Association of TNF polymorphisms with sarcoidosis, its prognosis and tumour necrosis factor (TNF)-α levels in Asian Indians

Abstract

Tumour necrosis factor (TNF)-alpha, an important proinflammatory cytokine, has been implicated in the pathogenesis of sarcoidosis, a multi-systemic granulomatous disorder of unknown aetiology. Here, we report for the first time the association of TNF haplotypes and genotypes with sarcoidosis and its prognosis in the Indian population. Five potentially functional promoter polymorphisms in the TNFA gene and a LTA_NcoI polymorphism (+252 position) of the LTA gene were genotyped in a clinically well-defined cohort of North-Indian patients with sarcoidosis (n = 96) and their regional controls (n = 155). Serum TNF-alpha (sTNF-alpha) and serum angiotensin converting enzyme (SACE) levels were measured and correlated with genotypes and haplotypes. The TNFA_-1031 and TNFA_-863 polymorphisms were identified as markers for disease onset (FET P = 0.006 and 0.042 for TNFA_-1031 and TNFA_-863, respectively). Additionally, the allele A of LTA_NcoI polymorphism was shown to be prevalent in the 'no treatment' group (FET P = 0.005), while the G allele was associated with frequent relapses on drug withdrawal (P = 0.057). Furthermore, the TNFA-308G>A and the TNFA-238G>A polymorphisms were found to influence sTNF-alpha (P = 0.054 and 0.0005, respectively) and SACE levels (P = 0.0017 and 0.056, respectively). The haplotype frequencies were significantly different in the patients and the controls (P = 0.0067). The haplotype GTCCGG was identified as the major risk/susceptibility haplotype (P = 0.003) and was associated with increased SACE levels in the patient population. In conclusion, our study suggests an association of TNF polymorphisms with sarcoidosis.