Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population

Abstract

Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(∗)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor.

Figure 1

Manhattan Plot of Genome Scanning The horizontal line indicates the significant level based on Bonferroni’s correction. The HLA locus on chromosome 6 and the IL12B region on chromosome 5 reached the significant level.

Figure 2

Associations of the IL12B and MLX Regions with the Susceptibility to TAK Associations of SNPs in the (A) IL12B and (B) MLX regions in the genome scanning are plotted according to the position of the markers. Red circles indicate results of the current genome scanning. Blue circles indicate results of the imputation analysis based on the current results. The middle panel indicates recombination rates. The lower panel indicates LD of markers. Asterisk indicates a recombination hot spot in the IL12B region.

Figure 3

Associations between rs6871626 Genotypes and Clinical Manifestations of TAK An association between rs6871626 genotypes and (A) development of AR, (B) severity of AR, and (C) time-averaged CRP levels in TAK cases. The p value was calculated by (A) logistic regression analysis, (B) linear regression analysis, and (C) linear regression analysis with time-averaged dosage of prednisolone as covariate. The recessive model is applied to all calculations. Severity of 1 to 3 in AR corresponds to mild, moderate, and severe, respectively. Mean ± SD are indicated for (B) and (C).

Figure 4

A Synergistic Effect between IL12B and HLA-B^∗52:01 on TAK Susceptibility ORs are shown for the four strata of subjects according to combination of rs6871626 and rs9263739 genotypes. Those who are negative for rs9263739 T allele, a proxy of HLA-B^∗52:01, and rs6871626 A allele are used as reference. ORs and 95% CI are indicated.