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Protector Genes

Victor McKusick

Genes and Resistance to Disease. Viktor Boulyjenkov, K. Berg and Yves Christen (eds.). xii + 180 pp. Springer, 2000. $95.

Forty years ago I read a fascinating book by Frederick Bruce Hutt of Cornell University titled Genetic Resistance to Disease in Domestic Animals (1958). It was an eye-opener. At the time the concept of genetic polymorphism was becoming appreciated in its implications for human genetics. Genetic polymorphism had been defined about 1940 by E. B. Ford in words often quoted like a verse of scripture: "The occurrence in the same habitat of two or more forms of a trait in such frequencies that the rarer cannot be maintained by recurrent mutation alone." Attention was being directed to the role of malaria as a selective factor influencing the frequency of the genes for sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. There was great interest in so-called balanced polymorphism, with loss of alleles in the homozygote (or hemizygote, in the case of the X-linked G6PD) being offset by the reproductive advantage enjoyed by heterozygotes for these three genetic defects of the red cell.

What have we learned since then? This collection offers a highly selective view of the current state of knowledge about genes and resistance to disease. It consists of a series of papers presented in February 1999 at a conference in Venice sponsored jointly by the World Health Organization (WHO) and the Ipsen Foundation, with which editors Viktor Boulyjenkov and Yves Christen are respectively associated. In the foreword, they note that although the standard medical approach to genetics has been to tease out risk factors for diseases, recent study of polymorphisms has made it clear that some alleles have beneficial effects. The conference focused on identifying these protective factors.

The papers concern noninfectious disorders (Boulyjenkov is in the Department of Noncommunicable Disease Prevention at WHO), with two exceptions: a review of genetic factors in malaria resistance (whose elucidation had started 40 years earlier) by Lucio Luzzatto and a discussion by Steve J. O'Brien and colleagues of much more recent information on specific human genes that limit AIDS. The other disorders discussed range from age-related macular dystrophy to cancer.

There is much discussion lately of whether heterozygosity for the gene that in its homozygous state causes the rare Stargardt's disease is a risk factor (susceptibility factor) for age-related macular dystrophy (ARMD), a common disorder. Here Philippe Amouyel describes his work demonstrating that carrying the E4 allele of the apolipoprotein E gene (APOE) appears to protect against ARMD. He undertook to study APOE as a candidate gene because drusen (the deposits in Bruch's membrane that are the main clinical retinal markers of ARMD) have a lipid component and APOE is involved in lipid transport. In Amouyel's study, the APOE E4 allele was found less often in patients with exudative ARMD, and the relative risk of developing exudative ARMD was almost fivefold higher for those who did not carry the E4 allele than for those who did. Therefore, despite being disadvantageous in terms of cardiovascular disease and Alzheimer's disease, the E4 allele is advantageous for ARMD.

Two articles take as their subject susceptibility (or resistance) to cancer. C. Roland Wolf discusses genetic differences in the handling of exogenous carcinogens, pointing out that our relative levels of the proteins expressed by genes that have evolved to protect against chemical toxicity (or to repair damage and prevent cell death) will determine our sensitivity or resistance to these agents. The paper focuses on genes involved in metabolizing and disposing of xenobiotic chemicals, such as those in the cytochrome P450 gene families. In another article, John J. Mulvihill reviews genes that protect against cancer and tumor suppressor genes.

In the cardiovascular realm, Kåre Berg discusses the possible relationship between atherosclerosis and variation in the cholesteryl ester transfer protein (CETP). Fran?ois Cambien reviews more generally the topic of candidate gene polymorphism and cardiovascular pathophysiology. He emphasizes the need not only for refined genotyping for polymorphism detection but also (and equally importantly) for more, and more accurate, phenotyping:

It is neglected at the moment, because the genetic side is attracting most of the attention and money; however, the naivete of an approach focussed mainly on the genotyp will rapidly become obvious. mRNA, cellular and circulating proteins, cellular and physiological functions, preclinical measurements and well-defined clinical sub-entities will be required for assessing the importance of candidate gene polymorphisms.

Colin L. Masters and Konrad Beyreuther discuss the genetic basis of resistance to Alzheimer's disease. I was taken aback by their initial statement that "There are two classes of adverse risk factors for Alzheimer's disease (AD): increasing age and genetics." The age-dependence of this disease is well known, and it seems unusual to view it as a risk factor. However, they point to studies suggesting that the incidence of Alzheimer's disease may decrease in the very elderly (those 90 to 100 years of age). Thus, they say, "longevity genes" may act through an Alzheimer's disease?protective pathway.

Other topics include leptin and resistance to obesity; apolipoprotein A-IMilano (a special case of uncertainty as to effects on atherosclerosis); genes for cognitive and emotional functions; and the theory that the endothelial cells of a transplanted organ may upregulate the expression of protective (anti-apoptotic) genes whose products prevent reactions that might lead to graft rejection.

A discussion of gene therapy by Inder Verma and colleagues is ably presented, but its inclusion seems forced.

Much of the material in this volume is interesting. However, I don't see what was achieved by the conference; most of the topics included have already been competently reviewed elsewhere. In addition, the book is expensive. I wonder whether it might have been better to publish these reviews in the periodical biomedical literature as a supplement to an established journal, so that they could more certainly find their way into libraries and indices.

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