Abstract
Gout is an increasingly common form of inflammatory arthritis caused by the deposition of urate, leading to the formation of monosodium urate (MSU) crystals in joints and other body tissue. This results in subsequent recurrent acute inflammation attacks (1). Gout prevalence is increasing worldwide and has a particularly high prevalence in the Māori and Pacific populations of New Zealand (9.3 to 13.9% of Māori men and 14.9% of Pacific Island men) (2). Risk factors for gout development can be either genetic or environmental. The risk of gout is different between ancestral groups, suggesting that they have genetic differences (3).
Rheumatic heart fever (RHF) is a systemic auto-inflammatory disease that is caused by infection of the upper respiratory tract (mainly the throat) by group A β-haemolytic streptococci (GABHS). RHF happens via antigen molecular mimicry and cross reactivity mechanisms between the host and bacteria. Cross reactivity of antibodies and/or T cells stimulates recognition between the S.pyrogenes peptides and the host protein and leads to inflammation and autoimmunity (4). RHF incidence and prevalence has steadily declined in developed countries since the early 1900s. However, it remains a leading cause of morbidity and mortality among young individuals (6 – 15 years) in developing countries. The risk of RHF can be familial or environmental e.g. as poor housing conditions, crowding, and poor health knowledge (5, 6).
The IL23R gene codes for the interleukin 23 receptor. The receptor is located on the cell membrane of cells that are involved in the immune system, which provide defence mechanisms against infection and disease from foreign microbes. During the TH17 immune response, activation of IL23R from interaction with its subunit (IL23) initiates inflammation (7). Previous studies have shown that genetic variants derived from IL23R are associated with auto-inflammatory related diseases, such as rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease. A study by Liu et al (2015) showed that the IL23R SNP rs7517847 minor allele G confers an association with gout in Chinese Han male population.
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Our aim was to test IL23R gene variants (rs11209026, rs7517847 and rs11465804) for association with gout and RHF in European and Polynesian populations using case-control sample sets recruited within New Zealand and (for gout) Europe. To test this hypothesis, SNPs were genotyped using Taqman assay and statistical analysis was carried out using R studio logistic regression to test for association of SNPs with gout and RHF. Common confounders including ancestry, sex and age were adjusted for in the regression analysis.
Gout results revealed that rs11465804 and rs11209026 in both European and Polynesian were not significantly associated with gout. However, the rs7517847 minor allele (G) showed a significant association with gout in Polynesian (Polynesian OR = 0.85, P = 0.04) (European OR = 0.94, P = 0.53), which is consistent with the Lui et al (2015) findings. These data replicate the Liu et al (2015) findings and support the claim that IL23R has a causal role in gout in people with Polynesian ancestry. Hence, the IL23R pathway is a target for gout treatment in the Polynesian population.
RHF results revealed that only SNP rs11209026 shows evidence of association with a protective effect for the minor allele (A) (OR = 0.07, P-value = 0.002) after adjustment. Therefore the rs11209026 major allele (G) is in a susceptible direction. This provides evidence that IL23R has a casual role in RHF development risk in Polynesian people.