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

Abstract

SummaryTumour necrosis factor (TNF)-a, 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-a (sTNF-a) 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-a (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.

Relationship between TNFA, TNFB and TNFRII gene polymorphisms and outcome after unrelated hematopoietic cell transplantation in a Chinese population

“…Several recent studies have demonstrated an association between the TNFB þ 252 G allele and a higher risk of breast cancer and sarcoidosis, demonstrating a pivotal role for TNF-b in host cellular immunity. [31][32][33] Moreover, both TNFA and TNFB gene polymorphisms have been shown to be associated with TNF-a generation potential. Thus, TNFA and TNFB gene polymorphisms may have functional significance in diseases whose pathogenetic mechanisms include TNF-a production.…”

Genetics of Sarcoidosis

“…[82] There was also an increased frequency of the -857T allele in British and Dutch sarcoidosis patients compared to controls. [78] The relationship between serum TNF-α levels and genotypes is unclear, one study found an increased serum TNF-α levels with the TNF-α-307(8)G and the TNF-α -238A alleles in a sarcoidosis population but not normal controls, [83] whereas another study did not detect any association in the spontaneous or stimulated release of TNF-α from BAL and PBMC cells with the TNF-α 308 and TNF-β (intron 1) genotypes. [84] The TNF-α-863 position lies further upstream in the promoter region.…”

“…[85] There was a marginal association of the allele TNF-1031A with the risk of sarcoidosis and an association of TNF-1031A and TNF-α-863A with chronic disease in an Indian cohort. [83] …”

Biomedical Importance of Host Genetic Factors in Infectious Diseases

“…Elevated serum TNF-(sTNF-) levels have been reported in advanced tuberculosis patients compared to those with mild tuberculosis and healthy controls. Several promoter polymorphisms region of TNF-and the intron-1 polymorphism of LT-, have been associated with altered levels of TNF- (Sharma et al, 2008;. Some of these polymorphisms have also been studied in several ethnic groups.…”