Dense mapping of IL18 shows no association in SLE

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease which behaves as a complex genetic trait. At least 20 SLE risk susceptibility loci have been mapped using both candidate gene and genome-wide association strategies. The gene encoding the pro-inflammatory cytokine, IL18, has been reported as a candidate gene showing an association with SLE. This pleiotropic cytokine is expressed in a range of immune cells and has been shown to induce interferon-γ and tumour necrosis factor-α. Serum interleukin-18 has been reported to be elevated in patients with SLE. Here we aimed to densely map single nucleotide polymorphisms (SNPs) across IL18 to investigate the association across this locus. We genotyped 36 across IL18 by Illumina bead express in 372 UK SLE trios. We also genotyped these SNPs in a further 508 non-trio UK cases and were able to accurately impute a dense marker set across IL18 in WTCCC2 controls with a total of 258 SNPs. To improve the study's power, we also imputed a total of 158 SNPs across the IL18 locus using data from an SLE genome-wide association study and performed association testing. In total, we analysed 1818 cases and 10 770 controls in this study. Our large well-powered study (98% to detect odds ratio = 1.5, with respect to rs360719) showed that no individual SNP or haplotype was associated with SLE in any of the cohorts studied. We conclude that we were unable to replicate the SLE association with rs360719 located upstream of IL18. No evidence for association with any other common variant at IL18 with SLE was found.

Figure 1.

(A) Gene diagram across chromosome 11 showing SNPs genotyped in this study. (B) IL18 gene showing the six exons along with the SNPs typed in 380 UK SLE trios. SNP 1 (rs7120010), SNP 2 (rs2564866), SNP 3 (rs2853127), SNP 4 (rs891360), SNP 5 (rs2518360), SNP 6 (rs2564871), SNP 7 (rs2518345), SNP 8 (rs1367038), SNP 9 (rs7938116), SNP 10 (rs11214139), SNP 11 (rs2250417), SNP 12 (rs2518356), SNP 13 (rs11214127), SNP 14 (rs10891337), SNP 15 (rs12797880), SNP 16 (rs11214108), SNP 17 (rs360719), SNP 18 (rs1946519), SNP 19 (rs187238), SNP 20 (rs360717), SNP 21 (rs4937113), SNP 22 (rs360722), SNP 23 (rs360721), SNP 24 (rs4988359), SNP 25 (rs5744256), SNP 26 (rs549908), SNP 27 (rs5744280), SNP 28 (rs543810), SNP 29 (rs243908), SNP 30 (rs578784), SNP 31 (rs4937075), SNP 32 (rs10891323), SNP 33 (rs11214093), SNP 34 (rs360726), SNP 35 (rs10789859), SNP 36 (rs9919624).

Figure 2.

(A) UK|CC data showing SNPs which were genotyped and imputed. Haplotype constructed from 508 cases and 2608 controls. Tagger SNPs are indicated by an asterisk. Numbers across the top of the haplotypes correspond to the SNP numbers in Figure 1. The haplotype number is in bold on the left of each haplotype. Haplotype frequencies are shown after each block in bold. (B) LD plot from Haploview which shows the pattern of LD across the UK|CC population with the brightest red showing regions of high pairwise D′.