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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 556-563. doi: 10.19723/j.issn.1671-167X.2019.03.027

• 论著 • 上一篇    下一篇

中国唇腭裂患者Sonic hedgehog信号通路相关单核苷酸多态性的分析

张杰铌1,*,宋凤岐1,*,周绍楠1,郑晖1,彭丽颖1,张倩2,赵望泓3,张韬文4,李巍然1,周治波5,林久祥1△(),陈峰2△()   

  1. 1. 北京大学口腔医学院·口腔医院,正畸科 国家口腔疾病临床医学研究中心 口腔数字化医疗技术和材料国家工程实验室 口腔数字医学北京市重点实验室, 北京 100081
    2. 北京大学口腔医学院·口腔医院中心实验室,北京 100081
    3. 南方医科大学南方医院口腔科,广州 510000
    4. 烟台市口腔医院口腔正畸科,山东烟台 264000
    5. 北京大学口腔医学院·口腔医院口腔颌面外科,北京 100081
  • 收稿日期:2019-03-20 出版日期:2019-05-10 发布日期:2019-06-26
  • 通讯作者: 张杰铌,宋凤岐 E-mail:jxlin@pku.edu.cn;chenfeng2011@hsc.pku.edu.cn
  • 作者简介:林久祥,博士、资深教授、主任医师,北京大学口腔医学院颅面生长发育研究中心主任,《中华口腔正畸学杂志》总编辑,Tweed中国中心主席;是我国培养的口腔正畸专业第一位博士,1991年破格晋升教授、主任医师双职称,同年成为我国正畸界唯一获得国家教育委员会和国务院学位委员会授予的“做出突出贡献的中国博士学位获得者”,1992年获政府特殊津贴,1993年取得博士生导师资格,1998年被评为卫生部有突出贡献的中青年专家。曾任中华医学会正畸专业委员会主任委员;在国内外正畸界首次提出了“健康矫治(正畸)理念”,并研发出适宜实施该理念的传动矫正器及技术,后者2008年被卫生部评为“十年百项”适宜推广技术,与恒牙期骨性Ⅲ类牙颌畸形非手术矫治的突破一起,于2012年获中华医学科技奖二等奖、北京市科技成果二等奖,并于2014年在卫生部24项只选2项的竞争答辩中,胜出上报申请国家发明奖;2018年12月由Tweed中国中心授予“终身成就奖”。目前主要研究方向为非综合征型唇腭裂相关基础研究、传动矫正技术及健康矫治研究以及口腔颅颌面生长发育研究。|陈峰,北京大学口腔医学院副研究员、博士生导师。负责北京大学口腔医学院中心实验室微生物平台,是中华口腔医学会口腔生物医学专业委员会委员、口腔科研管理分会青年委员。担任Ebiomedicine等多家杂志审稿专家,近五年作为通信作者在Journal of Dental Research、Journal of Bone and Mineral Research、Oral Oncology、Frontiers in Microbiology、Protein & Cell等期刊发表SCI论文50余篇。主持国家自然科学基金面上项目在内的各级科研项目4项,参与获得北京市科学技术三等奖1项。2018年与北京大学基础医学院吴聪颖研究员联合申请获批北京大学医学交叉研究种子基金-中央高校基本科研业务费(ECM29基因突变在非综合征型唇腭裂发病中的作用与机制研究)。目前主要研究方向为颅颌面发育缺陷疾病(唇腭裂)的分子机制和口腔微生态(微生物宏基因组学与唾液蛋白组学)。
  • 基金资助:
    北大医学交叉研究种子基金(BMU2018MX017)-中央高校基本科研业务费、北大医学青年科技创新培育基金(BMU2018PY025)-中央高校基本科研业务费、国家自然科学基金(81870747,81860194)

Analysis of single-nucleotide polymorphism of Sonic hedgehog signaling pathway in non-syndromic cleft lip and/or palate in the Chinese population

Jie-ni ZHANG1,*,Feng-qi SONG1,*,Shao-nan ZHOU1,Hui ZHENG1,Li-ying PENG1,Qian ZHANG2,Wang-hong ZHAO3,Tao-wen ZHANG4,Wei-ran LI1,Zhi-bo ZHOU5,Jiu-xiang LIN1△(),Feng CHEN2△()   

