TNFA2 and d2 alleles of the tumor necrosis factor alpha gene polymorphism are associated with onset/occurrence of idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN) has a strong association with the major histocompatibility complex HLA B8DR3(17) DQ2 haplotype. The tumor necrosis factor (TNF) A gene is located within the major histocompatibility complex region on chromosome 6. We have studied the influence of two functional polymorphisms; the -308 (promoter region) and the TNFd microsatellites on initiation and/or progression of IMN. This was a case-control study comparing data from 100 Caucasians patients (67 male subjects; 67%) with IMN to 232 Caucasians local controls (171 male subjects; 74%). We have analyzed genotypes and alleles distributions and the role of these polymorphisms in disease progression towards end-stage renal failure or patient death. For -308 TNFA polymorphism, distribution of genotypes was significantly different between IMN and controls (chi(2) = 16.25; P = 0.0003): the A2 allele frequency was 28.0% in IMN vs 15.3% in controls (chi(2) = 14.57; P = 0.0001). For TNFd polymorphism, alleles distribution (from d1 to d7) was also significantly different between IMN and controls (chi(2) = 56.74; P < 0.0001) with both diminished d3 allele frequency (chi(2) = 27.30; P < 0.0001; Pc = 0.001) and increased d2 allele frequency (chi(2) = 29.95; P < 0.0001; Pc = 0.001) in IMN. We could not isolate any significant and independent influence of these different genotypes on IMN disease progression. The TNFA2 and TNFd2 alleles were strongly associated with occurrence/initiation of IMN and should be considered as susceptibility genes for this disease.