries, because no longer can we argue that nothing medi disease. If they are not working, the cholesterol and fat stay in the cally can be done. Oral rehydration therapy has given us a conscience bloodstream and can build up on the walls of arteries as atheroscler Because something can be done, so something must be done. osis. Knockout mice with no APOE genes get atherosclerosis even

on a normal mouse diet. The genes for the lipoproteins themselves Heart disease is a preventable and treatable condition. Those and for the receptors on cells can also affect the way in which with the Ez gene in particular are acutely sensitive to fatty and cholesterol and fat behave in the blood and thereby facilitate heart cholesterol-rich diets, or to put it another way, they are easily treated attacks. An inherited predisposition to heart disease, called familial by being warned off such diets. This is extremely valuable genetic hypercholesterolaemia, results from a rare 'spelling change' in the knowledge. How many lives could be saved, and early heart attacks gene for cholesterol receptors.' averted, by simple genetic diagnosis to identify those at risk and What marks APOE out as special is that it is so 'polymorphic'. target treatment at them? Instead of us all having one version of the gene, with rare exceptions, Genetic screening does not automatically lead to such drastic APOE is like eye colour: it comes in three common kinds, known solutions as abortion or gene therapy. Increasingly a bad genetic as Ez, E; and E4. Because these three vary in their efficiency at diagnosis can lead to less drastic remedies: to the margarine tub and removing triglycerides from the blood, they also vary in their suscep the aerobics class. Instead of warning us all to steer clear of fatty tibility to heart disease. In Europe, A; is both the 'best' and the foods, the medical profession must soon learn to seek out which commonest kind: more than eighty per cent of people have at least of us could profit from such a warning and which of us can relax and one copy of Es and thirty-nine per cent have two copies. But the hit the ice cream. This might go against the profession's puritanical seven per cent of people who have two copies of Ey are at markedly instincts, but not against its Hippocratic oath. high risk of early heart disease, and so, in a slightly different way, However, I did not bring you to the APOE gene chiefly to write are the four per cent of people who have two copies of Ez. about heart disease, though I fear I am still breaking my rule by But that is a Europe-wide average. Like many such polymor- writing about another disease. The reason it is one of the most phisms, this one shows geographical trends. The further north in investigated genes of all is not because of its role in heart disease, Europe you go, the commoner Ey becomes, at the expense of E; but because of its pre-eminent role in a much more sinister and (E2 remains roughly constant). In Sweden and Finland the frequency much less curable condition: Alzheimer's disease. The devastating of Ey is nearly three times as high as in Italy. So, approximately, is loss of memory and of personality that accompanies old age in so the frequency of coronary heart disease. Further afield, there are many people - and that occurs in a few people when quite young even greater variations. Roughly thirty per cent of Europeans have - has been attributed to all sorts of factors, environmental, at least one copy of E4, Orientals have the lowest frequency at pathological and accidental. The diagnostic symptom of Alzheimer's roughly fifteen per cent; American blacks, Africans and Polynesians, is the appearance in brain cells of 'plaques' of insoluble protein over forty per cent; and New Guineans, more than fifty per cent. whose growth damages the cell. A viral infection was once suspected This probably reflects in part the amount of fat and fatty meat in to be the cause, as was a history of frequent blows to the head. The the diet during the last few millennia. It has been known for some presence of aluminium in the plaques threw suspicion on aluminium while that New Guineans have little heart disease when they eat cooking pots for a while. The conventional wisdom was that genetics their traditional diet of sugar cane, taro and occasional meals of lean had little or nothing to do with the disease. 'It is not inherited,' said bush meat from possums and tree kangaroos. But as soon as they one textbook firmly. get jobs at strip mines and start eating western hamburgers and But as Paul Berg, co-inventor of genetic engineering, has said, 'all chips, their risk of early heart attacks shoots up - much more quickly disease is genetic' even when it is also something else. Pedigrees than in most Europeans.* in which Alzheimer's disease appeared with high frequency were