  1. 1. Department of Orthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Department of Center Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China
    3. Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
    4. Department of Orthodontics, Yantai Stomatological Hospital, Yantai 264000, Shandong, China
    5. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2019-03-20 Online:2019-05-10 Published:2019-06-26
  • Contact: Jie-ni ZHANG,Feng-qi SONG E-mail:jxlin@pku.edu.cn;chenfeng2011@hsc.pku.edu.cn
  • Supported by:
    Supported by the Fundamental Research Funds for the Central Universities: Peking University Medicine Seed Fund for Interdisciplinary Research (BMU2018MX017), the Fundamental Research Funds for the Central Universities: Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation (BMU2018PY025), and the National Natural Science Foundation(81870747,81860194)

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摘要： 目的 探讨Sonic hedgehog(Shh)信号通路相关的单核苷酸多态性(single-nucleotide polymorphism, SNP)与非综合征型唇腭裂(non-syndromic cleft lip and/or palate, NSCL/P) 之间的关联,并对唇腭裂疾病的致病风险因素进行探索。方法 收集197例个体的外周血(NSCL/P患者100例,健康对照97例),基于国际人类基因组单体型图计划中中国北京汉族人口数据,使用Haploview软件进行单倍体型分析和标签SNP选择。针对Shh 信号通路中的4个候选基因SHH、PTCH1、SMO和GLI2共选择了27个SNP。使用Sequenom质谱技术检测27个SNP在4个Shh信号通路中候选基因的基因型,并进行分析。结果 所选择的SNP基本涵盖了候选基因的潜在功能性SNP,其最小等位基因频率(minor allele frequency,MAF)>0.05:GLI2 73.5%, PTCH1 91.0%, SMO 100.0%, SHH 75.0%。发现位于SMO基因的SNP(rs12674259)和位于PTCH1基因的SNP(rs2066836)的基因型频率在NSCL/P病例组和对照组之间的差异有统计学意义。同时在4个候选基因所在的3条染色体(第2、7、9号染色体)中均发现了连锁不平衡,但在连锁不平衡单倍体型分析中,病例组和对照组之间的差异无统计学意义。结论 提示Shh信号通路参与NSCL/P的发生,其信号通路中关键基因的某些特殊SNP位点与唇腭裂相关,为NSCL/P的病因研究提供了新的探索方向,可能为NSCL/P的早期筛查与风险预测提供帮助。

关键词: 非综合征型唇腭裂, Sonic hedgehog, 单核苷酸多态性, 质谱检测

Abstract: Objective: To study the relationship between Sonic hedgehog (Shh) associated single-nucleotide polymorphism (SNP) and non-syndromic cleft lip and/or palate (NSCL/P), and to explore the risk factors of cleft lip and/or palate. Many studies suggest that the pathogenesis of NSCL/P could be related to genes that control early development, in which the Shh signaling pathway plays an important role.Methods: Peripheral blood was collected from 197 individuals (100 patients with NSCL/P and 97 healthy controls). Haploview software was used for haplotype analysis and Tag SNP were selected, based on the population data of Han Chinese in Beijing of the international human genome haplotype mapping project. A total of 27 SNP were selected for the 4 candidate genes of SHH, PTCH1, SMO and GLI2 in the Shh signaling pathway. The genotypes of 27 SNP were detected and analyzed by Sequenom mass spectrometry. The data were analyzed by chi-squared test and an unconditional Logistic regression model. Results: The selected SNP basically covered the potential functional SNP of the target genes, and its minimum allele frequency (MAF) was >0.05: GLI2 73.5%, PTCH1 91.0%, SMO 100.0%, and SHH 75.0%. It was found that the genotype frequency of SNP (rs12674259) located in SMO gene and SNP (rs2066836) located in PTCH1 gene were significantly different between the NSCL/P group and the control group. Linkage disequilibrium was also found on 3 chromosomes (chromosomes 2, 7 and 9) where the 4 candidate genes were located. However, in the analysis of linkage imbalance haplotype, there was no significant difference between the disease group and the control group.Conclusion: In China, NSCL/P is the most common congenital disease in orofacial region. However, as it is a multigenic disease and could be affected by multiple factors, such as the external environment, the etiology of NSCL/P has not been clearly defined. This study indicates that Shh signaling pathway is involved in the occurrence of NSCL/P, and some special SNP of key genes in this pathway are related to cleft lip and/or palate, which provides a new direction for the etiology research of NSCL/P and may provide help for the early screening and risk prediction of NSCL/P.

