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Aging and disease    2018, Vol. 9 Issue (1) : 40-50     DOI: 10.14336/AD.2017.0308
Orginal Article |
Identification of MAVS as a Novel Risk Factor for the Development of Osteoarthritis
Liu Jie1, Tang Ling-yun2, Wang Yan-gui3, Lu Shun-yuan2, Zhang En-ning4, Wang Zhu-gang2,*, Zhang Hong-xin2,*
1Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
2State Key Laboratory of Medical Genomics, Research center for experimental medicine, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
3Department of Clinical Laboratory, Yantaishan Hospital, Yantai, Shandong, 264008, China
4Department of Medical Oncology, Yantaishan Hospital, Yantai, 264000, China
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Abstract  

Evidence indicated that inflammatory response and some pattern-recognition receptors play important roles in the occurrence and progression of osteoarthritis. This study is conducted to evaluate the role of RIG-I and its adaptor protein MAVS in the pathogenesis of osteoarthritis. Four SNPs in RIG-I gene and four in MAVS gene were genotyped in 1056 Chinese Han population. We also overexpressed MAVS in murine chondrogenic ATDC5 cells and analyzed the cell viability and apoptosis. Rs11795343 (P-allele: 0.063394) in RIG-I, rs17857295 (P-allele: 0.073518) and rs7262903 (P-allele: 0.054052, P-genotype: 0.067930) in MAVS were marginally associated with OA. Rs7269320 (P-allele: 0.014783, P-genotype: 0.03272) in MAVS was significant associated with OA. Further analyses in different genders indicated that rs7262903 (P-allele: 0.017256, P-genotype: 0.045683) and rs7269320 (P-allele: 0.013073, P-genotype: 0.038881) are significantly associated with OA in female group. Haplotype analyses indicated G-C-G (χ2: 4.328, P-value: 0.037503) in rs10813821-rs11795343-rs659527 block of RIG-I, G-C-A-T (χ2: 4.056, P-value: 0.044028) and G-C-C-C (χ2: 14.295, P-value: 0.000158) in rs17857295-rs2326369-rs7262903-rs7269320 block of MAVS were significantly associated with OA. Furthermore, forced expression of MAVS could suppress the viability and promote the apoptosis of ATDC5 chondrogenic cells. In conclusion, this study indicated that RIG-I and MAVS are probably associated with OA in the females of Chinese Han population. And MAVS might be a novel risk factor for OA which may involve in growth of chondrocytes and cartilage homeostasis.

Keywords Osteoarthritis      RIG-I      MAVS      SNP      apoptosis     
Corresponding Authors: Wang Zhu-gang,Zhang Hong-xin   
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These authors contribute equally to this work

Issue Date: 01 February 2018
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Liu Jie
Tang Ling-yun
Wang Yan-gui
Lu Shun-yuan
Zhang En-ning
Wang Zhu-gang
Zhang Hong-xin
Cite this article:   
Liu Jie,Tang Ling-yun,Wang Yan-gui, et al. Identification of MAVS as a Novel Risk Factor for the Development of Osteoarthritis[J]. Aging and disease, 2018, 9(1): 40-50.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0308     OR     http://www.aginganddisease.org/EN/Y2018/V9/I1/40
Figure 1.  Linkage disequilibrium (LD) block structure consisted of the 8 SNPs located in the two genes, separately

(A) LD block structure consisted of the 4 SNPs located in RIG-I gene; (B) LD block structure consisted of the 4 SNPs located in MAVS gene. The LD block was defined by a D’ value threshold of 0.8. The color scale ranges from red to white (color intensity decreases with decreasing D’ value, and all of D’ values were = 1). This locus was identified as one block, and the plot was generated by Haploview.