eventually discovered among the American descendants of some getting Alzheimer's is much higher for white E4/Eys than for black Volga Germans and by the early 1990s at least three genes had been or Hispanic E4/Es - compared with the risk for E;/Egs. Presum- associated with early-onset Alzheimer's disease, one on chromosome ably, susceptibility to Alzheimer's is affected by other genes, which 21 and two on chromosome 14. But a far more significant discovery vary between different races. Also, E4's effects seem to be more in 1993 was that a gene on chromosome 19 seemed to be associated severe among women than men. Not only do more women than with the disease in old people and that Alzheimer's in the elderly men get Alzheimer's, but females who are E4/E; are just as much might also have a partial genetic basis. Quite soon the culprit gene at risk as those who are E4/E4. Among men, having one E; gene was discovered to be none other than APOE itself. reduces risk." The association of a blood-lipid gene with a brain disease should You may be wondering why Ey exists at all, let alone at such high not have come as such a surprise as it did. After all, it had been frequencies. If it exacerbates both heart disease and Alzheimer's, it noticed for some time that Alzheimer's victims quite often had should surely have been driven extinct by the more benign E; and high cholesterol. None the less, the scale of the effect came as a Ez long ago. I'm tempted to answer the question by saying that shock. Once again, the 'bad' version of the gene is E4. In families high-fat diets were until recently so rare that the coronary side-effects that are especially prone to Alzheimer's disease, the chances of were of little importance, while Alzheimer's disease is all but irrele- getting Alzheimer's are twenty per cent for those with no E4 gene vant to natural selection, since it not only happens to people who and the mean age of onset is eighty-four. For those with one E4 have long ago reared their own children to independence, but strikes gene, the probability rises to forty-seven per cent and the mean age at an age when most Stone-Age folk were long dead anyway. But I of onset drops to seventy-five. For those with two E4 genes, the am not sure that is a good enough answer, because meaty and even probability is ninety-one per cent and the mean age of onset sixty- cheesy diets have been around a long time in some parts of the eight years. In other words, if you carry two Zy genes (and seven world - long enough for natural selection to go to work. I suspect per cent of Europeans do), your chances of eventually getting Alz- that E4 plays yet another role in the body, which we do not know heimer's disease are much greater than those of the population at about, and at which it is better than E3. Remember: GENES ARE large. There will still be some who escape either fate - indeed, one NOT THERE TO CAUSE DISEASES. study found an eighty-six-year-old E4/Ey man with all his wits. In The difference between Ey and the commoner Ez is that the many people who show no symptoms of memory loss, the classic 334th 'letter' in the gene is G instead of A. The difference between plaques of Alzheimer's are none the less present, and they are usually E; and Ez is that the 47and 'letter' is a G instead of an A. The worse in E4 carriers than E3. Those with at least one E2 version effect is to give Ez's protein two extra cysteines and E/'s two extra of the gene are even less likely to get Alzheimer's than those with arginines compared with each other, Ey being intermediate. These Ey genes, though the difference is small. This is no accidental side- tiny changes in a gene that is 897 'letters' long are sufficient to alter effect or statistical coincidence: this looks like something central to the way APOE's protein does its job. Quite what that job is remains the mechanism of the disease. obscure, but one theory is that it is to stabilise another protein called Recall that E4 is rare among Oriental people, commoner among tau, which is supposed in turn to keep in shape the tubular 'skeleton" whites, commoner still among Africans and commonest in New of a neuron. Tau has an addiction to phosphate, which prevents it Guinean Melanesians. It should follow that Alzheimer's obeys the doing its job; APOE's job is to keep tau off the phosphate. Another same gradient, but it is not quite so simple. The relative risk of theory is that APOE's job in the brain is not unlike its job in the

