Schena Francesco Paolo, Cerullo Giuseppina, Torres Diletta Domenica, Scolari Francesco, Foramitti Marina, Amoroso Antonio, Pirulli Doroti, Floege Jürgen, Mertens Peter Rene, Zerres Klaus, Alexopoulos Efstathios, Kirmizis Dimitrios, Zelante Leopoldo, Bisceglia Luigi
Renal Unit, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.
Eur J Hum Genet. 2006 Apr;14(4):488-96. doi: 10.1038/sj.ejhg.5201591.
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.
辅助性T（h）淋巴细胞在黏膜效应部位的致病性免疫反应中对IgA肾病（IgAN）起关键作用。我们通过一项基于家系的关联研究评估了一些Th1/Th2/Th3/T（R）型以及单核细胞/巨噬细胞细胞因子对IgAN易感性的影响，该研究纳入了53例患者、45个完整三联体、4个不完整三联体和36对不一致的同胞。使用基于家系的关联检验（FBAT）研究了对其产生具有潜在调节作用的细胞因子基因多态性：干扰素γ（IFNγ）内含子1第1349 - 1373位CA重复序列；白细胞介素13（IL - 13）-1055C/T；转化生长因子β（TGFβ）+915G/C；白细胞介素10（IL - 10）5'近端和远端微卫星；肿瘤坏死因子α（TNFα）-308G/A、-238G/A。FBAT多等位基因分析显示IFNγ多态性与IgAN易感性之间存在关联（P = 0.03）。双等位基因分析表明13 - CA重复等位基因优先传递给患病个体（P = 0.006；Bonferroni P值 = 0.04）。IFNγ扩增子的直接测序显示13 - CA重复等位基因与紧邻微卫星5'端的+874T/A单核苷酸多态性（SNP rs2430561）的A变体之间存在紧密关联。在10例基因分型患者的外周血单个核细胞中评估的IFNγ体外产生情况表明，+874A等位基因与较低的IFNγ产生相关（P = 0.028，曼 - 惠特尼检验）。该SNP影响位于转录因子NF - κB结合位点内的IFNγ产生。携带不同IFNγ基因多态性的IgAN患者在15年肾脏存活率方面未观察到显著差异。这项首个基于家系的关联研究表明，与IFNγ 13 - CA重复等位基因紧密相关的+874A等位基因赋予了IgAN易感性，但不影响肾脏存活率。
