Association between Single-Nucleotide Polymorphisms in Selectin Genes and Immunoglobulin A Nephropathy

Abstract

Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (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 (chi2=9.02, P=.0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38--5.38] for His-to-Tyr substitutions; chi2=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 (chi2=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 (chi2=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.

No association between E- and L-selectin genes and SLE: soluble L-selectin levels do correlate with genotype and a subset in SLE

“…We also examined the inheritance of other coding and regulatory polymorphisms in SELE and SELL that have been implicated in SLE, 26 atherosclerosis 27,29 and glomerulonephritis. 31 We found no association between rs5361 (561A4C) and SLE or renal involvement, which defines patients at the severe end of the lupus spectrum. Given the power of our study, this suggests that any effect of this polymorphism on SLE must be absent or slight.…”

“…No other selectin haplotype or single SNP was associated with SLE or any subgroup. Although rs5359 (1518C4T) has been associated with IgA nephropathy, 31 our negative results in lupus nephritis suggest that this may not act as a common susceptibility polymorphism to renal inflammation. LD was consistently strong across this locus in European-Caucasians, with D 0 values that approached unity, and haplotype diversity was restricted.…”

“…28 Polymorphism of the fifth short consensus repeat domain (rs5359, 1518C4T) may contribute to susceptibility to a common form of glomerulonephritis. 31 The L-selectin gene (SELL) has not been studied in lupus or related connective tissue diseases as far as we are aware.…”

Association between the Phe206Leu polymorphism of L-selectin and brucellosis

“…Recent studies have addressed the significant association between the F206L polymorphism and certain disorders, such as IgA nephropathy (Takei et al, 2002) and insulindependent diabetes mellitus (IDDM) (Kretowski & Kinalska, 2002). On the other hand, the strength of the binding of L-selectin to its ligands on other cells, particularly endothelial cells, may be influenced by the 206Leu allele, as the EGF domain is important in maintaining the secondary structure of selectins and, accordingly, plays a significant role in cell-cell interactions (Revelle et al, 1996).…”

The common variants of E-selectin gene in Graves’ disease

“…The two selectin genes might therefore contribute to the susceptibility to GD through either a mutual interaction or a common pathway, though we did not observe any direct evidence in this study. Moreover, SELE and SELL within the selectin gene cluster seem to be prone to contribute susceptibility to a single autoimmune disease together, as shown in the findings in IgA nephropathy 25 and coeliac disease. 26 In the light of the evidence in the association of SELL with GD, 9 the association of SELE with GD could be a reasonable deduction.…”