GC和CYP27B1基因多态性与汉族人群尘螨致敏的持续性变应性鼻炎的关联研究

doi:10.6040/j.issn.1673-3770.1.2019.006

山东大学耳鼻喉眼学报 ›› 2019, Vol. 33 ›› Issue (3): 71-78.doi: 10.6040/j.issn.1673-3770.1.2019.006

GC和CYP27B1基因多态性与汉族人群尘螨致敏的持续性变应性鼻炎的关联研究

田慧琴^1,²,吴中飞²,陆莹³,程雷^2,^4,⁵()

1. 南京医科大学第一附属医院江苏省人民医院妇幼分院儿童保健科，江苏南京 210036
2. 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
3. 南京医科大学第一附属医院江苏省人民医院妇幼分院群体保健科，江苏南京 210036
4. 南京医科大学国际变态反应研究中心，江苏南京 210029
5. 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:2019-02-14 修回日期:2019-04-18 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:
国家自然科学基金(81300834)

Association of vitamin D binding protein geneand CYP27B1 gene polymorphisms with mite-sensitized persistent allergic rhinitis among Han Chinese population

Huiqin TIAN^1,²,Zhongfei WU²,Ying LU³,Lei CHENG^2,^4,⁵()

1. Department of Child Healthcare, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210036, Jiangsu, China
2. Department of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
3. Department of Group Healthcare, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210036, Jiangsu, China
4. International Centre for Allergy Research, Nanjing Medical University, Nanjing 210029, Jiangsu, China
5. The Institute of Allergy and Autoimmune Disease, Jiangsu Clinical Medicine Research Institution, Nanjing 210029, Jiangsu, China

Received:2019-02-14 Revised:2019-04-18 Online:2019-05-20 Published:2019-08-07
Contact: Lei CHENG E-mail:chenglei@jsph.org.cn

摘要/Abstract

摘要： 目的

探讨维生素D代谢相关的维生素D结合蛋白基因（GC）及1α?羟化酶基因（CYP27B1）的多态性与汉族人群变应性鼻炎（AR）易感性的关联。

方法

应用病例-对照研究，纳入苏皖汉族人群中尘螨致敏的持续性AR患者564例和健康对照583例。选取GC及CYP27B1的单核苷酸多态性（SNPs）位点共8个，分别为GC的rs4588、rs7041、rs3733359、rs16847024、rs843008、rs1565572，rs11939173和CYP27B1的rs10877012。采用TaqMan法对两组研究对象的候选位点SNPs进行分析。

结果

GC的7个位点及CYP27B1的rs10877012位点与持续性AR的易感性均未发现有统计学关联。但对病例组进行年龄、性别、是否合并哮喘及总IgE水平的高低分层后发现，GC的rs16847024位点中，年龄≥17岁的基因型CT（调整OR=0.62, 95% CI=0.41~0.94）和CT/TT（调整OR=0.62，95% CI =0.42~0.90）、男性的基因型CT/TT（调整OR=0.68，95% CI = 0.48~0.96）、不伴哮喘的基因型CT（调整OR=0.70，95% CI =0.52~0.95）和CT/TT（调整OR=0.72，95% CI =0.54~0.97），以及总IgE水平较低者的基因型CT（调整OR=0.70，95% CI =0.52~0.95）和CT/TT（调整OR=0.71，95% CI =0.53~0.94）与野生基因型CC相比，均可降低持续性AR的发病风险。GC和CYP27B1的基因交互作用分析发现，涉及GC基因两个位点（rs3733359和rs1565572）的模型具有统计学意义（P=0.001），而同时涉及两个基因位点的模型均未发现统计学意义。

结论

维生素D代谢相关基因GC的rs16847024位点与汉族人群尘螨致敏的持续性AR的易感性关联可能受患者年龄、性别、是否合并哮喘及总IgE水平的影响。GC基因rs3733359位点和rs1565572位点在持续性AR的遗传学发病机制中可能存在联合作用。

关键词: 变应性鼻炎, GC基因, CYP27B1基因, 单核苷酸多态性, 遗传学关联研究

Abstract: Objective

To evaluate whether polymorphisms in the vitamin D binding protein gene (GC) and CYP27B1 gene are associated with mite-sensitized persistent allergic rhinitis(AR) in this population.

