Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms.

The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity.

OBJECTIVE: To determine whether functional cytokine gene polymorphisms influence disease susceptibility and phenotype in patients with psoriatic arthritis (PsA). METHODS: DNA was obtained from 147 PsA patients and 389 controls. Seven functional proinflammatory (interleukin-1beta [IL-1beta] +3953, IL-6 -174, tumor necrosis factor alpha [TNFalpha] -308, TNFbeta +252) and antiinflammatory (IL-10 -1082, IL-10 -592, IL-1 receptor antagonist [intron 2, 86 bp, variable-number tandem repeat]) gene polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism assays. RESULTS: No significant difference in genotype frequencies was observed between the control and the PsA patient populations, and no association with Steinbrocker functional class, disease classification (polyarticular or oligoarticular), presence of spinal involvement, or age at PsA onset was observed. The presence of joint erosions was significantly associated with the TNFalpha -308 and TNFbeta +252 polymorphisms (P < 0.0001 and P = 0.0017, respectively). Frequencies of the TNFalpha -308 and TNFbeta +252 genotypes were also significantly different (P = 0.0078 and P = 0.0486, respectively) in a group of progressors (patients with early PsA in whom the number of joint erosions in the hands and feet increased over a median interval of 24 months) compared with a group of nonprogressors. Age at psoriasis onset was significantly associated with the TNFbeta +252 and TNFalpha -308 polymorphisms (P = 0.0003 and P = 0.0081, respectively). The TNFB2B2 and TNFalpha -308 AA genotypes were associated with the earliest mean ages at psoriasis onset. CONCLUSION: The TNFalpha -308 and TNFbeta +252 polymorphisms were significantly associated with age at psoriasis onset, presence of joint erosions in PsA, and progression of joint erosions in early PsA. TNF gene polymorphisms may be useful prognostic markers in PsA, and these results support the rationale for using anti-TNF treatment in patients with severe, progressive PsA.

Lactic acidosis after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes.

BACKGROUND: Lactic acidosis after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of lactic acidosis after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed lactic acidosis (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of lactic acidosis after cardiac surgery.