GenesSNP IDAllelesaOR(95%CI)2P-value1GenotypesHWe PbP-value
RIG-Irs10813821A(freq) G(freq)A/A(freq) A/G(freq) G/G(freq)
Case190(0.158) 1014(0.842)0.958298[0.755065-1.216233]0.72613515(0.025) 160(0.266) 427(0.709)0.480520
Control140(0.164) 716(0.836)16(0.037) 108(0.252) 304(0.710)0.107796
rs11795343C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case316(0.262) 888(0.738)1.214312[0.989084-1.490828]0.06339445(0.075) 226(0.375) 331(0.550)0.184901
Control194(0.227) 662(0.773)25(0.058) 144(0.336) 259(0.605)0.405492
rs659527A(freq) G(freq)A/A(freq) A/G(freq) G/G(freq)
Case723(0.600) 481(0.400)0.897384[0.749408-1.074579]0.238849222(0.369) 279(0.463) 101(0.168)0.502193
Control536(0.626) 320(0.374)170(0.397) 196(0.458) 62(0.145)0.651586
MAVSrs17857295C(freq) G(freq)C/C(freq) C/G(freq) G/G(freq)
Case615(0.511) 589(0.489)1.173689[0.984821-1.398777]0.073518167(0.277) 281(0.467) 154(0.256)0.220791
Control403(0.471) 453(0.529)103(0.241) 197(0.460) 128(0.299)0.114502
rs2326369C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case920(0.764) 284(0.236)0.930425[0.755102-1.146454]0.498393349(0.580) 222(0.369) 31(0.051)0.697337
Control665(0.777) 191(0.223)259(0.605) 147(0.343) 22(0.051)0.847191
rs7262903A(freq) C(freq)A/A(freq) A/C(freq) C/C(freq)
Case137(0.114) 1067(0.886)1.337045[0.994199-1.798119]0.05405212(0.020) 113(0.188) 477(0.792)0.067930
Control75(0.088) 781(0.912)2(0.005) 71(0.166) 355(0.829)0.436946
rs7269320C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case1066(0.885) 138(0.115)0.687945[0.508620-0.930495]0.014783476(0.791) 114(0.189) 12(0.020)0.032720
Control786(0.918) 70(0.082)360(0.841) 66(0.154) 2(0.005)0.578922
Table 1  Allele and genotype frequency of the 7 loci in total group.
GenesSNP IDAllelesaOR(95%CI)2P-value1GenotypesHWe PbP-value
RIG-Irs10813821A(freq) G(freq)A/A(freq) A/G(freq) G/G(freq)
Case133(0.150) 753(0.850)1.062972[0.756771-1.493067]0.72460410(0.023) 113(0.255) 320(0.722)0.348698
Control55(0.142) 331(0.858)7(0.036) 41(0.212) 145(0.751)0.069465
rs11795343C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case241(0.272) 645(0.728)1.265292[0.956216-1.674272]0.09920436(0.081) 169(0.381) 238(0.537)0.252739
Control88(0.228) 298(0.772)10(0.052) 68(0.352) 115(0.596)0.989850
rs659527A(freq) G(freq)A/A(freq) A/G(freq) G/G(freq)
Case534(0.603) 352(0.397)0.953754[0.746394-1.218722]0.705020165(0.372) 204(0.460) 74(0.167)0.241120
Control237(0.614) 149(0.386)68(0.352) 101(0.523) 24(0.124)0.148447
MAVSrs17857295C(freq) G(freq)C/C(freq) C/G(freq) G/G(freq)
Case452(0.510) 434(0.490)1.063286[0.837171-1.350472]0.614937124(0.280) 204(0.460) 115(0.260)0.889261
Control191(0.495) 195(0.505)51(0.264) 89(0.461) 53(0.275)0.280861
rs2326369C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case674(0.761) 212(0.239)1.009112[0.762890-1.334803]0.949302255(0.576) 164(0.370) 24(0.054)0.989339
Control293(0.759) 93(0.241)111(0.575) 71(0.368) 11(0.057)0.936182
rs7262903A(freq) C(freq)A/A(freq) A/C(freq) C/C(freq)
Case95(0.107) 791(0.893)1.734260[1.097198-2.741217]0.0172568(0.018) 79(0.178) 356(0.804)0.045683
Control25(0.065) 361(0.935)0(0.000) 25(0.130) 168(0.870)0.335999
rs7269320C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case792(0.894) 94(0.106)0.558599[0.350810-0.889462]0.013073356(0.804) 80(0.181) 7(0.016)0.038881
Control362(0.938) 24(0.062)169(0.876) 24(0.124) 0(0.000)0.357019
Table 2  Allele and genotype frequency of the 7 loci in female group.
GenesSNP IDAllelesaOR(95%CI)2P-value1GenotypesaHWe PbP-value
RIG-Irs10813821A(freq) G(freq)A/A(freq) A/G(freq) G/G(freq)
Case57(0.179) 261(0.821)0.989182[0.682903-1.432825]0.9541005(0.031) 47(0.296) 107(0.673)0.921633
Control85(0.181) 385(0.819)9(0.038) 67(0.285) 159(0.677)0.562933
rs11795343C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case75(0.236) 243(0.764)1.059865[0.756359-1.485159]0.7355289(0.057) 57(0.358) 93(0.585)0.759756
Control106(0.226) 364(0.774)15(0.064) 76(0.323) 144(0.613)0.255147
rs659527A(freq) G(freq)A/A(freq) A/G(freq) G/G(freq)
Case189(0.594) 129(0.406)0.837909[0.625558-1.122345]0.23542557(0.358) 75(0.472) 27(0.170)0.304381
Control299(0.636) 171(0.364)102(0.434) 95(0.404) 38(0.162)0.052084
MAVSrs17857295C(freq) G(freq)C/C(freq) C/G(freq) G/G(freq)
Case163(0.513) 155(0.487)1.279793[0.962189~1.702233]0.08982243(0.270) 77(0.484) 39(0.245)0.239040
Control212(0.451) 258(0.549)52(0.221) 108(0.460) 75(0.319)0.269945
rs2326369C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case246(0.774) 72(0.226)0.900090[0.637949-1.269947]0.54888094(0.591) 58(0.365) 7(0.044)0.696490
Control372(0.791) 98(0.209)148(0.630) 76(0.323) 11(0.047)0.756956
rs7262903A(freq) C(freq)A/A(freq) A/C(freq) C/C(freq)
Case42(0.132) 276(0.868)1.278261[0.825347-1.979714]0.2704964(0.025) 34(0.214) 121(0.761)0.363315
Control50(0.106) 420(0.894)2(0.009) 46(0.196) 187(0.796)0.650864
rs7269320C(freq) T(freq)C/C(freq) C/T(freq) T/T(freq)
Case274(0.862) 44(0.138)0.675600[0.434962-1.049371]0.079560120(0.755) 34(0.214) 5(0.031)0.148153
Control424(0.902) 46(0.098)191(0.813) 42(0.179) 2(0.009)0.852830
Table 3  Allele and genotype frequency of the 7 loci in male group.
Figure 2.  Overexpression of MAVS could suppress viability and promote apoptosis in murine ATDC5 chondrogenic cell