Methods

An ongoing hospital-based case-control study consisting of 564 patients with mite-sensitized persistent AR and 583 healthy controls was conducted. Seven single nucleotide polymorphisms (SNPs) in GC and one SNP in CYP27B1 were selected for genotyping.

Results

The genotype and allele frequencies of rs4588，rs7041，rs3733359，rs16847024，rs843008，rs1565572，and rs11939173 in GC as well as rs10877012 in CYP27B1 were not significantly associated with susceptibility to mite-sensitized persistent AR. After stratification analyses, however, there are genotypes in different subgroups of rs16847024 in GC exhibited significantly decreased risk of mite-sensitized persistent AR, compared to wild CC genotype, and they are: CT (adjusted OR=0.62, 95% CI=0.41-0.94) and CT/TT (adjusted OR=0.62，95% CI =0.42-0.90)genotypes in the age subgroup of ≥17 years old, the CT/TT (adjusted OR=0.68，95% CI = 0.48-0.96) genotypes in the male subgroup, the CT (adjusted OR=0.70，95% CI =0.52-0.95) and CT/TT (adjusted OR=0.72，95% CI =0.54-0.97) genotypes in the subgroup of persistent AR without concomitant of asthma, and the CT (adjusted OR=0.70，95% CI =0.52-0.95) and CT/TT (adjusted OR=0.71，95% CI =0.53-0.94) genotypes in the subgroup of lower total IgE level. Analysis of the locus-locus interactions of GC and CYP27B1 revealed one model that involved two SNPs of only GC were statistically significant (P=0.001).

Conclusion

Our data suggest that ≥17 years old, male, no concomitant of asthma, and lower total IgE level may have an impact on the association of SNP rs16847024 in GC of the vitamin D pathway with the risk of mite-sensitized persistent AR in this Chinese population. Two variants of GC may be involved in genetic interactions in the pathogenesis of persistent AR.

Key words: Allergic rhinitis, GC gene, CYP27B1 gene, Single nucleotide polymorphism, Genetic association studies

中图分类号:

R765.2

田慧琴,吴中飞,陆莹,程雷. GC和CYP27B1基因多态性与汉族人群尘螨致敏的持续性变应性鼻炎的关联研究[J]. 山东大学耳鼻喉眼学报, 2019, 33(3): 71-78.

Huiqin TIAN,Zhongfei WU,Ying LU,Lei CHENG. Association of vitamin D binding protein geneand CYP27B1 gene polymorphisms with mite-sensitized persistent allergic rhinitis among Han Chinese population[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2019, 33(3): 71-78.

图/表 6

表1

表2

表3

表4

GC和CYP27B1基因多态性在病例组和对照组人群中的分布"

