叉头盒E1基因与中国汉族人群非综合征型唇腭裂的关联研究

doi:10.7518/hxkq.2024.2024110

华西口腔医学杂志 ›› 2025, Vol. 43 ›› Issue (1): 28-36.doi: 10.7518/hxkq.2024.2024110

叉头盒E1基因与中国汉族人群非综合征型唇腭裂的关联研究

贾思璇(), 张思荻, 尤玥, 孙嘉琳, 段世均, 石冰, 贾仲林()

口腔疾病防治全国重点实验室国家口腔医学中心国家口腔疾病临床医学研究中心四川大学华西口腔医院唇腭裂外科，成都 610041

收稿日期:2024-03-29 修回日期:2024-10-23 出版日期:2025-02-01 发布日期:2025-01-22
通讯作者: 贾仲林 E-mail:1241774453@qq.com;zhonglinjia@scu.edu.cn
作者简介:贾思璇，硕士，E-mail：1241774453@qq.com
基金资助:
国家自然科学基金面上项目(82170919);四川大学华西口腔医院交叉项目(RD-03-202301);四川省科技厅自然科学基金面上项目(2024NSFSC0649)

Association analysis between forkhead box E1 gene and non-syndromic cleft lip with or without cleft palate in Han Chinese population

Jia Sixuan(), Zhang Sidi, You Yue, Sun Jialin, Duan Shijun, Shi Bing, Jia Zhonglin()

State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China

Received:2024-03-29 Revised:2024-10-23 Online:2025-02-01 Published:2025-01-22
Contact: Jia Zhonglin E-mail:1241774453@qq.com;zhonglinjia@scu.edu.cn
Supported by:
National Natural Science Foundation of China(82170919);Research and Develop Program of West China Hospital of Stomatology, Sichuan University(RD-03-202301);Natural Science Foundation of Sichuan Province Science and Technology(2024NSFSC0649)

摘要/Abstract

摘要：

目的探究叉头盒E1（FOXE1）基因所在单倍型区域hg19 chr9:100560865-100660865附近的单核苷酸多态性（SNPs）位点与中国西部汉族人群非综合征型唇腭裂（NSCL/P）发生的相关性。方法第一阶段纳入159名NSCL/P患者，采用目标区域捕获测序的方法，拟筛查FOXE1基因所在单倍型区域附近与NSCL/P发生相关的SNPs位点。第二阶段，选择21个常见SNPs位点，在1 000名非综合征型单纯唇裂（NSCLO）患者，1 000名非综合征型单纯腭裂（NSCPO）患者和1 000名正常对照样本中进行验证。使用PLINK软件对研究人群进行哈迪-温伯格平衡（HWE）分析，对常见变异进行关联分析，对罕见变异进行基因负荷分析并使用Mutation Taster等软件对非同义突变的SNPs进行功能预测。结果第一阶段，共筛选出126个变异位点，包括76个SNPs变异位点和50个插入/缺失。纳入的所有SNPs在研究人群中遵循HWE。对筛选出的罕见变异进行功能有害性预测和基因负荷分析，差异均无统计学意义；对常见变异的关联分析表明，FOXE1基因的rs13292899位点与NSCL/P发生显著相关（P=1.85E-27），并且该位点与NSCLO（P=6.41E-23）、NSCLP（P=2.36E-15）发生也有相关性。随后在验证阶段，发现rs79268293（P=0.013，P=0.022）、rs10983951（P=0.009 2，P=0.007 6）、rs117227387（P=0.009 2，P=0.007 6）、rs3758250（P=0.009 2，P=0.007 6）和rs116899397（P=0.009 2，P=0.007 6），这5个SNPs位点与NSCLO和NSCPO均有显著关联性；另外，rs13292899（P=0.008 5）、rs74606599（P=0.008 3）、rs143226042（P=0.008 3）和rs117236550（P=0.01），这4个SNPs位点与NSCLO发生相关；rs12343182（P=0.008 7）、rs10119760（P=0.012）、rs10113907（P=0.012）和rs13299924（P=0.012），这4个SNPs位点与NSCPO发生相关。结论本研究在FOXE1基因上发现了一个新的易感SNPs位点rs13292899与NSCL/P及NSCLO发生密切相关，以及其他13个SNPs位点与NSCLO或NSCPO发生相关。

关键词: 非综合征型唇腭裂, 叉头盒E1基因, 目标区域捕获测序, 单核苷酸多态性, 关联分析

Abstract:

