Association of -27T>C and its haplotype at the putative promoter for IgA-specific receptor gene with IgA nephropathy among the Chinese Han population

Background. One-third to half of IgA nephropathy (IgAN) patients have raised serum IgA levels. Decreased clearance of IgA/IgA complex has been observed in IgAN patients. FCAR codes for IgA-specific receptor and plays an important role in IgA metabolism. Previous small sample-sized studies reported controversial findings in its association with IgAN. Methods. We re-sequenced the FCAR in 107 IgAN patients and 112 controls. Association of � 27T/C and their haplotypes were performed in 606 patients versus 606 controls, its two independent subsets: 293 single patients with family members and 313 cases versus 606 controls. Functional impact of � 27T>C and their haplotypes were analyzed by bioinformatics, allelic differential expression and luciferase activity assays. Cell surface FCAR density between � 27T/C heterozygous patients and � 27T/T homozygous controls was assessed by flow cytometry. Results. � 27T>C, on the consensus TATA box of transcription factor-binding motif in the putative promoter of the gene was the only variation identified in all coding, splice-site and known protein-binding sequence in resequencing. � 27C and its haplotype were associated with IgAN (P ¼ 0.0034/0.0013, 0.0099/0.0054, 0.0129/0.0076 and 0.00039/0.00014 in 606 cases versus 606 controls, family-based study, 313 cases versus 606 controls and meta-analysis, respectively). Bioinformatics predicted 2 bp binding changes by � 27C. Allelic differential expression and luciferase activity assays showed a reduced expression/ activity by the associated haplotype/allele (P < 0.001). � 27T/C heterozygous patients had a lower receptor density on cell surface compared to � 27T/T homozygous controls (P < 0.001). Conclusions. Our results provide evidence for genetic variation at the putative promoter region of FCAR conferring susceptibility to IgAN, suggesting � 27C and its haplotype may be causative for the susceptibility among the Chinese Han population.