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DNA polymorphisms as disease markers
589
Literature
DNA Polymorphisms as Disease Markers, edited by DJ Galton, G Assmann, Plenum Press, pp 160. 'DNA Polymorphisms as Disease Markers', edited by DJ Galton from St Bartholomew's Hospital, London and G Asmann from Westfalische Wilhelms-Universitiit, Miinster, Germany, are the proceedings of a NATO Advanced Research Workshop held in September 1990 in London. As said in the preface by the editors: 'the purpose of the workshop was to assess the value of DNA polymorphisms for the prediction, diagnosis or elucidation of aetiology for common metabolic diseases such as diabetes, hyperlipidaemia and atherosclerosis'. It is true that a large number of restriction site polymorphisms and hypervariable sequences around candidate genes coding for proteins potentially involved in the development of these diseases have been identified in recent years and that a large number of clinical studies has been performed to look for disease-marker associations; it was therJ a good idea to assemble researchers who contributed to these developments to discuss the implications of their studies. Prof A Motulsky explains that the current working model for the genetics of multifactorial diseases is that one or a few genes have large effects, and that such major genes should be identifiable by current laboratory techniques. He also insists on the genetic heterogeneity of these diseases, ie the involvement of different sets of genes in different pedigrees which complicates the familial approach, and also on the interaction of genetic and environmental factors. Boerwinkle and Chan, using as an example the polymorphism of the ApoB signal peptide they discovered, discuss the possible reasons explaining why the results of many association studies are contradictory or not consistent. The first reason to consider is obviously that the observed association is spurious; it would have been useful to list and analyse the factors increasing the likelihood of finding spurious associations (large number of small independent studies, large number of phenotypes and genotypes studied, poor control of sampling, absence of clear a priori statement of tested hypotheses, etc), since a large number of reported studies in this field may be criticized on this ground. The second set of reasons is the true heterogeneity of associations across populations which may be due to complex interactions with other genetic or environmental factors or to the involvement of different causal genetic variants in linkage disequilibrium with the markers in different populations. Funke et al advocate the complementary use of association studies, linkage studies and candidate gene sequencing to approach the genetic component of multifactorial genetic diseases. It is unfortunate that the very significant work of Leitersdorf et al who used such a strategy to identify frequent mutations of the LDL receptor gene causing familial hypercholesterolemia in French Canadians and Afrikaners have not been included in this book. Permutt et al provide an excellent review of the literature on the molecular approaches of non-insulin dependent diabetes mellitus and mention the new approaches using mini- and microsatellites.
An account of the interest of studying rare mutants is given by Asman et al, who briefly summarize their important work on mutants involved in abnormalities of HDL and reverse cholesterol transport. There are several reports on the polymorphisms of the ApoAI-CIII-AIV locus and there is clearly some redundancy on this topic; conversely, the ApoB gene is only treated superficially despite its major biological role and the large amount of work concerning its polymorphism. The tables in the paper by Ordovas et al show that a very large number of studies have explored the ApoAI-CIlI-AIV gene polymorphisms. However, although mentioned, many of these studies were of very small size and had low power to detect any difference of interest, and pooling the results of different studies may not be appropriate. Price and Kitchin report the results of one of the first epidemiological investigations relating RFLP markers and prevalence of CHD. In their study of two Scottish populations, they show that RFLPs of the ApoA-CllI-AIV locus are related to the prevalence of CHD in presence of a family history of CHD. Large numbers of subjects were obvioulsy needed to identify this interaction. It is particularly surprising that the well-established statistical methods, including sampling and analysis, used by epidemioIogists have been seldom used before in this field. An account of these methods and of their application to bi-allelic and multi-allelic markers would have been a valuable addition to this work. In their concluding chapter, Galton and Alcolado mention interesting new areas of research, in particular through the use of highly polymorphic markers and by the study of monozygotic twins or sib pairs. However, the potential of new powerful techniques was not developed, for example, the detection of variants with allele specific oligonucleotides, a technique which can be used easily to screen large populations; pulse field electrophoresis which may be the method of choice to study the polymorphism of Ape(a), techniques such as SSCP, DGGE or direct sequencing of PCR products which are used to detect unknown variants of candidate genes located on particular haplotypes identified by markers, etc. An account of the potential of automation of molecular biology techniques to study large populations would also have been of interest. This volume of proceedings provides some interesting chapters, however, it covers only a limited part of the field and it fails to offer the methodological support needed by many scientists wishing to study associations between genetic markers and polygenic diseases. F Cambien