基因型	病例组		对照组		OR值 (95%CI)	调整OR值 (95%CI)^b,c
基因型	n	%	n	%	OR值 (95%CI)	调整OR值 (95%CI)^b,c
GC
rs4588	n = 561		n = 577
CC	264	47.1	258	44.7	1.00	1.00
CA	245	43.7	269	46.6	1.12 (0.88~1.43)	1.13 (0.88~1.44)
AA	52	9.3	50	8.7	0.98 (0.64~1.50)	0.98 (0.64~1.50)
CA/AA	297	52.9	319	55.3	1.10 (0.87~1.39)	1.10 (0.87~1.39)
A等位基因^a					1.04 (0.87~1.24)	1.04 (0.87~1.24)
rs7041	n = 563		n = 583
TT	304	54.0	321	55.1	1.00	1.00
TG	216	38.4	223	38.3	0.98 (0.77~1.25)	0.98 (0.77~1.25)
GG	43	7.6	39	6.7	0.86 (0.54~1.36)	0.86 (0.54~1.37)
TG/GG	259	46.0	262	44.9	0.96 (0.76~1.21)	0.96 (0.76~1.21)
G等位基因^a					0.95 (0.79~1.14)	0.95 (0.79~1.15)
rs3733359	n = 562		n= 576
CC	242	43.1	274	46.7	1.00	1.00
CT	257	45.7	239	41.5	0.82 (0.64~1.05)	0.82 (0.64~1.05)
TT	63	11.2	63	10.9	0.88 (0.60~1.30)	0.88 (0.60~1.31)
CT/TT	320	56.9	302	52.4	0.83 (0.66~1.05)	0.83 (0.66~1.05)
T等位基因^a					0.90 (0.75~1.07)	0.90 (0.75~1.07)
rs16847024	n = 564		n= 582
CC	414	73.4	455	78.2	1.00	1.00
CT	132	23.4	109	18.7	0.75 (0.56~1.00)	0.75 (0.56~1.00)
TT	18	3.2	18	3.1	0.91 (0.47~1.77)	0.91 (0.47~1.77)
CT/TT	150	26.6	127	21.8	0.77 (0.59~1.01)	0.77 (0.59~1.01)
T等位基因^a					0.81 (0.64~1.03)	0.81 (0.64~1.03)
rs843008	n= 564		n= 582
TT	349	61.9	364	62.5	1.00	1.00
TG	194	34.4	187	32.1	0.92 (0.72~1.19)	0.92 (0.72~1.18)
GG	21	3.7	31	5.3	1.42 (0.80~2.51)	1.42 (0.80~2.52)
TG/GG	215	38.1	218	37.5	0.97 (0.77~1.23)	0.97 (0.77~1.23)
G等位基因^a					1.03 (0.84~1.26)	1.03 (0.84~1.26)
rs1565572	n= 560		n = 574
AA	181	32.3	167	29.1	1.00	1.00
AC	261	46.6	284	49.5	1.18 (0.90~1.54)	1.18 (0.90~1.54)
CC	118	21.1	123	21.4	1.13 (0.81~1.57)	1.14 (0.82~1.58)
AC/CC	379	67.7	407	70.9	1.16 (0.90~1.50)	1.16 (0.91~1.50)
C等位基因^a					1.08 (0.91~1.27)	1.08 (0.91~1.27)
rs11939173	n= 564		n = 582
GG	394	69.9	409	70.3	1.00	1.00
GA	149	26.4	159	27.3	1.03 (0.79~1.34)	1.03 (0.79~1.34)
AA	21	3.7	14	2.4	0.64 (0.32~1.28)	0.65 (0.33~1.30)
GA/AA	170	30.1	173	29.7	0.98 (0.76~1.26)	0.99 (0.76~1.27)
A等位基因^a					0.94 (0.75~1.17)	0.94 (0.76~1.18)
CYP27B1
rs10877012	n = 561		n = 578
TT	231	41.2	261	45.2	1.00	1.00
TG	253	45.1	247	42.7	0.86 (0.67~1.11)	0.86 (0.67~1.10)
GG	77	13.7	70	12.1	0.81 (0.57~1.16)	0.80 (0.56~1.16)
TG/GG	330	58.8	317	54.8	0.85 (0.67~1.08)	0.85 (0.67~1.07)
G等位基因^a					0.88 (0.74~1.05)	0.88 (0.74~1.05)

表4

表5

表6

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变量	病例组 (n=564)		对照组( n=583)		Z/χ²值^b	P
变量	n	%	n	%	Z/χ²值^b	P
年龄(岁), M (IQR)	17.0 (11.0~29.0)		19.0 (8.0~29.0)		1.178	0.239
性别
男	374	66.3	372	63.8	0.791	0.386
女	190	33.7	211	36.2
合并哮喘^a
是	121	21.5
否	443	78.5
血清总IgE (kU/L), M (IQR)	248.0 (113.0~543.0)		20.5(13.6~59.4)		24.236	<0.001
血清特异性IgE (kU_A/L)， M (IQR)
屋尘螨	25.9(5.3~69.2)
粉尘螨	21.4(5.5~61.3)

SNPs	位置	等位基因^a	生物学效应	MAF ^b
GC
rs4588	外显子	C>A	错义突变	0.278
rs7041	外显子	T >G	错义突变	0.289
rs3733359	5′UTR	C>T	上游调控序列	0.360
rs16847024	5′NEAR	C>T	上游调控序列	0.116
rs843008	5′NEAR	T >G	上游调控序列	0.233
rs1565572	5′NEAR	A>C	上游调控序列	0.453
rs11939173	5′NEAR	G>A	上游调控序列	0.198
CYP27B1
rs10877012	5′NEAR	T >G	上游调控序列	0.402