Key words: Non-syndromic cleft lip and/or palate, Sonic hedgehog, Single-nucleotide polymorphism, Sequennom massarray

中图分类号: 

  • R393

Table 1

Minor allele frequencies of SNP in samples"

表2

27个SNP的哈迪-温伯格平衡检验结果"

CHR SNP A1 A2 GENO(A1A1/A1A2/A2A2) P
2 rs17390009 G C 0/4/67 1.000
2 rs7604538 T C 19/46/31 0.836
2 rs735557 A G 11/42/42 1.000
2 rs4848122 T C 13/40/32 1.000
2 rs7582470 A G 23/40/34 0.104
2 rs1992900 C T 14/48/33 0.674
2 rs895479 G A 3/39/55 0.266
2 rs4848124 C T 3/39/53 0.261
2 rs277555 C T 4/40/52 0.414
2 rs277536 A G 13/39/42 0.493
2 rs1187935 C A 7/31/48 0.577
2 rs3738880 A C 21/52/23 0.540
7 rs2718107 A C 22/38/35 0.093
7 rs4731562 A G 8/43/43 0.638
7 rs2566871 T C 24/41/32 0.154
7 rs12674259 T G 4/19/77 0.062
7 rs9607 A G 5/37/52 0.786
7 rs4728160 G C 3/37/55 0.385
7 rs1233560 C T 1/40/56 0.038
7 rs208684 C A 4/33/58 1.000
9 rs16909859 A G 5/22/73 0.069
9 rs357564 G A 21/39/33 0.204
9 rs2236407 G A 12/42/43 0.821
9 rs2066836 T C 0/15/75 1.000
9 rs2277184 G A 2/20/75 0.632
9 rs2297088 A G 13/42/42 0.657
9 rs2282041 G A 1/22/74 1.000

表3

对照组和病例组的SNP卡方检验"

SNP A1 A2 CHISQ P OR SE 95%CI
rs17390009 G C 0.605 0.437 1.736 0.718 0.425-7.086
rs7604538 T C 0.044 0.833 0.956 0.214 0.629-1.454
rs735557 A G 0.138 0.710 0.919 0.227 0.589-1.434
rs4848122 T C 0.869 0.351 1.256 0.245 0.777-2.031
2 rs4848124 C T 0.256 0.4776
2 rs277555 C T 0.254 0.3475
2 rs277536 A G 0.342 0.435
2 rs1187935 C A 0.260 0.4666
2 rs3738880 A C 0.490 0.4396
7 rs2718107 A C 0.418 0.4318
7 rs4731562 A G 0.338 0.3347
7 rs2566871 T C 0.447 0.4588
7 rs12674259 T G 0.160 0.0426
7 rs9607 A G 0.244 0.266
7 rs4728160 G C 0.235 0.2468
7 rs1233560 C T 0.239 0.4629
7 rs208684 C A 0.236 0.2683
9 rs16909859 A G 0.178 0.1479
9 rs357564 G A 0.414 0.3814
9 rs2236407 G A 0.343 0.3832
9 rs2066836 T C 0.090 0.1094
9 rs2277184 G A 0.150 0.0865
9 rs2297088 A G 0.360 0.4098
9 rs2282041 G A 0.113 0.1163

表4

病例组和对照组的Logistic回归分析"

