Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

Figures & data

Figure 1. IL-17⁺ cells and IBD. (a) High amounts of inflammatory cytokines are found in the IBD environment. These cytokines are produced by a variety of cells including myeloid APC, stromal cells, epithelial cells and neutrophils. (b) Myeloid APC along with IL-1, IL-6 and IL-23 lead to T_H17 cell expansion. (c) T_H17 cells further induce epithelial and stromal cells to express more pro-inflammatory cytokines, promote neutrophil recruitment and accelerate local inflammation. (d) T_reg/T_H17 (IL-17⁺Foxp3⁺) cells are also found in IBD environments. T_reg/T_H17 cells suppress adaptive T-cell immunity, but also secrete inflammatory cytokines. Thus, these cells are termed as inflammatory T_reg cells.

Figure 2. The arginine at position 381 of the IL23R is absolutely conserved across different species. (a) Map of IL23R gene. (b) Sequence alignment of IL23R protein sequences from different species (adapted from Pidasheva et al. 2011).

Figure 3. IL-23R Linkage disequilibrium (LD) plot. Two haplotype blocks were constructed for the IL23R (adapted from Ferguson et al. 2010).

Figure 4. Linkage disequilibrium (LD) patterns of region around IL23R and IL17A genes in a Chinese Han population. (a) IL23R. (b) IL17A. Numbers indicate extent of D’ between two SNP and in the dark area which have no digital respective D’ = 1. Dark color indicates strong connection. Three linkage disequilibrium blocks were found in IL-23R and one in IL-17A (adapted from Yu et al. 2012).

Figure 5. Increase of ulcerative colitis risk with the haplotypes of IL23R and IL-17A. Relative risk haplotypes were plotted and demonstrate association between IL-23R block1 haplotype3 and IL-17A haplotype4 (p = 0.014 for interaction) (adapted from Yu et al. 2012).

Figure 6. Summary of results obtained in study using genotype-selectable normal donors is depicted. IL23RQ381 donors had a significant decrease in IL23R⁺ T-cells, leading to decreased IL-23-induced STAT3 phosphorylation. A decrease in STAT3 signaling in T-cells like T_H17 could then modulate the extent/duration of the response in the host, leading to decreased secretion of pro-inflammatory cytokines like IL-17 and IL-22 in the gut. This could help explain the protective effect of R381Q variant in CD and other autoimmune disorders (adapted from Pidasheva et al. 2011).

Figure 7. Importance of IL-23 and IL23R R381Q gene variant in T_H17 cell function. The IL-23/IL-23R axis plays a pivotal role in both T_H17 differentiation in the lymph nodes and T_H17 cell effector functions in peripheral tissues, with the latter becoming increasingly relevant, especially in the context of IL-23-induced pathologies, like psoriasis and Crohn’s disease. This protective effect against autoimmune disease is driven through impairment of T_H17 cell effector functions, i.e. IL-17A production, rather than T_H17 differentiation (adapted from Di Meglio et al. 2011).

Table 1. Summary of association study results related to IL-23R rs11209026.

Disease	Population	Population size	Effect size (OR with 95% CI)	Type of association study	Case MAF (%)	Control MAF (%)	p-Value	Association	References
CD	Non- Jewish	547	0.26 (0.15–0.43)	GWAS	1.9	7.0	5.0 × 10^−9	Protective	Duerr et al. (2006)
CD	Jewish	401	0.45 (0.27–0.73)	GWAS	3.3	7.0	8.0 × 10^−4	Protective	Lakatos et al. (2008)
CD	Spanish White	460	0.30 (0.30– 0.70)	Candidate gene  (Replication study)	2.0	7.0	1.0 × 10^−3	Protective	Oliver et al. (2007)
IBD	Netherlands	518	0.19 (0.09–0.31)	Candidate gene	1.2	6.5	5.8 × 10^−8	Protective	Weersma et al. (2008)
CD	UK Caucasian	604	0.43 (0.29–0.64)	Candidate gene	2.6	5.9	6.8 × 10^−6	Protective	Fraser Cummings et al. (2007)
UC	UK Caucasian	647	0.63 (0.45–0.89)	Candidate gene	3.8	5.9	8.1 × 10^−3	Protective	Fraser Cummings et al. (2007)
CD	German	833	0.43 (0.31–0.59)	Candidate gene	3.0	6.8	8.0 × 10^−8	Protective	Glas et al. (2007)
UC	German	856	0.70 (0.50–0.98)	Candidate gene	4.9	6.8	3.6 × 10^−2	Protective	Glas et al. (2007)
CD	Italian	210	0.33 (0.22–0.53)	Candidate gene	2.1	9.9	6.7 × 10^−3	Protective	Borgiani et al. (2007)
CD	New Zealand	496	0.54 (0.34–0.77)	Candidate gene	4.0	7.0	2.6 × 10^−3	Protective	Roberts et al. (2007)
UC	New Zealand	466	0.66 (0.43–0.72)	Candidate gene	4.0	7.0	3.7 × 10^−2	Protective	Roberts et al. (2007)
CD	UK Caucasian	1902	0.38 (0.29–0.50)	Candidate gene	2.5	6.2	1.1 × 10^−12	Protective	Tremelling et al. (2007)
Psoriasis	UK Caucasian	519	0.49 (0.25–0.57)	Candidate gene	3.6	7	1.4 × 10^−4	Protective	Capon et al. (2007)
Psoriasis	Caucasian	1446	0.63 (0.38–0.78)	Candidate gene	3.5–5.1	6.0–7.7	1.9 × 10^−4	Protective	Cargill et al. (2007)
AS	Spanish	365	0.46 (0.20–0.70)	Candidate gene	3.0	7.0	0.001	Protective	Rueda et al. (2008)
AS	UK Caucasian	1000	0.63 (0.45–0.72)	Candidate gene  (Replication study)	4.0	6.0	4.00E-0.06	Protective	Burton et al. (2007)
CD	British Caucasian	236	0. 37 (0.21–0.67)	Candidate gene	2.8	7.1	6.0 × 10^−4	Protective	Cotterill et al. (2010)
UC	British Caucasian	167	0.69 (0.40–1.18)	Candidate gene	5.0	7.1	1.8 × 10^−1	Protective	Cotterill et al. (2010)
CD	Japanese	484		Candidate gene	0.0	0.0		None	Yamazaki et al. (2007)
CD	Hungarian	266	0.38 (0.16–0.87)	Candidate gene	3.8	9.4	3.7 × 10^−2	Protective	Lakatos et al. (2008)
IBD	Chilean	100	0.96 (0.18–6.45)	Candidate gene	2.5	2.6	5.0 × 10^−2	Protective	Venegas et al. (2008)
RA	Egyptian	120	0.37 (0.26–0.57)	Candidate gene	5	38.3	1.0 × 10^−3	Protective	Hamdy et al. (2015)
RSA	Iranian	200	0.25 (0.12–0.61)	Candidate gene	2	7.5	1.0 × 10^−2	Protective	Abdollahi et al. (2015)
Asthma	Iranian	209	0.27 (0.12–0.60)	Candidate gene	3.8	13.0	1.0 × 10^−3	Protective	Mosayebian et al. (2015)

GWAS: Genome-Wide Association Study; MAF: Minor Allele Frequency; OR: Odds Ratio; CD: Crohn’s Disease; UC: Ulcerative Colitis; IBD: Inflammatory Bowel Disease; AS: Ankylosing Spondylitis; RA: Rheumatoid Arthritis; RSA: Recurrent Spontaneous Abortion.

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