A comparison of genetic variants associated with cutaneous and systemic vasculitis using an international classification of diseases (ICD-10) based approach in the uk biobank

Description of Background: Cutaneous vasculitis consists of a group of inflammatory disorders that affect the skin blood vessels and has no visceral involvement. Visceral involvement, if occurs, can present later, revealing an underlying systemic process. Prior to the diagnosis of cutaneous vasculitis, a workup is required to rule out systemic involvement. Since genes contribute to the pathogenesis of vasculitis, it may also help differentiate between cutaneous and systemic vasculitis.

Methods: The UK Biobank is a prospective cohort that contains clinical and genetic data from over 500,000 individuals. We ran two genome-wide association studies (GWAS) to identify variants associated with cutaneous vasculitis [ICD code L95] and systemic vasculitis [ICD codes I73.1, M05.2, M30.0, M30.1, M30.2, M30.8, M30.3, M31.3, M31.7, M31.2, M31.4, M31.5 and M31.6]. We compared cases to age, sex, and ancestry-matched controls in a 1:20 ratio. We used a cut-off of 1x10-6 to identify variants with possible significance and a cut-off of 5x10-8 for statistical significance. We only assessed genes outside the HLA locus on chromosome 6.

Results: There were 161 and 925 cases of cutaneous and systemic vasculitis respectively. In the cutaneous vasculitis group, we identified 28 variants linked to 19 genes with p< 1x10-6. Of those, 3 variants linked to 3 genes with p< 5x10-8: ITK (IL2 inducible T cell kinase) OR 8.9, P= 1.9x10-10; PEX14 (peroxisomal biogenesis factor 14) OR=5.5, p = 3.9x10-8; RTL4 (retrotransposon Gag like 4) OR=2.9, p = 4.68x10-8. In the systemic vasculitis group, we identified 28 variants linked to 11 genes with p< 1x10-6. Of those, 1 had p< 5x10-8 (MIR4318 (microRNA 4318) OR=3.4, p = 2.6x10-8). There was no overlap in the variants that met the p< 1x10-6 threshold between the two groups.

Conclusion: Using the UK Biobank, we identified variants in both systemic and cutaneous vasculitis with p< 1x10-6. Both IL2 and peroxisomes are involved in regulating inflammation. Additionally, microRNAs have been associated with ANCA vasculitis. The lack of overlap suggests that there is a potential to utilize genetics to differentiate between cutaneous and systemic vasculitis with a greater degree of accuracy. Further studies are required to verify the results of this analysis.

Learning Objective: Identify variants associated with cutaneous vasculitis including ITK, PEX14 and RTL4. Identify variants associated with systemic vasculitis including MIR4318.