441
I Med Genet 1992; 29: 441-446
REVIEW ARTICLE
The genetics of type I (insulin dependent) diabetes mellitus David Cavan, Stephen Bain, Anthony Barnett
Over the past decade major advances have been made in elucidating the molecular genetics of the single gene disorders. The common diseases of the developed world, such as coronary artery disease, cancer, and diabetes, are, however, likely to be influenced by several genes as well as environmental factors. This article will concentrate on the genetics of type I diabetes, but the methods used may apply to the study of the genetics of other complex diseases.
Population associations These involve identification of polymorphic genes and comparison of their frequency in patients versus controls (association analysis). A significant association with disease suggests either a causative role for the gene polymorphism or linkage between the marker allele and a disease susceptibility allele. Unless the marker is very close to a susceptibility locus, recombination events are likely to have occurred in many members of the population and a significant association between two loci will not be detected. In addition, it is important that the patients and controls are precisely matched for ethnic background. Such matching may be difficult since unrecognised population stratification may exist. If these strata have varying frequencies of disease or markers then spurious associations may be seen.
Undergraduate Centre, University of Birmingham, East Birmingham Hospital, Bordesley Green East, Birmingham B9 5ST. D Cavan S Bain A Barnett Correspondence to Dr Bamett.
Family studies Linkage analysis estimates genetic distance between a susceptibility locus and a marker locus from the study of inheritance of disease and marker in family pedigrees. Recombination is less likely than in a population enabling detection of linkage between much more widely separated loci. Classical linkage analysis requires a knowledge of the mode of inheritance of the disease and the penetrance. These problems can be alleviated somewhat by the use of computer programmes which can test multiple models.' The chance of recording a type 1 error (false positive result) is considerably increased when many tests are performed and the level of statistical significance required from such analyses has yet to be clearly defined.
An alternative to classical linkage is the affected relative pair method. In this analysis, the frequency with which relatives with disease share 0, 1, or 2 marker loci/haplotypes identical by descent (IBD) is compared with the frequencies expected if the marker and disease were unrelated (that is, for sibs 25%, 50%, and 25% respectively). Demonstration of genotypic concordance among affected relatives in excess of what would be expected is taken as evidence for existence of a disease susceptibility locus linked to the marker. The ability of affected sib pair methods to detect significant linkage to disease susceptibility genes is dependent on a number of factors: the genetic contribution of a susceptibility locus to disease; the availability of highly informative genetic markers; the presence of genetic heterogeneity and disease phenocopies. It is likely that the latter two problems can be overcome by analysing large numbers of pedigrees. The lack of available multiplex families (at least two affected sibs and living parents), however, has been a problem in the study of many complex diseases.
Animal models The short time between birth and fecundity and the potential for inbreeding experiments have allowed close study of linkage and segregation of marker genes with various diseases. Animal models may identify candidate genes or candidate areas of particular chromosomes which can then be targeted in the human genome.
Type I diabetes Type I (insulin dependent) diabetes is a T cell dependent autoimmune disease affecting about 0-3% of the population of the UK.2 Studies of identical twins indicate that where the index twin has the disease the genetically identical co-twin develops diabetes in 30 to 40% of cases.3 The average risk to sibs is approximately 6%, rising to 12% for HLA identical sibs. These data indicate that the disease phenotype is dependent upon both environmental factors and the action of several genes.2 Approximately 60 to 70% of genetic susceptibility is estimated to be HLA encoded and 30 to 40% encoded by genes outside the HLA re-
gion.4
Cavan, Bain, Barnett
442
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I Med Genet 1992; 29: 441-446
REVIEW ARTICLE
The genetics of type I (insulin dependent) diabetes mellitus David Cavan, Stephen Bain, Anthony Barnett
Over the past decade major advances have been made in elucidating the molecular genetics of the single gene disorders. The common diseases of the developed world, such as coronary artery disease, cancer, and diabetes, are, however, likely to be influenced by several genes as well as environmental factors. This article will concentrate on the genetics of type I diabetes, but the methods used may apply to the study of the genetics of other complex diseases.
Population associations These involve identification of polymorphic genes and comparison of their frequency in patients versus controls (association analysis). A significant association with disease suggests either a causative role for the gene polymorphism or linkage between the marker allele and a disease susceptibility allele. Unless the marker is very close to a susceptibility locus, recombination events are likely to have occurred in many members of the population and a significant association between two loci will not be detected. In addition, it is important that the patients and controls are precisely matched for ethnic background. Such matching may be difficult since unrecognised population stratification may exist. If these strata have varying frequencies of disease or markers then spurious associations may be seen.
Undergraduate Centre, University of Birmingham, East Birmingham Hospital, Bordesley Green East, Birmingham B9 5ST. D Cavan S Bain A Barnett Correspondence to Dr Bamett.
Family studies Linkage analysis estimates genetic distance between a susceptibility locus and a marker locus from the study of inheritance of disease and marker in family pedigrees. Recombination is less likely than in a population enabling detection of linkage between much more widely separated loci. Classical linkage analysis requires a knowledge of the mode of inheritance of the disease and the penetrance. These problems can be alleviated somewhat by the use of computer programmes which can test multiple models.' The chance of recording a type 1 error (false positive result) is considerably increased when many tests are performed and the level of statistical significance required from such analyses has yet to be clearly defined.
An alternative to classical linkage is the affected relative pair method. In this analysis, the frequency with which relatives with disease share 0, 1, or 2 marker loci/haplotypes identical by descent (IBD) is compared with the frequencies expected if the marker and disease were unrelated (that is, for sibs 25%, 50%, and 25% respectively). Demonstration of genotypic concordance among affected relatives in excess of what would be expected is taken as evidence for existence of a disease susceptibility locus linked to the marker. The ability of affected sib pair methods to detect significant linkage to disease susceptibility genes is dependent on a number of factors: the genetic contribution of a susceptibility locus to disease; the availability of highly informative genetic markers; the presence of genetic heterogeneity and disease phenocopies. It is likely that the latter two problems can be overcome by analysing large numbers of pedigrees. The lack of available multiplex families (at least two affected sibs and living parents), however, has been a problem in the study of many complex diseases.
Animal models The short time between birth and fecundity and the potential for inbreeding experiments have allowed close study of linkage and segregation of marker genes with various diseases. Animal models may identify candidate genes or candidate areas of particular chromosomes which can then be targeted in the human genome.
Type I diabetes Type I (insulin dependent) diabetes is a T cell dependent autoimmune disease affecting about 0-3% of the population of the UK.2 Studies of identical twins indicate that where the index twin has the disease the genetically identical co-twin develops diabetes in 30 to 40% of cases.3 The average risk to sibs is approximately 6%, rising to 12% for HLA identical sibs. These data indicate that the disease phenotype is dependent upon both environmental factors and the action of several genes.2 Approximately 60 to 70% of genetic susceptibility is estimated to be HLA encoded and 30 to 40% encoded by genes outside the HLA re-
gion.4
Cavan, Bain, Barnett
442
Class 11
Class III
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Z
o0
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0
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0 0
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