(A) The proteins expression of MAVS was measured by western blotting. (B) CCK-8 cell proliferation assay showed that MAVS overexpression led to decreased cell proliferative capabilities compared with the control cells (P < 0.01). (C) Annexin V-FITC/PI staining of ATDC5 cells transfected with MAVS expression vectors as analyzed by flow cytometry. (D) The percentages of different cell groups were calculated and expressed as mean ± SD, n = 3 in each group. **P < 0.01 versus control group.

GroupHaplotypeCase(freq) (%)Control (freq)(%)χ2POR[95%CI]
rs10813821-rs11795343-rs659527A C A0.00(0.000)1.37(0.002)---
A C G95.49(0.079)66.27(0.077)0.0170.897551.022 [0.737~1.416]
A T A1.34(0.001)3.37(0.004)---
A T G93.17(0.077)68.99(0.081)0.0880.7671990.952 [0.688~1.317]
G C G220.51(0.183)126.36(0.148)4.3280.0375031.288 [1.014~1.635]
G T A721.66(0.599)531.26(0.621)1.2100.2712670.904 [0.755~1.082]
G T G71.83(0.060)58.38(0.068)0.6580.4171680.863 [0.604~1.233]
rs17857295-rs2326369-rs7262903-rs7269320C C A C0.41(0.000)2.98(0.003)---
C C A T36.50(0.030)19.31(0.023)1.1180.2903001.350 [0.772~2.361]
C C C C380.31(0.316)236.89(0.277)3.4990.0614221.202 [0.991~1.459]
C T A C0.00(0.000)0.14(0.000)---
C T A T0.00(0.000)0.03(0.000)---
C T C C197.49(0.164)143.65(0.168)0.0670.7963210.969 [0.766~1.227]
G C A C3.60(0.003)3.90(0.005)---
G C A T96.37(0.080)48.63(0.057)4.0560.0440281.440 [1.008~2.057]
G C C C397.79(0.330)351.28(0.410)14.2950.0001580.704 [0.587~0.845]
G C C T4.74(0.004)2.02(0.002)---
G T C C86.39(0.072)47.17(0.055)2.2360.1347871.321 [0.916~1.906]
C C C T0.27(0.000)0.00(0.000)---
G T A T0.11(0.000)0.00(0.000)---
rs2583760-rs2583759 Global result:
Global chi2 is 156.695374 while df=1 (frequency<0.03 in both control & case has been dropped.)
Pearson’s p value is 0.00E+000
Permutation p value(Pearson) is 0.0000
rs2583764-rs2583760-rs6993386-rs2583759 Global result:
Global chi2 is 291.831390 while df=5 (frequency<0.03 in both control & case has been dropped.)
Pearson’s p value is Pearson’s p value is 0.00E+000
Permutation p value(Pearson) is 0.0000
Table 4  Haplotype analysis.
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