Role of interferon-gamma 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): IFNgamma intron-1 CA repeat at position 1349-1373; IL-13 -1055C/T; TGFbeta +915G/C; IL-10 5'-proximal and distal microsatellites; TNFalpha -308G/A, -238G/A. The FBAT multi-allelic analysis showed an association between IFNgamma 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 IFNgamma 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 IFNgamma evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNgamma (P=0.028 Mann-Whitney test). This SNP affects IFNgamma production lying within a binding site for the transcription factor NF-kappaB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNgamma gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNgamma 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.
Schena
Francesco Paolo
FP
Renal Unit, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. fp.schena@nephro.uniba.it
Cerullo
Giuseppina
G
Torres
Diletta Domenica
DD
Scolari
Francesco
F
Foramitti
Marina
M
Amoroso
Antonio
A
Pirulli
Doroti
D
Floege
Jürgen
J
Mertens
Peter Rene
PR
Zerres
Klaus
K
Alexopoulos
Efstathios
E
Kirmizis
Dimitrios
D
Zelante
Leopoldo
L
Bisceglia
Luigi
L
D000483:Alleles; D016022:Case-Control Studies; D018900:Dinucleotide Repeats / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
D007371:Interferon-gamma