CHR SNP A1 A2 OR SE 95%CI P
2 rs17390009 G C 2.173 0.746 0.503-9.380 0.298
2 rs17390009 G C 2.173 0.746 0.503-9.380 0.298
2 rs7604538 T C 0.960 0.212 0.634-1.453 0.846
2 rs735557 A G 0.902 0.224 0.582-1.398 0.644
2 rs4848122 T C 1.266 0.243 0.787-2.037 0.331
2 rs7582470 A G 1.041 0.202 0.701-1.545 0.843
2 rs1992900 C T 1.146 0.230 0.731-1.796 0.553
2 rs895479 G A 0.947 0.259 0.570-1.573 0.834
2 rs4848124 C T 1.387 0.261 0.832-2.312 0.209
2 rs277555 C T 1.125 0.254 0.684-1.850 0.644
2 rs277536 A G 0.974 0.227 0.625-1.518 0.907
2 rs1187935 C A 0.975 0.247 0.601-1.583 0.920
2 rs3738880 A C 1.004 0.209 0.666-1.513 0.986
7 rs2718107 A C 0.882 0.209 0.586-1.329 0.549
7 rs4731562 A G 1.374 0.245 0.850-2.221 0.195
7 rs2566871 T C 0.888 0.207 0.592-1.333 0.567
7 rs12674259 T G 0.696 0.298 0.388-1.249 0.225
7 rs9607 A G 0.861 0.253 0.525-1.413 0.553
7 rs4728160 G C 1.003 0.255 0.608-1.653 0.991
7 rs1233560 C T 1.450 0.271 0.852-2.466 0.171
7 rs208684 C A 1.206 0.247 0.744-1.955 0.447
9 rs16909859 A G 0.752 0.251 0.460-1.231 0.257
9 rs357564 G A 0.871 0.207 0.581-1.308 0.507
9 rs2236407 G A 0.981 0.227 0.629-1.529 0.931
9 rs2066836 T C 1.224 0.358 0.607-2.467 0.572
9 rs2277184 G A 1.475 0.297 0.825-2.637 0.190
9 rs2297088 A G 1.043 0.215 0.684-1.589 0.846
9 rs2282041 G A 0.666 0.346 0.338-1.313 0.241

表5

病例组与对照组的统计关联"

SNP Genotype Control NSCL/P OR (95%CI) P(OR) P(Logistic) P(Bonferroni) P(HWE)
rs12674259 G/G 77 (77%) 61 (62.9%) 1
G/T 19 (19%) 36 (37.1%) 0.42 (0.22-0.81) 0.0017 0.0016 0.043 0.062
T/T 4 (4%) 0 (0%) NA (0.00-NA)
rs7582470 A G 0.062 0.804 1.054 0.213 0.695-1.599
rs1992900 C T 0.337 0.561 1.134 0.217 0.742-1.735
rs895479 G A 0.088 0.767 0.930 0.247 0.573-1.507
rs4848124 C T 1.851 0.174 1.402 0.249 0.861-2.283
rs277555 C T 0.375 0.540 1.162 0.246 0.718-1.882
rs277536 A G 0.000 0.989 1.003 0.225 0.646-1.559
rs1187935 C A 0.001 0.974 0.992 0.253 0.604-1.628
rs3738880 A C 0.000 1.000 1.000 0.211 0.661-1.512
rs2718107 A C 0.347 0.556 0.881 0.215 0.578-1.343
rs4731562 A G 1.596 0.207 1.336 0.229 0.852-2.093
rs2566871 T C 0.304 0.581 0.890 0.212 0.587-1.348
rs12674259 T G 1.527 0.217 0.698 0.292 0.393-1.237
rs9607 A G 0.450 0.503 0.846 0.250 0.519-1.380
rs4728160 G C 0.001 0.973 0.992 0.250 0.607-1.619
rs1233560 C T 1.640 0.200 1.380 0.252 0.842-2.261
rs208684 C A 0.790 0.374 1.248 0.250 0.765-2.035
rs16909859 A G 1.489 0.222 0.714 0.277 0.415-1.228
rs357564 G A 0.479 0.489 0.860 0.218 0.561-1.318
rs2236407 G A 0.002 0.965 1.010 0.221 0.655-1.558
rs2066836 T C 0.310 0.578 1.239 0.386 0.581-2.642
rs2277184 G A 2.396 0.122 1.588 0.300 0.881-2.859
rs2297088 A G 0.114 0.736 1.077 0.219 0.701-1.653
rs2282041 G A 1.227 0.268 0.686 0.342 0.351-1.340

图1

rs2066836和rs12674259的Sequenom质谱测序结果"

图2

4个候选基因GLI2(2q14)、 SMO(7q32)、 SHH(7q36)和 PTCH1(9q22)的连锁不平衡分析"

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