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A functional variant of pre-miRNA-196a2 confers risk for Behcet’s disease but not for Vogt–Koyanagi–Harada syndrome or AAU in ankylosing spondylitis

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Abstract

This study aimed to investigate the predisposition of common pre-miRNA SNPs with Behcet’s disease (BD), Vogt–Koyanagi–Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS). A two-stage association study was carried out in 859 BD, 400 VKH syndrome, 209 AAU+AS+ patients and 1,685 controls all belonging to a Chinese Han population. Genotyping, the expression of miR-196a and Bach1 (the target gene of miR-196a), cell proliferation, cytokine production were examined by PCR–RFLP, real-time PCR, CCK8 and ELISA. In the first stage study, the results showed significantly increased frequencies of the miR-196a2/rs11614913 TT genotype and T allele in BD patients (adjusted P c = 0.024, OR = 1.63; adjusted P c = 5.4 × 10−3, OR = 1.45, respectively). However, no significant association of the tested SNPs with VKH and AAU+AS+ patients was observed. The second stage and combined studies confirmed the association of rs11614913 with BD (TT genotype: adjusted P c = 6×10−5, OR = 1.53; T allele: adjusted P c = 8×10−6, OR = 1.35; CC genotype: adjusted P c = 0.024, OR = 0.68). A stratified analysis showed an association of the rs11614913 TT genotype and T allele with the arthritis subgroup of BD (P c = 5.3 × 10−3, OR = 1.89; P c = 0.015, OR = 1.56, respectively). Functional experiments showed a decreased miR-196a expression, an increased Bach1 expression and an increased production of IL-1β and MCP-1 in TT cases compared to CC cases (P = 0.023, P = 0.0073, P = 0.012, P = 0.002, respectively). This study shows that a functional variant of miR-196a2 confers risk for BD but not for VKH syndrome or AAU+AS+ by modulating the miR-196a gene expression and by regulating pro-inflammatory IL-1β and MCP-1 production.

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Acknowledgments

This work was supported by National Basic Research Program of China (973 Program) (2011CB510200), Key Project of Natural Science Foundation (81130019), Research Fund for the Doctoral Program of Higher Education of China (20115503110002), Clinic Key Project of Ministry of Health, Basic Research program of Chongqing (cstc2013jcyjC10001), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), Key Project of Health Bureau of Chongqing (2012-1-003) and Fund for PAR-EU Scholars Program. We would like to thank all donors enrolled in the present study.

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Authors and Affiliations

  1. The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, 400016, People’s Republic of China

    Jian Qi, Shengping Hou, Qi Zhang, Dan Liao, Lin Wei, Jing Fang, Yan Zhou & Peizeng Yang

  2. University Eye Clinic Maastricht, Maastricht, The Netherlands

    Aize Kijlstra

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  1. Jian Qi
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  2. Shengping Hou
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  3. Qi Zhang
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  4. Dan Liao
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  7. Yan Zhou
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Correspondence to Peizeng Yang.

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439_2013_1346_MOESM2_ESM.tif

Supplementary Fig. S1 The role of rs11614913 plays in the pathogenesis of BD. A model figure has shown that rs11614913 might lead to an imbalance of the Bach1/HO-1 pathway mediated via an altered miR-196a expression, which subsequently contributes to the pathogenesis of Behect’ disease (TIFF 324 kb)

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Qi, J., Hou, S., Zhang, Q. et al. A functional variant of pre-miRNA-196a2 confers risk for Behcet’s disease but not for Vogt–Koyanagi–Harada syndrome or AAU in ankylosing spondylitis. Hum Genet 132, 1395–1404 (2013). https://doi.org/10.1007/s00439-013-1346-8

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