An amino acid motif in HLA-DRß1 distinguishes patients with uveitis in juvenile idiopathic arthritis

A.J.W. Haasnoot; M.W. Schilham; S.S.M. Kamphuis; P.C.E. Hissink Muller; A. Heiligenhaus; D. Foell; R.A. Ophoff; T.R.D.J. Radstake; A.I. Den Hollander; T.H.C.M. Reinards; S. Hiddingh; N. Schalij-Delfos; E.P.A.H. Hoppenreijs; M.A.J. van Rossum; C. Wouters; R.K. Saurenmann; N. Wulffraat; R. ten Cate; J.H. de Boer; S.L. Pulit; J.J.W. Kuiper

The relatively high frequency of serine-11 in the JIA cases that did not develop uveitis ( Table 2) indicates the likely involvement of additional (epi)genetic and environmental factors. Indeed, genes outside the MHC have been implicated in JIA-uveitis, including a . CC-BY-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/140954 doi: bioRxiv preprint polymorphism in VTCN1 53 and variants near the immune genes TRAF1 and C5. 54 More than half of patients with JIA-uveitis display elevated titers of anti-parvovirus B19 antibody in ocular fluids, 43, 55 and human parvovirus B19 infection can cause various clinical features, including arthritis, uveitis and ANA production. 56, 57 In addition, immunity to Parvo-B19 infection is strongly associated with HLA-DRB1 and involves T helper cells. These observations collectively outline a complex interplay of both biologic and environmental factors in JIA-uveitis. [58] [59] [60] [61] Though we were able to identify the serine-11 association in this collection of JIA-uveitis and JIA without uveitis samples, our analyses leave unanswered questions as to the genetic underpinnings of uveitis, and potential sex-based differences in their pathogenesis. Given our sample size, we were well powered to detect common (frequency >10%) and highlypenetrant (odds ratio > 3, Supplementary Figure 9 ) variation that associates with increased uveitis risk compared to JIA individuals without uveitis. However, we are underpowered to identify common, modestly-penetrant variation -the hallmark genetic feature of complex phenotypes 62,63 -that may further distinguish the two phenotypes. In the current study, we included only patients for whom we were able to obtain detailed ophthalmological follow-up for ≥ 4 year (±90% of uveitis develops within 4 years after onset). 64 While imperative to revealing the serine-11 association, this strategy limited case ascertainment. Future genetic studies will likely benefit from broader inclusion of cases, including essential, detailed phenotype information, 7,65 in order to identify additional genetic associations that are shared across or distinct to particular uveitis subtypes of gender. 66 In addition, clinical studies -including clinical trials -may be improved by being well-powered in both sexes to enable sex-specific investigations.