山东大学耳鼻喉眼学报 ›› 2019, Vol. 33 ›› Issue (3): 79-87.doi: 10.6040/j.issn.1673-3770.1.2019.008

• 论著 • 上一篇    下一篇

TLR通路基因多态性与变应性鼻炎的关联研究

陈若希1,张清照1,陆美萍1,朱歆洁1,程雷1,2,3()   

  1. 1. 南京医科大学第一附属医院 江苏省人民医院耳鼻咽喉科,江苏 南京 210029
    2. 南京医科大学国际变态反应研究中心,江苏 南京 210029
    3. 江苏省临床医学研究院过敏与自身免疫性疾病研究所,江苏 南京 210029
  • 收稿日期:2019-02-15 修回日期:2019-05-06 出版日期:2019-05-20 发布日期:2019-08-07
  • 通讯作者: 程雷 E-mail:chenglei@jsph.org.cn
  • 基金资助:
    江苏省“科教兴卫工程”医学重点学科(XK200719);医学重点人才(RC2007065)

Association of Toll-like receptor pathway gene polymorphisms with allergic rhinitis

Ruoxi CHEN1,Qingzhao ZHANG1,Meiping LU1,Xinjie ZHU1,Lei CHENG1,2,3()   

  1. 1. Department of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
    2. International Centre for Allergy Research, Nanjing Medical University, Nanjing 210029, Jiangsu, China
    3. The Institute of Allergy and Autoimmune Disease,Jiangsu Clinical Medicine Research Institution,Nanjing 210029,Jiangsu,China
  • Received:2019-02-15 Revised:2019-05-06 Online:2019-05-20 Published:2019-08-07
  • Contact: Lei CHENG E-mail:chenglei@jsph.org.cn

摘要: 目的

Toll样受体(TLR)信号通路一直是变应性鼻炎(AR)和哮喘等变态反应性疾病的研究热点,研究TLR通路基因单核苷酸多态性(SNPs)与AR发病的相关性及机制。

方法

采用基于医院的病例-对照研究,选择持续性AR患者452例及正常人群495例。通过生物信息学数据库系统筛选TLR通路基因6个SNPs,分别是TLR2的rs7656411、rs76112010、rs7682814,CD14的rs2563298、rs2569190、rs2569191。采用TaqMan技术对SNPs进行分型,ImmunoCAP100变应原体外检测系统测定血清总IgE、特异性IgE,分析SNPs与AR发病率的相关性,并探讨基因-基因相互作用。

结果

CD14的rs2563298、rs2569191基因分布在AR组与对照组比较有统计学意义(P<0.05)。TLR2的rs7656411和CD14的rs2563298、rs2569191在AR伴随哮喘组与正常对照组中基因分布有明显差异。此外TLR2的rs7656411在AR男性组和有家族史组与对照组的基因分布有明显差异,CD14的rs2563298、rs2569191在AR分组中与对照组均有明显差异。基因交互发现rs7656411,rs2563298、rs2569191三个位点存在阳性关联。

结论

TLR通路基因TLR2、CD14多态性与AR发病风险及其临床表型存在一定相关性。

关键词: 变应性鼻炎, Toll样受体, CD14, 单核苷酸多态性, 遗传学关联研究

Abstract: Objective

The involvement of the Toll-like receptor (TLR) signaling pathway in allergic rhinitis (AR), asthma, and other allergic diseases is being intensively studied. The present study assessed the correlation between TLR pathway gene single nucleotide polymorphisms (SNPs) and incidence of AR, and investigated the influence of SNPs in the pathogenesis of AR.

Methods

Candidate TLR pathway SNPs were screened by a search of a bioinformatics database system using the TaqMan SNP genotyping system as part of a hospital-based case-control study of 452 AR patients and 491 healthy controls. Serum levels of eosinophil cationic protein, total IgE, and allergen-specific IgE were measured by the Immuno CAP blood test.