Objective This study aims to explore the association between single nucleotide polymorphisms (SNPs) loci near the haplotype region hg19 chr9:100560865-100660865 of the forkhead box E1 (FOXE1) gene and the occurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P) in western Han Chinese population. Methods In the first stage, our study recruited 159 NSCL/P patients and performed targeted region sequencing to screen SNPs loci near the haplotype region of the FOXE1 gene associated with NSCL/P. In the second stage, we selected 21 common SNPs and re-enrolled 1 000 non-syndromic cleft lip only (NSCLO) patients, 1 000 non-syndromic cleft palate only (NSCPO) patients, and 1 000 normal controls to verify the association. PLINK software was used to perform Hardy-Weinberg equilibrium (HWE) test. Association analysis for common variants, gene burden analysis for rare mutations, and function prediction of SNPs with non-synonymous mutations were performed using Mutation Taster and other software programs. Results In the first stage, 126 variants, including 76 single nucleotide variants and 50 insertion-deletions were identified. All the included SNPs confirmed to HWE, and the results of gene burden analysis and prediction of functional harmfulness for rare variants were not statistically significant. Association analysis showed that rs13292899 of the FOXE1 gene was significantly associated with NSCL/P (P=1.85E-27) and was also correlated with NSCLO (P=6.41E-23) and non-syndromic cleft lip with cleft palate (NSCLP) (P=2.36E-15) subtypes. In the validation phase, rs79268293 (P=0.013, P=0.022), rs10983951 (P=0.009 2, P=0.007 6), rs117227387 (P=0.009 2, P=0.007 6), rs3758250 (P=0.009 2, P=0.007 6), and rs116899397 (P=0.009 2, P=0.007 6) were significantly associated with NSCLO and NSCPO; rs13292899 (P=0.008 5), rs74606599 (P=0.008 3), rs143226042 (P=0.008 3), and rs117236550 (P=0.01) were associated with the occurrence of NSCLO; and rs12343182 (P=0.008 7), rs10119760 (P=0.012), rs10113907 (P=0.012), and rs13299924 (P=0.012) were associated with the occurrence of NSCPO. Conclusion This study found a new susceptible SNP rs13292899 of the FOXE1 gene that is closely associated with NSCL/P and NSCLO subtype and 13 other SNPs associated with NSCLO or NSCPO.

Key words: non-syndromic cleft lip with or without cleft palate, forkhead box E1 gene, target region sequen-cing, single nucleotide polymorphisms, association analysis

中图分类号:

Q786

贾思璇, 张思荻, 尤玥, 孙嘉琳, 段世均, 石冰, 贾仲林. 叉头盒E1基因与中国汉族人群非综合征型唇腭裂的关联研究[J]. 华西口腔医学杂志, 2025, 43(1): 28-36.

Jia Sixuan, Zhang Sidi, You Yue, Sun Jialin, Duan Shijun, Shi Bing, Jia Zhonglin. Association analysis between forkhead box E1 gene and non-syndromic cleft lip with or without cleft palate in Han Chinese population[J]. West China Journal of Stomatology, 2025, 43(1): 28-36.

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表型	SNP	位置	Ref	Alt	AF/%	患者		对照		P值	OR（95%CI）
表型	SNP	位置	Ref	Alt	AF/%	Alt	Ref	Alt	Ref	P值	OR（95%CI）
NSCLO	rs13292899	100610865	G	T	15.19	24	134	0	1 084	6.41E-23	-
	rs874004	100622118	C	G	84.81	134	24	874	210	0.23	1.34（0.85~2.13）
	rs10113907	100624748	C	G	84.81	134	24	875	209	0.23	1.33（0.84~2.11）
	rs117236550	100623216	C	T	7.59	12	146	62	1 022	0.37	1.36（0.71~2.58）
	rs3758250	100614001	C	T	7.59	12	146	64	1 020	0.38	1.31（0.69~2.49）
	rs10983951	100608012	G	A	7.59	12	146	65	1 019	0.48	1.29（0.68~2.44）
	rs117227387	100612135	A	T	7.59	12	146	65	1 019	0.48	1.29（0.68~2.44）
	rs116899397	100617879	T	C	7.59	12	146	65	1 019	0.48	1.29（0.68~2.44）
NSCLP	rs79268293	100606701	A	G	6.88	11	149	40	1 042	0.083	1.92（0.97~3.83）
	rs4743136	100608059	C	G	6.88	11	149	47	1 037	0.16	1.63（0.83~3.21）
	rs74396330	100608239	T	C	6.88	11	149	40	1 044	0.083	1.93（0.97~3.84）
	100608456	100608456	C	G	6.88	11	149	47	1 037	0.16	1.63（0.83~3.21）
	rs10759960	100608745	A	G	91.88	147	13	1 030	54	0.13	0.59（0.32~1.11）
	rs115269261	100610146	G	T	6.88	11	149	40	1 044	0.083	1.93（0.97~3.84）
	rs13292899	100610865	G	T	10.12	16	142	0	1 084	2.36E-15	-
	rs72753507	100613836	T	C	6.88	11	149	47	1 037	0.16	1.63（0.83~3.21）
	rs111846096	100614331	C	G	6.88	11	149	40	1 042	0.083	1.92（0.97~3.83）
	rs74606599	100614651	G	T	6.88	11	149	40	1 044	0.083	1.93（0.97~3.84）
	rs72753509	100615000	A	G	6.88	11	149	47	1 037	0.16	1.63（0.83~3.21）
	rs143226042	100615552	C	A	6.88	11	149	40	1 044	0.083	1.93（0.97~3.84）
	rs7043516	100617433	A	C	6.88	11	149	40	1 037	0.084	1.91（0.96~3.81）
	rs41274260	100617949	T	C	6.88	11	149	47	1 044	0.16	1.64（0.83~3.23）
	rs76305281	100618578	C	T	6.88	11	149	40	1 044	0.083	1.93（0.97~3.84）
	rs12343182	100624259	G	C	94.38	151	9	999	85	0.42	1.43（0.70~2.90）
	rs10119760	100624602	G	C	94.38	151	9	999	85	0.42	1.43（0.70~2.90）
	rs7860144	100626884	A	G	94.38	151	9	999	85	0.42	1.43（0.70~2.90）
	rs13299924	100627562	C	T	94.38	151	9	999	85	0.42	1.43（0.70~2.90）
NSCL/P	rs13292899	100610865	G	T	12.66	40	276	0	1 084	1.85E-27	-
	rs10759960	100608745	G	T	94.02	299	19	1 030	54	0.48	0.84（0.48~1.41）

