Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome.
OBJECTIVE
Imbalances in the genetically controlled pro- and anti-inflammatory cytokine production may promote ongoing low-grade inflammation after an acute gastroenteritis, and subsequently, irritable bowel syndrome (IBS) (post-infectious IBS, PI-IBS). We studied gene promoter single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNF-alpha, pro-inflammatory) and interleukin-10 (IL-10, anti-inflammatory) in IBS patients and controls.


METHODS
DNA was extracted from peripheral blood leucocytes of 111 IBS patients and 162 healthy controls. Genotype and allele frequencies were assessed by analyzing SNPs at position -308 (TNF-alpha) and -1082 and -819 (IL-10).


RESULTS
Homozygous high producers for TNF-alpha (A/A) were rare (overall prevalence 2.6%). The heterozygous TNF-alpha genotype (G/A, high producer) was significantly more prevalent in IBS compared to controls (41%vs 26%, p= 0.02). More patients (41%) than controls (30%) were positive for the A allele (p= 0.044; odds ratio (OR) 1.68, 95% confidence interval (CI) 1.01-2.79), with a similar trend for diarrhea (54%) versus constipation and alternating subtypes (<33%, p= 0.079), but not for subgroups according to a history of acute gastroenteritis. IL-10 genotypes were similarly distributed in patients and controls for both SNPs. Possession of a high producer TNF-alpha and a low producer IL-10 genotype were significantly more prevalent in IBS (9%) versus controls (3%, p= 0.035; OR 3.11, 95% CI 1.03-9.36) and in diarrhea (20%) compared to other IBS subtypes (<4%, p= 0.026).


CONCLUSIONS
Our results support the emerging hypothesis that genetically determined immune activity plays a role in the pathophysiology of IBS. Future studies in larger, clinically relevant, IBS subgroups are warranted to establish definite associations with cytokine gene polymorphisms.
van der Veek
Patrick P J
PP
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
van den Berg
Marlies
M
de Kroon
Yvette E
YE
Verspaget
Hein W
HW
Masclee
Ad A M
AA
D000225:Adenine; D000328:Adult; D003248:Constipation / Q000235:genetics / Q000503:physiopathology; D003967:Diarrhea / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005759:Gastroenteritis / Q000150:complications; D005787:Gene Frequency; D005838:Genotype; D006147:Guanine; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D018836:Inflammation Mediators; D016753:Interleukin-10 / Q000235:genetics*; D043183:Irritable Bowel Syndrome / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006147:Guanine; D000225:Adenine