Role of interferon- γ gene polymorphisms in susceptibility to IgA nephropathy: a family-based association study

T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/T R -type, and of monocyte/macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFN γ intron-1 CA repeat at position 1349–1373; IL-13 −1055C/T; TGF β +915G/C; IL-10 5′-proximal and distal microsatellites; TNF α −308G/A, −238G/A. The FBAT multi-allelic analysis showed an association between IFN γ polymorphism and susceptibility to IgAN ( P =0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals ( P =0.006; Bonferroni P -value=0.04). The direct sequencing of IFN γ amplicons showed a strict association between the 13-CA repeat allele and the A variant of the +874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5′ end of the microsatellite. The in vitro production of IFN γ evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFN γ ( P =0.028 Mann–Whitney test). This SNP affects IFN γ production lying within a binding site for the transcription factor NF- κ B. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFN γ gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFN γ 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.