Results

Six SNPs were identified (TLR2 rs7656411, rs76112010, rs7682814 and CD14 rs2563298, rs2569190, rs2569191). Genotype frequencies of CD14 rs2563298 and rs2569191 were significantly different between the cases and controls (P<0.05). AR patients with asthma were significantly associated with the rs7656411, rs2563298, and rs2569191. Genotype frequencies of TLR2 rs7656411 were significantly different between controls and the male and history case subgroups. Significant differences were also found in genotypes of CD14 rs2563298 and rs2569191 compared with control and subgroups of cases. Gene interaction analysis revealed a three-locus interaction involving TLR2 rs7656411, CD14 rs2563298, and CD14 rs2569191 in AR cases.

Conclusion

Polymorphisms of TLR2 and CD14 in the TLR pathway may contribute to susceptibility of AR in this Chinese population.

Key words: Allergic rhinitis, Toll-like receptors, CD14, Single nucleotide polymorphism, Genetic association studies

中图分类号: 

  • R765.21

表1

TLR2和CD14等位基因的基本信息及基因频率分布"

序号 SNPs 染色体位置 碱基变化 最小等位基因(MAF) HWE P a
数据库 病例组 对照组
1 rs7656411 3′near gene G/T 0.419 0.482 0.451 0.168
2 rs76112010 5′near gene A/G 0.136 0.203 0.169 0.661
3 rs7682814 5′near gene A/G 0.167 0.202 0.172 0.286
4 rs2563298 3′UTR A/C 0.151 0.123 0.184 0.067
5 rs2569190 5′UTR A/T 0.500 0.380 0.412 0.988
6 rs2569191 5′near gene C/T 0.453 0.363 0.426 0.625

表2

病例组和对照组研究对象的临床特征"

变量 病例组 (n = 452) 对照组 (n = 495) P
年龄 (岁, x ˉ ± s ) 19.70 ± 12.60 20.10 ± 12.61 0.597a
性别[n(%)]
302(66.8) 303(61.2) 0.073a
150(33.2) 192(38.8)
鼻炎病程 (年, x ˉ ± s ) 6.62 ± 5.87
鼻腔总症状 ( x ˉ ± s ) 5.25 ± 2.39
血清总IgE [kU/L, M (IQR)] 264.0 (120.6~593.5) 26.8 (11.1~52.2) < 0.001b
特异性IgE [kUA/L, M (IQR)]
屋尘螨 29.0(4.6~72.5)
粉尘螨 24.1 (5.0~69.9)
ECP [μg/L, median(IQR)] 12.7 (5.2~28.7) 4.6 (3.1~7.5) < 0.001b
伴随哮喘
118(26.1)
271(60.0)
家族史
122(27.0)
269(59.5)

表3

TLR2和CD14多态性基因分型及在病例与对照组中的频率分布"

SNPs 基因型 病例组 对照组 Crude OR(95%CI)