Literature
DNA Polymorphisms as Disease Markers, edited by DJ Galton, G Assmann, Plenum Press, pp 160. 'DNA Polymorphisms as Disease Markers', edited by DJ Galton from St Bartholomew's Hospital, London and G Asmann from Westfalische Wilhelms-Universitiit, Miinster, Germany, are the proceedings of a NATO Advanced Research Workshop held in September 1990 in London. As said in the preface by the editors: 'the purpose of the workshop was to assess the value of DNA polymorphisms for the prediction, diagnosis or elucidation of aetiology for common metabolic diseases such as diabetes, hyperlipidaemia and atherosclerosis'. It is true that a large number of restriction site polymorphisms and hypervariable sequences around candidate genes coding for proteins potentially involved in the development of these diseases have been identified in recent years and that a large number of clinical studies has been performed to look for disease-marker associations; it was therJ a good idea to assemble researchers who contributed to these developments to discuss the implications of their studies. Prof A Motulsky explains that the current working model for the genetics of multifactorial diseases is that one or a few genes have large effects, and that such major genes should be identifiable by current laboratory techniques. He also insists on the genetic heterogeneity of these diseases, ie the involvement of different sets of genes in different pedigrees which complicates the familial approach, and also on the interaction of genetic and environmental factors. Boerwinkle and Chan, using as an example the polymorphism of the ApoB signal peptide they discovered, discuss the possible reasons explaining why the results of many association studies are contradictory or not consistent. The first reason to consider is obviously that the observed association is spurious; it would have been useful to list and analyse the factors increasing the likelihood of finding spurious associations (large number of small independent studies, large number of phenotypes and genotypes studied, poor control of sampling, absence of clear a priori statement of tested hypotheses, etc), since a large number of reported studies in this field may be criticized on this ground. The second set of reasons is the true heterogeneity of associations across populations which may be due to complex interactions with other genetic or environmental factors or to the involvement of different causal genetic variants in linkage disequilibrium with the markers in different populations. Funke et al advocate the complementary use of association studies, linkage studies and candidate gene sequencing to approach the genetic component of multifactorial genetic diseases. It is unfortunate that the very significant work of Leitersdorf et al who used such a strategy to identify frequent mutations of the LDL receptor gene causing familial hypercholesterolemia in French Canadians and Afrikaners have not been included in this book. Permutt et al provide an excellent review of the literature on the molecular approaches of non-insulin dependent diabetes mellitus and mention the new approaches using mini- and microsatellites.
An account of the interest of studying rare mutants is given by Asman et al, who briefly summarize their important work on mutants involved in abnormalities of HDL and reverse cholesterol transport. There are several reports on the polymorphisms of the ApoAI-CIII-AIV locus and there is clearly some redundancy on this topic; conversely, the ApoB gene is only treated superficially despite its major biological role and the large amount of work concerning its polymorphism. The tables in the paper by Ordovas et al show that a very large number of studies have explored the ApoAI-CIlI-AIV gene polymorphisms. However, although mentioned, many of these studies were of very small size and had low power to detect any difference of interest, and pooling the results of different studies may not be appropriate. Price and Kitchin report the results of one of the first epidemiological investigations relating RFLP markers and prevalence of CHD. In their study of two Scottish populations, they show that RFLPs of the ApoA-CllI-AIV locus are related to the prevalence of CHD in presence of a family history of CHD. Large numbers of subjects were obvioulsy needed to identify this interaction. It is particularly surprising that the well-established statistical methods, including sampling and analysis, used by epidemioIogists have been seldom used before in this field. An account of these methods and of their application to bi-allelic and multi-allelic markers would have been a valuable addition to this work. In their concluding chapter, Galton and Alcolado mention interesting new areas of research, in particular through the use of highly polymorphic markers and by the study of monozygotic twins or sib pairs. However, the potential of new powerful techniques was not developed, for example, the detection of variants with allele specific oligonucleotides, a technique which can be used easily to screen large populations; pulse field electrophoresis which may be the method of choice to study the polymorphism of Ape(a), techniques such as SSCP, DGGE or direct sequencing of PCR products which are used to detect unknown variants of candidate genes located on particular haplotypes identified by markers, etc. An account of the potential of automation of molecular biology techniques to study large populations would also have been of interest. This volume of proceedings provides some interesting chapters, however, it covers only a limited part of the field and it fails to offer the methodological support needed by many scientists wishing to study associations between genetic markers and polygenic diseases. F Cambien