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Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using gene-based single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin µ-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (?2 =17.1,p=0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p=0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy. [ABSTRACT FROM AUTHOR]

Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A ne-phropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (x² = 9.02, P = .0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38 - 5.38] for His-to-Tyr substitutions; x² = 17.4, P = .000031, odds ratio = 3.61 [95% CI 1.91 - 6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (x² = 19.5, P = .000010, odds ratio = 3.77 [95% CI 2.02 - 7.05].) The TGT haplotype at these three loci was associated significantly with IgAN (x² = 18.67, P = .000016, odds ratio = 1.88 [95% CI 1.41-2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration. [ABSTRACT FROM AUTHOR]