Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 56, Issue 3, Pages 1517-1523Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.14-15030
Keywords
acute anterior uveitis; ankylosing spondylitis; Behcet's disease; copy number variants; Toll-like receptor 7; Toll-like receptor; uveitis; Vogt-Koyanagi-Harada syndrome
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Funding
- Natural Science Foundation Major International (Regional) Joint Research Project [81320108009]
- Key Project of Natural Science Foundation [81130019]
- National Natural Science Foundation Project [31370893]
- Clinic Key Project of Ministry of Health [201002019]
- Basic Research Program of Chongqing [cstc2013jcyjC10001]
- Chongqing Key Laboratory of Ophthalmology (CSTC) [2008CA5003]
- National Key Clinical Specialties Construction Program of China
- Key Project of Health Bureau of Chongqing [2012-1-003]
- Fund for PAR-EU Scholars Program
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PURPOSE. The purpose of this study was to test whether gene copy number variations (CNVs) of Toll-like receptors (TLRs) are associated with uveitis. METHODS. Copy number variations of TLRs were detected by real-time PCR. The first stage of the study consisted of enrolling 400 Behcet's disease (BD) patients, 400 Vogt-Koyanagi-Harada syndrome patients, 400 patients with acute anterior uveitis associated with or without ankylosing spondylitis, and 600 healthy subjects. The second stage included another set of 578 BD patients and 1000 healthy controls. The frequencies of TLR gene copy number types (TLR1, TLR2, TLR3, TLR5, TLR6, TLR7, TLR9, TLR10) were compared among patients and controls by using the chi(2) test. Real-time PCR was used to detect mRNA expression from peripheral blood mononuclear cells (PBMCs) obtained from healthy controls following stimulation with the TLR7 agonist R848. Levels of TNF-alpha, IL-6, IL-1 beta, and IFN-beta in culture supernatants were measured by ELISA. RESULTS. All TLRs tested, except for TLR7, had a gene copy number of two in more than 98% of individuals tested. In the first stage, we found a significantly increased frequency of more than one copy of TLR7 (located on the X chromosome) in male BD patients and more than two copies in female patients (correction of P value [P-C] = 0.021; P-C = 0.048, respectively). A second stage and combined study confirmed the association (P-C = 1.14 x 10(-6); P-C = 9.12 x 10(-5), respectively). TLR7 mRNA expression in PBMCs was increased in healthy male carriers having more than one copy of TLR7 or females having more than two copies following stimulation with R848 (P = 0.021, P = 0.006, respectively). No effect of the various TLR7 copies on the release of TNF-alpha, IL-6, IL-1 beta, and IFN-beta could be detected. CONCLUSIONS. This study provides evidence that a high copy number of TLR7 confers risk for BD in a Chinese Han population.
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