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

doi:10.7518/hxkq.2024.2024110

Abstract

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

CLC Number:

Q786

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）

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