We also defined a novel HLA-DRA haplotype that confers an increased risk for lupus nephritis (LN) and alleles in HLA-DRA2 and TNFSF4 genes as genetic risk factors for developing neuropsychiatric (NP) SLE.
In conclusion, single nucleotide polymorphisms in ITGAM, TNFSF4, TNFAIP3 and STAT4 genes are associated with susceptibility to SLE in a North Indian population.
In this study, we evaluated the contribution of Ox40L and its cognate receptor, Ox40, using in vivo agonist and antagonist approaches in the NZB × NZW (NZB/W) F1 mouse model of SLE.
We further show that in two models of SLE-a spontaneous congenic model and the H2-IA<sup>bm12</sup> graft-versus-host-induced model-loss of B cell OX40L ameliorates the autoimmune phenotype.
The tumor necrosis factor ligand superfamily member 4 (TNFSF4) gene encodes a vital co-stimulatory molecule of the immune system and has been identified as a susceptibility locus for systemic lupus erythematosus, systemic sclerosis, and primary Sjögren's syndrome.
The frequency of minor T allele of TNFSF4rs2205960 was significant in Chinese and Indian patients with SLE, with P values of 0.05 (OR = 1.27, 95% CI: 1.00-1.61) and 0.004 (OR = 3.16, 95% CI: 1.41-7.05), respectively.
Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA).
The SNPs of TNFSF4 were associated with renal involvement in lupus patients from the Chinese population (P values for rs2205960 and rs10489265 were 0.014 and 0.005 in additive model, resp.).
The results of our meta-analysis suggest that the TNFSF4rs2205960 polymorphism may confer susceptibility to SLE in different populations and that the TNFSF4rs1234315 polymorphism is associated with susceptibility to SLE in Asians.
Our results suggest that changes in the expression levels of TNFSF4 and TRAF2 mRNAs may significantly correlate with the pathogenesis of SLE, the disease activity and different clinical features of lupus, particularly lupus nephritis, atherosclerosis and arthritis.
Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry.
Our study not only suggested that the TNFSF4 gene was associated with SLE in Chinese Han population, but also implied that it might be a common genetic factor predisposing to the development of SLE in multiple populations.
Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10(-6), OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25).
A total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.
With these studies, it has been established that a number of genes associated with SLE in Caucasians are also risk factors in Asians: HLA class II genes, STAT4, BANK1, BLK, IRF5, TNFSF4, ITGAM, etc., while there are also novel genetic risk factors identified by these studies in Asians, for instance, the ETS1 and WDFY4 in Chinese.
The precise immunological consequences are yet to be determined; however, signalling through OX40-OX40L is bidirectional and the reverse signalling pathway via OX40L may quantitatively enhance B cell proliferation to augment the B cell hyperactivity found in SLE.