Besides linkage studies for chromosomal regions harboring susceptibility genes for DN and subsequent positional cloning of the putative genes in those regions, an alternative strategy currently employed by many investigators is the "candidate gene" approach (7,37). Unlike genome scans that do not require prior knowledge of the biology of the susceptibility gene, this approach is hypothesis-driven because it focuses on proteins suspected of involvement in the pathogenesis of DN. A gene encoding for one of these proteins is screened for the presence of DNA polymorphisms (single-nucleotide polymorphisms [SNPs], insertion/deletions, or microsatellite markers). Then the distributions of alleles and genotypes of these polymorphisms are examined in unrelated diabetic patients with nephropathy (cases) and unrelated diabetic patients who have remained free of DN despite a long duration of diabetes (controls) to determine whether there are differences. If the groups of cases and controls are inadvertently drawn from populations having different admixtures of subpopulations (population stratification), the case-control study design will return false positive results. Therefore, to confirm positive results from case-control observations, some investigators have turned to the family-based study design, the so-called transmission disequilibrium testing (TDT), which is free of biases owing to the population stratification (38). The selection of "candidate genes" for examination is based on the current understanding of the pathways whereby the hyperglycemia of diabetes is translated into the manifestation of DN. Although the mechanisms have not been fully elucidated, several interrelated pathways can be hypothesized to control the risk of proteinuria and ESRD in patients with diabetes (39-41). In Table 6, four pathways are described, together with a selective list of genes encoding proteins important to each. Sequence differences in any of those genes that result in an abnormal structure or expression of these proteins may contribute to the development of proteinuria and ESRD. Candidate genes located in genetic regions for which there is evidence for linkage with proteinuria (Table 4 and Fig. 3) or ESRD (Table 5) are, for obvious reasons, the primary candidates for examination.
So far, almost 100 different genes have been postulated as candidate genes for DN. These genes were examined mainly in case-control studies. Unfortunately, owing to various methodological deficiencies the results of these studies are difficult to reproduce. In the following sections we describe the results of the examinations of two candidate genes that showed some consistent findings to illustrate the nature of candidate gene studies.
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