Rev Bras Reumatol. 2013 Apr;53(2):199-205.

Lack of association between interleukin-18 polymorphisms and rheumatoid arthritis.

Farias TD, Canto LM, Medeiros MD, Sereia AF, Back LK, Mello FM, Zimmermann AF, Pereira IA, Muniz YC, Marrero AR, Souza IR.

Laboratory of genetic polymorphisms, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.



OBJECTIVE: To assess the association of the polymorphisms of the interleukin-18 (IL-18) gene with rheumatoid arthritis (RA) and with risk factors for cardiovascular diseases (CVD).

METHODS: This sample comprised 97 patients with RA and 151 healthy controls. In the patients, risk factors for CVD were analyzed, such as cholesterol levels, arterial hypertension, smoking habit, C-reactive protein (CRP) level, and rheumatoid factor. DNA was extracted and the single nucleotide polymorphisms (SNP) at the -607C/A and -137G/C positions of the IL-18 gene were assessed in both groups. The Hardy-Weinberg equilibrium (HWE) was calculated and the odds ratio (OR) test performed, considering a 95% CI and P < 0.05.

RESULTS: The frequencies of the -607A allele in patients with RA and in controls were 0,443 and 0.424, respectively, and of the -137C allele, 0.304 and 0.291, respectively. The genotype frequencies were in HWE, except for controls in the -137 locus (P = 0.006). Association of the polymorphisms of the IL-18 gene was found with neither RA nor risk factors for CVD, including cholesterol level and CRP (P > 0.05). In addition, more smokers were found among patients with RA as compared with controls (OR = 1.691; P = 0.088), and the CRP levels were slightly higher in patients who smoked than in patients who did not (OR = 2.673; P = 0.061).

CONCLUSIONS: In this sample of patients with RA in the South of Brazil, association of the polymorphisms of the IL-18 gene was observed with neither RA nor risk factors for CVD. 2013 Elsevier Editora Ltda.

PMID: 23856797



Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and multiple clinical manifestations. Besides environmental factors, it is shown that changes in specific genes can contribute to RA development. As symptoms vary in different populations, it is important to study the genetic profile of different groups of patients, and a heterogeneous population, such as the Brazilian, can help us unravel causes of RA onset and progression.

Since chronic inflammation is one of the main characteristics seen in patients with RA, we decided to study a member of the immune system responsible for inflammation activation. Interleukin-18 (IL-18) is a pro-inflammatory cytokine produced by several synovia cells. It is shown to play a role in the development of erosive and inflammatory arthritis, and it is considered a cardiovascular disease (CVD) risk, presumably acting as a mediator of vascular inflammation itself, leading to atherosclerosis. Plasma IL-18 concentration has shown to be increased in post myocardial infarction patients and was associated with coronary atherosclerosis, ischemic stroke,myocardial infarction, and higher cardiovascular mortality risk. Moreover, IL-18 serum levels were associated with traditional CVD risk factors such as LDL- and HDL-cholesterol abnormal values, obesity, insulin resistance and cell dysfunction.

Even though the levels of IL-18 are regulated by multiple factors, individual differences in the gene sequence could also affect the cytokine activity. Therefore based on previous results, we chose two IL-18 single nucleotide polymorphisms (SNPs) located in the promoter region of the gene that could be responsible for a higher susceptibility to autoimmune disorders in individuals carrying more active IL-18 alleles.

In order to do that, we selected RA patients and healthy people from the South region of Brazil, and we genotyped them for the two regions of the IL-18 gene, at -607C/A and -137G/C position. Then, we compared the frequencies of the alleles in patients and controls, so we could see whether patients had higher frequencies of one pair of alleles versus the other. Moreover, we observed these frequencies in patients with CVD risk factors, such as dyslipidemia, blood pressure, and smoking.

Our results reveal that the polymorphisms -607 and -137 of IL-18 gene do not play a major role in RA susceptibility in our population. In addition, these polymorphisms are not associated with CVD risk factors in our RA patients.

It is important to highlight that in face of such complex disease, all collected information can help us solve part of the RA puzzle. We know that IL-18 exhibits pleiotropic activities in RA, with a wide variety of effects that are influenced by the overall cytokine network. Therefore, future studies considering novel genetic markers within IL-18 or other genes involved in the cytokine network should be performed to evaluate their relevance in the context of RA and other inflammatory diseases.

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