Positional Cloning of Type Diabetes Genes

The candidate gene approach presents limitations as it is now clear that at least some Type 2 diabetes susceptibility genes are likely to code for proteins of unknown function or a function not obviously implicated in glucose metabolism. The genome-wide linkage approach attempts to locate these unknown genes by a systematic search throughout the genome. This consists of genotyping the entire genome of affected sib-pairs or families with panels of 250-300 anonymous polymorphic markers to identify regions showing excess of allele sharing with the disease. This strategy requires no presumptions as to the function of the susceptibility loci. This total genome approach has been successful in other multifactorial diseases such as Type l diabetes (l23) and obesity (5). More than 20 genome-scans for Type 2 diabetes are currently underway, involving thousands of pedigrees from different populations and ethnic groups. One of the limitations of the genome-scan approach is the relatively low power of the method, unable to detect weak linkage signal, which is due to the low relative risk for diabetes in siblings (about 3 -5-fold increase compared to the general population). Working on large family collections, in homogeneous ethnic groups, or in large pedigrees using quantitative traits instead of the dichotomous diabetes status could improve the efficiency of linkage detection. Moreover, because of the large number of markers that are tested, false positive results are likely to occur. Thus, stringent criteria for linkage (p < l0 ~5) need to be used to minimize the bias due to multiple testing. Although a large number of regions of presumed linkage have been mapped in various populations (124-127), identification of the susceptibility genes is proceeding at very slow pace.

Results of several genome-scans have already been published. A locus for Type 2 diabetes on chromosome 2q (NIDDM1) was localized in Mexican Americans (124), and it was shown that an interaction of this locus with a locus on chromosome 15 further increases the susceptibility to diabetes in this population (128). Linkage was found at a locus near MODY3 on chromosome 12q in Finnish Type 2 diabetes families characterized by predominant insulin secretion defect (125). Evidence for an obesity-diabetes locus on chromosome 11q23-q25 (129) and linkage of several chromosomal regions with pre-diabetic traits (126) were observed in Pima Indians from Arizona, an ethnic group with a high prevalence of diabetes and obesity. A strong linkage between diabetes and chromosome 1q21-1q23 was reported in multi-generational families of Northern European ancestry from Utah (127). Linkages with diabetes and with the age at onset of diabetes were found in a region on chromosome 10q in Mexican American families from San Antonio (130). Evidence for the presence of one or more diabetes loci on chromosome 20 was found in different populations (131,132). In these and other studies a large amount of loci showing only suggestive or weak indication of linkage with diabetes-related traits have also been reported, several of which fall in overlapping regions. Although many of these loci may represent false positive results, some may harbour true diabetes-susceptibility genes. Comparisons of linkage results in different populations or family collections and/or meta-analysis of the data may now help to guide positional cloning efforts. New statistical methods exploiting multiloci effects or analyzing quantitative traits should lead to more effective results from genome-scan data.

These genome scans have mapped loci within large chromosomal regions containing 10-20 million nucleotides. Now the challenge is to identify the diabetes-related genes within this interval. The classical approach, that consisted in building up a physical map of the region through contiguous artificial chromosomes spanning the entire region of linkage, followed by the cloning of the gene, is limited by the size of the regions of linkage. An integrated genomic approach might be needed. It would combine linkage disequilibrium mapping, in order to define more precise gene locations, and techniques to pick out the genes of these smaller regions, such as micro-arrays for the identification of genes differentially expressed in diabetic and non-diabetic subjects. These investigations will benefit from recent technological developments in SNP identification and geno-typing. Moreover, the results from the Human Genome project, which include genomic DNA sequences, expressed sequences and expression profile data-banks, will certainly make the identification of Type 2 diabetes susceptibility genes by positional cloning much easier. The recent identification by Graeme Bell and coworkers of NIDDM1 as the gene encoding calpain 10 (cAPN10), a non-lysosomal cysteine protease, demonstrates the feasibility of positional cloning of polygenic Type 2 diabetes genes. Currently, it is believed that less than 15% of the genetic determinants of Type 2 diabetes have been unveiled. However, it is likely that other genes contributing to the genetic risk of Type 2 diabetes will soon be discovered.

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