blood. It carries cholesterol between and within brain cells so they where there is less certainty, such as the APOE case, the test would can build and repair their fat-insulated cell membranes. A third and be of still less value. You can still - if you are very lucky - have more direct theory is that, whatever APOE's job, the Ey version two Ey genes and live to an old age with no symptoms, just as you has a special affinity for something called amyloid beta peptide, can still - if you are very unlucky - have no Ey genes and get which is the substance that builds up inside neurons of Alzheimer's Alzheimer's at sixty-five. Since a diagnosis of two E4 genes is neither sufferers. Somehow, it assists the growth of these destructive sufficient nor necessary to predict Alzheimer's, and since there is plaques. no cure, you should not be offered the test unless you are already The details will matter one day, but for now the important fact symptomatic. is that we are suddenly in possession of a means of making predict At first I found all these arguments convincing, but now I am tions. We can test the genes of individuals and make very good not so sure. After all, it has been considered ethical to offer people forecasts about whether they will get Alzheimer's disease. The geneti- the test for the HIV virus if they want it, even though AIDS was cist Eric Lander recently raised an alarming possibility. We now (until recently) incurable. AIDS is not an inevitable outcome of know that Ronald Reagan has Alzheimer's, and it seems likely in HIV infection: some people survive indefinitely with HIV infec retrospect that he had the early stages of the disease when he was tion. True, there is in the case of AIDS the additional interest of in the White House. Suppose that some enterprising but biased society in preventing the spread of the infection, which does not journalist, anxious to find some way of discrediting Reagan as a apply to Alzheimer's disease, but it is the individual at risk we are presidential candidate in 1979, had snatched a napkin on which considering here, not society at large. The Nuffield Council addresses Reagan had wiped his mouth and tested the DNA on it (gloss this argument by implicitly making a distinction between genetic over the fact that the test was not then invented). Suppose he had and other tests. To attribute a person's susceptibility to an illness discovered that this second-oldest-ever presidential candidate was to their genetic make-up distorts attitudes, argued the report's author, very likely to develop the disease in his term of office and had Dame Fiona Caldicott. It makes people believe wrongly that genetic printed this finding in his newspaper. influences are paramount and causes them to neglect social and The story illustrates the dangers for civil liberties that genetic other causes; that, in turn, increases the stigma attached to mental testing brings with it. When asked if we should offer APOE tests illness." to individuals curious to know if they will get Alzheimer's, most in This is a fair argument unfairly applied. The Nuffield Council is the medical profession say no. After cogitating on the issue recently, operating a double standard. 'Social' explanations of mental prob- the Nuffield Council on Bioethics, Britain's leading think-tank on lems offered by psychoanalysts and psychiatrists are licensed to such matters, reached the same conclusion. To test somebody for practise on the flimsiest of evidence, yet they are just as likely to a disease that is incurable is dubious at best. It can buy reassurance stigmatise people as genetic ones. They continue to flourish while for those who find themselves with no E4 gene, but at a terrible the great and the good of bioethics outlaw diagnoses that are sup- price: the almost-certain sentence to an incurable dementia for those ported by evidence merely because they are genetic explanations. In with two E4 genes. If the diagnosis were absolutely certain, then striving to find reasons to outlaw genetic explanations while allowing (as Nancy Wexler argued in the case of Huntington's - see the social ones to flourish, the Nuffield Council even resorted to calling chapter on chromosome 4), the test could be even more devastating. the predictive power of the APOE, test 'very low' - bizarre word- On the other hand, it would at least not be misleading. But in cases ing for an eleven-fold difference in risk between the E4/E4s and

the E3/E;s." As John Maddox has commented," citing APOE as frames because architects have not made them big enough for tall a case in point, "There are grounds for suspecting that physicians people to walk through, I wonder myself what my APOE genes are not pursuing valuable opportunities out of diffidence at revealing looks like. Maybe I should have them tested. unwelcome genetic information to their patients . . . but diffidence Testing could be valuable in other ways. At least three new Alz- can be taken too far.' heimer's drugs are in development and testing. One that is already Besides, although Alzheimer's disease is incurable, there are here, tacrine, is now known to work better in those with E; and already drugs that alleviate some of the symptoms and there may Ez genes than in E4 carriers. Again and again the genome drives be precautions of uncertain value that people can take to head it home the lesson of our individuality. The diversity of humanity is off. Is it not better to know if one should take every precaution? its greatest message. Yet there is still a marked reluctance in the If I had two E4 genes, I might well want to know so that I could medical profession to treat the individual rather than the population. volunteer for trials of experimental drugs. For those who indulge A treatment that is suitable for one person may not suit another. in activities that raise their risk of Alzheimer's disease, the test Dietary advice that could save one person's life might do no good certainly makes sense. It is, for example, now apparent that pro- at all to another. The day will come when a doctor will not prescribe fessional boxers who have two E4 genes are at such risk of you many kinds of medicine until he has checked which version of developing early Alzheimer's that boxers are indeed best advised to a gene or genes you have. The technology is already being developed, take a test and not box if they find themselves with two E4s. One in by a small Californian company called Affymetrix among others, to six boxers get Parkinson's disease or Alzheimer's - the microscopic put a whole genome-full of genetic sequences on a single silicon symptoms are similar, though the genes involved are not - by the chip. One day we might each carry with us exactly such a chip from age of fifty, and many, including Mohammed Ali, suffer even which the doctor's computer can read any gene the better to tailor younger. Among those boxers who do get Alzheimer's, the E4 gene his prescription to us." is unusually common, as it is among people who suffer head injury Perhaps you have already sensed what the problem with this and later turn out to have plaques in their neurons. would be - and what is the real reason behind the experts' squeam What is true for boxers may be true for other sports in which ishness about APOE tests. Suppose I do have E4/E4 and I am a the head is struck. Alerted by anecdotal evidence that many great professional boxer. I therefore stand a much higher than average footballers sink into premature senility in old age - Danny chance of contracting angina and premature Alzheimer's disease. Blanchflower, Joe Mercer and Bill Paisley being sad, recent examples Suppose that today, instead of going to see my doctor, I am going from British clubs - neurologists have begun to study the prevalence to see an insurance broker to arrange a new life-insurance policy to of Alzheimer's disease in such sportsmen. Somebody has calculated go with my mortgage, or to get health insurance to cover future that a soccer player on average heads the ball 800 times in a season; illness. I am handed a form and asked to fill in questions about the wear and tear could be considerable. A Dutch study did indeed whether I smoke, how much I drink, whether I have AIDS and find worse memory loss in footballers than in other sportsmen and what I weigh. Do I have a family history of heart disease? - a genetic a Norwegian one found evidence of brain damage in soccer players. question. Each question is designed to narrow me down into a Once more it is plausible that the E4/E4 homozygotes might benefit particular category of risk so that I can be quoted an appropriately from at least knowing at the outset of their careers that they were profitable, but still competitive premium. It is only logical that the specially at risk. As somebody who frequently hits his head on door insurance company will soon ask to see my genes as well, to ask if