SNPs	引物（5′-3′）	探针
GC
rs4588	F:CAGACTGGCAGAGCGACTAAAA R:GCAGTTGGAGGCAAAGTCTGA	C: FAM-TGCCACACCCACGG-MGB A: HEX-TGCCACACCCAAGG-MGB
rs7041	F:CAGACTGGCAGAGCGACTAAAA R:GCAGTTGGAGGCAAAGTCTGA	G: FAM-AAAATTGCCTGAGGCC-MGB T: HEX-CAAAATTGCCTGATGC-MGB
rs3733359	F:CTACCAGAGAGTCTTGCAGCACCT R:GCTTCTGTTTAATAATAATTCTGTGTTGC	A: FAM-CTCTCTCCTATAGGTGAC-MGB G: HEX-TCTCTCCTGTAGGTGAC-MGB
rs16847024	F: AAAAACCAGGAGTGGAACTCATCT	G: FAM-ATTCCAATGAATGATCTACCTA-MGB
rs16847024	R: CACTGGGTAAATTCTGTGACTTGTCT	A: HEX-TTCCAATAAATGATCTACC-MGB
rs843008	F: CAAAACCAATTATAGCAATAAGAACATTAAACA	A: FAM-TGAACTAAACAATCCAAG-MGB
rs843008	R: GAACCATTCAAACATCTTGCTTGTT	C: HEX-TGAACTAAACACTCCAAG-MGB
rs1565572	F: GGGCATGGTTAGAGGTTGTATATTAAC	C: FAM-AGCATTGCAGCCTT-MGB
rs1565572	R: GAATCAATTGGCTGGCAAAAC	A: HEX-TGGAGCATTGAAGCC-MGB
rs11939173	F:CAACCCAGTACCAAAAATAAAGGAA R:CCGAGGAAGCTGCATCATCT	T: FAM-CCCTGTAGGACCC-MGB C: HEX-TAACCCTGCAGGACC-MGB
CYP27B1
rs10877012	F:GGGAGTAAGGAGCAGAGAGGTAAA R:AAGGCTGCAGTGAGTTATGATTGT	C: FAM-TGTGGGAGATTCTTTTA-MGB A: HEX-TGTGGGAGATTATTT-MGB

SNPs	分层变量	亚组	N (病例/对照) ^b	调整OR (95%CI) ^{c, d}
SNPs	分层变量	亚组	N (病例/对照) ^b	XY ^e	YY ^e	XY/YY ^e
GC
rs16847024
	年龄 (岁)	<17	278/280	0.91(0.61~1.36)	1.77(0.52~6.03)	0.96(0.65~1.42)
		≥17	286/303	0.62(0.41~0.94)	0.60(0.26~1.38)	0.62(0.42~0.90)
	性别	男	374/372	0.72(0.50~1.02)	0.46(0.18~1.19)	0.68(0.48~0.96)
		女	190/211	0.83(0.51~1.35)	2.00(0.67~5.96)	0.94(0.60~1.49)
	合并哮喘	是	121/583	0.95(0.58~1.57)	1.18(0.34~4.15)	0.98(0.61~1.58)
		否	443/583	0.70(0.52~0.95)	0.88(0.44~1.79)	0.72(0.54~0.97)
	总IgE水平^a	低	450/583	0.70(0.52~0.95)	0.72(0.37~1.41)	0.71(0.53~0.94)
		高	114/583	0.95(0.57~1.58)	—	1.11(0.67~1.82)

模型 ^a	训练样本	检验样本	交叉一致性	P
A4	0.5275	0.4907	6/10	0.8281
A3 A6	0.5636	0.5588	10/10	0.0010
A1 A3 A6	0.5807	0.5015	6/10	0.6320

GC和CYP27B1基因多态性与汉族人群尘螨致敏的持续性变应性鼻炎的关联研究

Association of vitamin D binding protein geneand CYP27B1 gene polymorphisms with mite-sensitized persistent allergic rhinitis among Han Chinese population

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