Adjusted OR

(95%CI)a

P b
n % n %
TLR2
rs7656411 n = 441 n =493
GG 112 25.4 156 31.6 1.00 (reference) 1.00 (reference) 0.079
GT 233 52.8 229 46.5 1.42 (1.05~1.92) 1.41 (1.04~1.91)
TT 96 21.8 108 21.9 1.23 (0.86~1.79) 1.22 (0.84~1.76)
GT/TT 329 74.6 337 68.4 1.36 (1.02~1.81) 1.35 (1.01~1.79) 0.035
T allele 0.451 0.186
rs76112010 n = 446 n = 485
GG 287 64.4 331 68.3 1.00 (reference) 1.00 (reference) 0.144
GA 137 30.7 141 29.1 1.12 (0.84~1.49) 1.15 (0.86~1.53)
AA 22 4.96 13 2.7 1.95 (0.97~3.95) 1.98 (0.98~4.02)
GA/AA 159 35.7 154 31.2 1.19 (0.91~1.53) 1.22 (0.93~1.60) 0.209
A allele 0.203 0.089
rs7682814 n = 441 n = 486
GG 285 64.6 330 67.9 1.00 (reference) 1.00 (reference) 0.074
GA 134 30.4 145 29.8 1.07 (0.81~1.42) 1.09 (0.82~1.45)
AA 22 5.00 11 2.26 2.32 (1.10~4.86) 2.29 (1.09~4.81)
GA/AA 42 15.9 38 13.9 1.15 (0.88~1.52) 1.17 (0.90~1.55) 0.292
A allele 0.202 0.097
CD14
rs2563298 n = 434 n =479
CC 336 77.4 326 68.1 1.00 (reference) 1.00 (reference) 0.003
CA 89 20.5 131 27.3 0.66 (0.48~0.90) 0.65 (0.48~0.89)
AA 9 2.1 22 4.60 0.40 (0.18~0.88) 0.40 (0.18~0.89)
CA/AA 98 68.5 153 31.9 0.62 (0.46~0.84) 0.62 (0.46~0.83) 0.002
A allele 0.123 <0.001
rs2569190 n = 450 n = 481
AA 174 38.7 166 34.5 1.00 (reference) 1.00 (reference) 0.351
AG 210 46.7 233 48.4 0.86 (0.65~1.14) 0.86 (0.64~1.15)
GG 66 14.7 82 17.1 0.78 (0.88~1.92) 0.76 (0.52~1.94)
AG/GG 276 61.3 315 65.5 0.84 (0.52~1.31) 0.84 (0.64~1.09) 0.188
G allele 0.380 0.150
rs2569191 n = 441 n = 472
CC 187 42.4 153 32.4 1.00 (reference) 1.00 (reference) 0.008
CT 188 42.6 236 50.0 0.65 (0.49~0.87) 0.65 (0.48~0.87)
TT 66 15.0 83 17.6 0.65 (0.44~0.96) 0.64 (0.44~0.95)
CT/TT 254 57.6 319 67.6 0.65 (0.50~0.85) 0.65 (0.49~0.85) 0.002
T allele 0.363 0.006

表4

TLR2和CD14基因分型(MW/MM)与变应性鼻炎易感因素的分层分析"

变量 分组 rs7656411 病例/对照 rs2563298 病例/对照 rs2569191 病例/对照
例数

Adjusted OR

(95%CI)b

例数

Adjusted OR

(95%CI)b

例数

Adjusted OR

(95%CI)b

年龄(岁) <18 247/239 1.33(0.88~1.99) 244/239 0.54(0.36~0.80) 247/236 0.65(0.44~0.94)
≥18 194/254 1.36(0.91~2.06) 191/240 0.73(0.47~1.13) 194/236 0.66(0.44~0.98)
性别 295/303 1.60(1.12~2.30) 289/296 0.75(0.52~1.07) 293/289 0.66(0.47~0.93)
146/190 0.97(0.60~1.57) 146/183 0.42(0.25~0.72) 148/183 0.62(0.40~0.98)
哮喘 263/493 1.28(0.81~2.03) 261/479 0.45(0.27~0.75) 262/472 0.53(0.35~0.81)
116/493 1.61(1.13~2.28) 115/479 0.60(0.42~0.85) 116/472 0.70(0.51~0.96)
家族史 120/493 1.20(0.76~1.89) 118/479 0.56(0.35~0.92) 120/472 0.85(0.56~1.31)
260/493 1.64(1.16~2.33) 260/479 0.55(0.38~0.79) 260/472 0.57(0.42~0.78)
VAS <5 247/493 1.25(0.88~1.77) 241/479 0.65(0.45~0.92) 246/472 0.72(0.52~0.99)
≥5 194/493 1.45(0.99~2.12) 193/479 0.60(0.40~0.88) 195/472 0.57(0.41~0.80)
IgE a 135/493 1.41(0.99~2.00) 234/479 0.45(0.31~0.67) 237/472 0.61(0.44~0.84)
206/493 1.31(0.90~1.89) 200/479 0.82(0.57~1.19) 204/472 0.71(0.50~0.99)

表5

多因子降维模型分析基因-基因交互作用"

模型a 训练样本准确度 检测样本准确度

交叉验证一致

P
A6 0.5491 0.5264 8/10 0.0036
A3 A6 0.5712 0.5196 8/10 < 0.0001
A1 A4 A6 0.5953 0.5487 8/10 < 0.0001

图1

最佳模型树状图。距离越近的位点,交互作用越强。连线颜色为红色,位点间的交互作用越接近协同作用,若连线颜色越浅,则表示交互作用较弱"

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