I am E4/ E4, or if I have a pair of Egs instead. Not only does it to smoke and drink, even the decision that led to his catching AIDS, fear that I might be loading up on life insurance precisely because was in some sense a voluntary one. His decision to have two E4 I know from a recent genetic test that I am doomed, thus ripping genes at the APO/ gene was not a decision at all; it was determined it off as surely as a man who insures a building he plans to burn for him by nature. Discriminating on the basis of APOE genes is down. It also sees that it can attract profitable business by offering like discriminating on the basis of skin colour or gender. A non- discounts to people whose tests prove reassuring. This is known as smoker might justifiably object to subsidising the premium of a cherry picking, and it is exactly why a young, slim, heterosexual smoker by being lumped with him in the same risk category, but if non-smoker already finds he can get life insurance cheaper than an an E3/E; objected to subsidising the premium of an E4/E4, he old, plump, homosexual smoker. Having two Ey genes is not so would be expressing bigotry and prejudice against somebody who very different. was guilty of nothing but bad luck. 12 Little wonder that in America health-insurance companies are The spectre of employers using genetic tests to screen potential already showing interest in genetic tests for Alzheimer's, a disease staff is less fraught. Even when more tests are available, there will that can be very costly for them (in Britain, where health cover is be few temptations for employers to use them. Indeed, once we basically free, the main concern is life insurance). But mindful of get more used to the idea that genes lie behind susceptibilityes to the fury the industry unleashed when it began charging homosexual environmental risks, some tests might become good practice for men higher premiums than heterosexuals to reflect the risk of employer and employee alike. In a job where there is some exposure AIDS, the industry is treading warily. If genetic testing were to to known carcinogens (such as bright sunlight - the job of lifeguard, become routine for lots of genes, the entire concept of pooled risk, say), the employer may in future be neglecting his duty of care to on which insurance is based, would be undermined. Once my exact his workers if he employs people with faulty ps3 genes. He might, fate is known, I would be quoted a premium that covered the exact on the other hand, be asking applicants to take a genetic test for cost of my life. For the genetically unfortunate, it might prove more selfish motives: to select people with healthier dispositions or unaffordable: they would become an insurance underclass. Sensitive more outgoing personalities (exactly what job interviews are designed to these issues, in 1997 the insurance industry association in Britain to do), but there are already laws against discrimination. agreed that for two years it would not demand genetic tests as a Meanwhile, there is a danger that the hobgoblin of genetic condition of insurance and would not (for mortgages smaller than insurance tests and genetic employment tests will scare us away (100,000) demand to know the results of genetic tests you may from using genetic tests in the interests of good medicine. There is, already have taken. Some companies went even further, saying that however, another hobgoblin that scares me more: the spectre of genetic tests were not part of their plans. But this shyness may not government telling me what I may do with my genes. I am keen last. not to share my genetic code with my insurer, I am keen that my Why do people feel so strongly about this issue, when it would doctor should know it and use it, but I am adamant to the point in practice mean cheaper premiums for many? Indeed, unlike so of fanaticism that it is my decision. My genome is my property and many things in life, genetic good fortune is equitably distributed not the state's. It is not for the government to decide with whom among the privileged as well as the less privileged - the rich cannot I may share the contents of my genes. It is not for the government buy good genes and the rich spend more on insurance anyway. The to decide whether I may have the test done. It is for me. There is answer, I think, goes to the heart of determinism. A person's decision a terrible, paternalist tendency to think that 'we' must have one

policy on this matter, and that government must lay down rules about how much of your own genetic code you may see and whom you may show it to. It is yours, not the government's, and you should always remember that.

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