Cytokine Gene Polymorphisms across Tuberculosis Clinical Spectrum in Pakistani Patients

BACKGROUND: Pakistan ranks 7(th) globally in terms of tuberculosis (TB) disease burden (incidence 181/100000 pop./yr; prevalence of 329/pop./yr). Reports from different populations show variable associations of TB susceptibility and severity with cytokine gene polymorphisms. Tuberculosis clinical severity is multi-factorial and cytokines play a pivotal role in the modulation of disease severity. We have recently reported that the ratio of two key cytokines (IFNgamma and IL10) show significant correlation with the severity spectrum of tuberculosis. The objective of the current study was to analyze the frequency of cytokine gene polymorphisms linked to high and low responder phenotypes (IFNgamma +874 T(hi)-->A(lo) and IL10 -1082 G(lo)-->A(hi)) in tuberculosis patients. METHODS AND FINDINGS: STUDY GROUPS WERE STRATIFIED ACCORDING TO DISEASE SITE AS WELL AS DISEASE SEVERITY: Pulmonary N = 111 (Minimal, PMN = 19; Moderate, PMD = 63; Advance, PAD = 29); Extra-pulmonary N = 67 (Disseminated DTB = 20, Localized LTB = 47) and compared with healthy controls (TBNA = 188). Genotype analyses were carried out using amplification refractory mutation system-PCR (ARMS-PCR) and stimulated whole blood (WB) culture assay was used for assessing cytokine profiles. Our results suggest that the IFNgamma +874 TT genotype and T allele was overrepresented in PMN (p = 0.01) and PMD (p = 0.02). IFNgamma +874 TT in combination with IL10 GG(lo) genotypes showed the highest association (chi(2) = 6.66, OR = 6.06, 95% CI = 1.31-28.07, p = 0.01). IFNgamma AA(lo) on the other hand in combination with IL10 GG(lo) increased the risk of PAD (OR = 5.26; p = 0.005) and DTB (OR = 3.59; p = 0.045). CONCLUSION: These findings are consistent with the role of IL10 in reducing collateral tissue damage and the protective role of IFNgamma in limiting disease in the lung

Genetics of immunoglobulin-A vasculitis (Henoch-Schönlein purpura): An updated review

Immunoglobulin-A vasculitis (IgAV) is classically a childhood small-sized blood vessel vasculitis with predominant involvement of the skin. Gastrointestinal and joint manifestations are common in patients diagnosed with this condition. Nephritis, which is more severe in adults, constitutes the most feared complication of this vasculitis. The molecular bases underlying the origin of IgAV have not been completely elucidated. Nevertheless, several pieces of evidence support the claim that genes play a crucial role in the pathogenesis of this disease. The human leukocyte antigen (HLA) region is, until now, the main genetic factor associated with IgAV pathogenesis. Besides a strong association with HLA class II alleles, specifically HLA-DRB1 alleles, HLA class I alleles also seem to influence on the predisposition of this disease. Other gene polymorphisms located outside the HLA region, including those coding cytokines, chemokines, adhesion molecules as well as those related to T-cells, aberrant glycosylation of IgA1, nitric oxide production, neoangiogenesis, renin-angiotensin system and lipid, Pyrin and homocysteine metabolism, may be implicated not only in the predisposition to IgAV but also in its severity. An update of the current knowledge of the genetic component associated with the pathogenesis of IgAV is detailed in this review.Acknowledgements: RL-Mis supported by the Miguel Servet I programme of the Spanish Ministry of Economy and Competitiveness through the grant CP16/ 00033. FG is recipient of a Sara Borrell postdoctoral fellowship from the “Instituto Carlos III de Salud” at the Spanish Ministry of Health (Spain) (CD15/00095). SR-M is supported by funds from the RETICS Program (RIER) (RD16/0012/0009). FDC is supported by the Ramón y Cajal programme of the Spanish Ministry of Economy and Competitiveness through the grant RYC-2014-16458

Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a prevalent psychiatric disorder of unknown etiology. However, there is some evidence that the immune system may play an important role in its pathogenesis. In the present study, two polymorphisms (rs1800795 and rs361525) in the promoter region of the cytokine tumor necrosis factor-alpha (TNFA) gene were genotyped in 183 OCD patients and in 249 healthy controls. The statistical tests were performed using the PLINK® software. We found that the A allele of the TNFA rs361525 polymorphism was significantly associated with OCD subjects, according to the allelic χ² association test (p=0.007). The presence of genetic markers, such as inflammatory cytokines genes linked to OCD, may represent additional evidence supporting the role of the immune system in its pathogenesis