Abstract
Little is known about the nature of genetic variation underlying complex diseases in humans. The recognition that susceptibility to type 2 diabetes mellitus has a strong inherited component provides a mechanism for developing the molecular understanding of the pathogenesis of type 2 diabetes mellitus through various genetic approaches. The main
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aim of the Breda study described in this thesis was to identify genetic factors involved in type 2 diabetes mellitus in a defined Dutch population. This thesis gives gives an overview of the approaches that can be used to identify genetic factors in type 2 diabetes mellitus and, in particular, the role of candidate gene analysis and genome-wide scanning is emphasised.
This thesis also describes the results of a genome-wide scan performed for type 2 diabetes mellitus in a defined Dutch population. The genome-wide scan was carried out using identity-by-descent analysis in affected sibpairs. Since obesity and type 2 diabetes mellitus are inter-related, the data set was stratified for the sub-phenotype body mass index (BMI), corrected for age and gender. This resulted in a suggestive maximum multi-point LOD score of 2.3 (p-value 9.7 x 10-4] for the most obese 20% pedigrees of the data set in the region flanked by marker loci D18S471 and D18S843 (chromosome region 18p11). We hereby confirmed the presence of a susceptibility locus on chromosome 18, reported earlier from a Finnish/Swedish population. This finding provided solid and independent evidence that the chromosome 18p11 locus is of definite interest for type 2 diabetes mellitus in connection with obesity in the Breda study cohort. In addition, we demonstrated that in the lowest 80% obese pedigrees ("lean" type 2 diabetes mellitus) two interesting loci on chromosomes 2 and 19 were found with LODs of 1.5 and 1.3, respectively (p-values 7.5 x 10-3 and 11.2 x 10-3].
Further more this thesis describes the analysis for linkage to loci influencing BMI (using quantitative trait locus (QTL) mapping) in 420 type 2 diabetes mellitus patients from the Breda cohort for which BMI values where available. Subsequently, the genotype data from the 20% most obese type 2 diabetes mellitus pedigrees ("obese" type 2 diabetes mellitus) was also analysed for linkage to type 2 diabetes mellitus using the ASP analysis. The QTL results support previous findings of a susceptibility locus (QTL) influencing BMI in type 2 diabetes mellitus residing on chromosome region 11q. In addition, suggestive evidence was found and previous findings confirmed for linkage with type 2 diabetes mellitus on chromosome regions 1q, 11p, and 12q. In general, it appears that the linkage found for type 2 diabetes mellitus in the present cohort is strongly influenced by obesity. This supports the notion that a genetic predisposition to obesity is closely intertwined with one predisposition to type 2 diabetes mellitus. However, our study fails to determine to what extent obesity and type 2 diabetes mellitus are genetically unique entities in their own right.
Complementary to these approaches described above also candidate gene association studies were performed with the sulphonylurea receptor 1 (SUR1) gene and type 2 diabetes mellitus, and with the beta-adrenergic receptor-2 (B2ADR) gene and obesity in type 2 diabetes mellitus subjects from the Breda study cohort. In our cohort, no significant association was found with the SNP16 variant of the SUR1 gene in type 2 diabetes patients compared to controls. The genotypes of SNP27 variant in the B2ADR gene were matched to the BMI values of 542 patients in our cohort and were compared using ANOVA with age and gender as covariates. No statistically significant difference was observed between the various groups, implying that, in our cohort, this polymorphism has no important effect on body mass index. Also no effect was found for this polymorphism on either the age of diagnosis of diabetes or on plasma lipids levels.
The results of this thesis will, together with previously reported results, help accelerate the efforts to identify susceptibility genes for type 2 diabetes mellitus located in the regions described above. Combined with new developments in the fields of bioinformatics, genomics and proteomics, this will lead to a greater understanding of the pathogenesis of type 2 diabetes mellitus. Identifying new pathways involved in the disease aetiology may help identify new therapeutic goals, and direct efforts to target therapies to relevant tissues. By improving the classification of type 2 diabetes, together with new insights in pharmacogenetics, this genetic information may form the basis for the development of new drug therapies and hopefully, in the future, will lead to the prevention of type 2 diabetes mellitus.
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