SNP	位置	A1	F_U	NSCLO			NSCPO
SNP	位置	A1	F_U	卡方检验	P值	OR（95%CI）	卡方检验	P值	OR（95%CI）
rs79268293	100606701	A	0.13	4.18	0.013	0.84（0.72~0.99）	4.66	0.022	0.83（4.66~0.98）
rs10983951	100608012	A	0.072	5.78	0.009 2	0.76（0.61~0.95）	5.29	0.007 6	0.77（5.29~0.96）
rs4743136	100608059	G	0.056	0.17	0.68	0.95（0.76~1.2）	0.25	0.62	0.94（0.25~1.19）
rs12378536	100608456	G	0.056	0.17	0.68	0.95（0.76~1.2）	0.25	0.62	0.94（0.25~1.19）
rs10759960	100608745	A	0.052	2.44	0.12	0.82（0.64~1.05）	5.80E-05	0.99	1（0~1.27）
rs13292899	100610865	A	0.13	3.81	0.008 5	0.85（0.73~1）	4.99	0.032	0.83（4.99~0.98）
rs117227387	100612135	T	0.072	5.78	0.009 2	0.76（0.61~0.95）	5.29	0.007 6	0.77（5.29~0.96）
rs72753507	100613836	C	0.056	0.17	0.68	0.95（0.76~1.2）	0.25	0.62	0.94（0.25~1.19）
rs3758250	100614001	T	0.072	5.78	0.009 2	0.76（0.61~0.95）	5.29	0.007 6	0.77（5.29~0.96）
rs74606599	100614651	G	0.13	5.01	0.008 3	0.83（0.71~0.98）	3.88	0.035	0.85（3.88~1）
rs72753509	100615000	G	0.056	0.19	0.66	0.95（0.75~1.2）	0.19	0.66	0.95（0.19~1.2）
rs143226042	100615552	A	0.13	5.01	0.008 3	0.83（0.71~0.98）	3.88	0.035	0.85（3.88~1）
rs7043516	100617433	C	0.056	0.19	0.66	0.95（0.75~1.2）	0.19	0.66	0.95（0.19~1.2）
rs116899397	100617879	C	0.072	5.78	0.009 2	0.76（0.61~0.95）	5.29	0.007 6	0.77（5.29~0.96）
rs874004	100622118	C	0.20	3.34	0.068	0.88（0.77~1.01）	2.83	0.092	0.89（2.83~1.02）
rs117236550	100623216	T	0.069	4.19	0.01	0.79（0.64~0.99）	3.79	0.051	0.8（3.79~1）
rs12343182	100624259	G	0.085	3.42	0.064	0.83（0.68~1.01）	3.79	0.008 7	0.8（3.79~1）
rs10119760	100624602	G	0.085	3.42	0.064	0.83（0.68~1.01）	5.06	0.012	0.79（5.06~0.97）
rs10113907	100624748	C	0.20	3.36	0.067	0.88（0.77~1.01）	5.06	0.012	0.79（5.06~0.97）
rs7860144	100626884	A	0.085	3.15	0.076	0.84（0.69~1.02）	2.67	0.1	0.89（2.67~1.02）
rs13299924	100627562	C	0.0 85	3.15	0.076	0.84（0.69~1.02）	5.06	0.012	0.79（5.06~0.97）

[1]	多力昆·吾甫尔, 地丽拜尔·依明江, 卡米力江·买买提明, 李军, 乌丽凡·托勒恒. 新疆地区人群非综合征型唇腭裂与外周血FOXN3-SIN3A复合物表达量相关性研究[J]. 华西口腔医学杂志, 2024, 42(3): 313-318.
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叉头盒E1基因与中国汉族人群非综合征型唇腭裂的关联研究

Association analysis between forkhead box E1 gene and non-syndromic cleft lip with or without cleft palate in Han Chinese population

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研究阶段	表型	男性	女性	性别不详	总计
目标区域测序	NSCLO	46	33	0	79
目标区域测序	NSCLP	56	21	3	80
验证（来自2019年GWAS中的基因型数据^[30]）	NSCLO	560	397	43	1 000
	NSCPO	419	580	1	1 000
	正常对照	390	610	0	1 000