Identifying susceptibility genes of IgA nephropathy: research in progress

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide and a significant cause of end-stage renal disease [1]. Although dysregulation of mucosal immunity is a notable feature of this disease, the pathogenesis of IgAN remains poorly understood and its treatment is limited. Familial clustering of patients with IgAN suggests a genetic predisposition [2–5]. Recent genome-wide studies of multiplex families with IgAN have identified two loci with significant linkage on chr. 6q22 [6] and chr. 2q36 [7], and two loci (see the Appendix) with suggestive linkage on chr. 4q26–31 and chr. 17q12–22 [8]. Moreover, the absence of linkage to these loci in a large family with multiple affected members suggests additional genetic heterogeneity (see the Appendix) [5]. Taken together, these data indicate that IgAN is a complex disease likely influenced by multiple genetic and environmental factors. The identification of susceptibility genes for IgAN has the potential to improve risk prediction and may yield novel insights into the primary pathogenesis of this disease. The latter knowledge is essential for future development of mechanism-based therapeutics. However, none of these putative susceptibility genes for IgAN has been identified thus far. To map these susceptibility genes, a candidate gene or genome-wide approach can be taken [9–12]. The former requires a conscious effort to select and then test polymorphic markers (see the Appendix) from one or more candidate gene loci among ∼25 000 genes in the human genome [13] for association or linkage with the disease. In contrast, the latter tests a dense set of equally spaced polymorphic markers across the entire genome for association or linkage with the disease and is agnostic for any underlying assumptions. To date, the candidate gene approach has been used exclusively for sporadic IgAN [1,14–18], while three genome-wide linkage studies have been employed for familial IgAN [6–8]. Candidate gene association studies