缺血性脑卒中全基因组关联研究提示阳性基因位点与睡眠行为的交互作用

doi:10.19723/j.issn.1671-167X.2022.03.004

摘要/Abstract

摘要：

目的: 探讨睡眠行为(睡眠时长、睡眠效率、入睡时间)和全基因组关联研究(genome-wide association studies, GWAS)提示阳性缺血性脑卒中(ischemic stroke, IS)基因位点与IS风险的关联，以及睡眠-基因交互作用与IS风险的关联。方法: 基于北京市房山家系队列，在基线对所有研究对象进行问卷调查、体格检查、血生化检测和基因型检测。采用多因素广义线性模型分析睡眠、基因与IS的关联。结果: 共纳入研究对象4 648人，平均年龄(58.5±8.7)岁，其中IS患者有1 316人。相比于非患者，IS患者睡眠时长≥9 h、睡眠效率 < 80%及入睡时间早于22:00占比更高(P均 < 0.05)。多因素广义线性模型下，未见睡眠时长与IS风险的线性关联(OR=1.04，95%CI：0.99~1.10，P=0.085)。睡眠效率与IS风险呈线性负相关(OR=0.18，95%CI：0.06~0.53，P=0.002)；相比于睡眠效率≥80%，睡眠效率 < 80%的IS风险为其1.47倍(95%CI：1.03~2.10，P=0.033)。相较于在22:00—22:59入睡，入睡时间早于22:00的IS风险是其1.26倍(95%CI：1.04~1.52，P=0.017)。多因素模型发现ABO基因上rs579459位点与入睡时间存在交互作用(P_交互=0.040)，rs579459致病等位基因T个数为2时，相比于入睡时间22:00—22:59，早于22:00入睡者IS风险显著升高，为其1.56倍(95%CI：1.20~2.04，P=0.001)，而致病等位基因个数为0或1时无显著关联。仅调整性别、年龄、家系的模型中，睡眠时长与PITX2基因上rs2634074致病等位基因T的个数对IS存在交互作用(P_交互=0.033)。结论: 睡眠效率降低与IS风险增高有关，入睡时间早于22:00与较高的IS风险相关。入睡时间与ABO基因上rs579459和IS风险存在交互作用；睡眠时长与PITX2基因上rs2634074和IS风险可能存在潜在的交互作用。

关键词: 基因位点, 睡眠, 缺血性脑卒中, 交互作用

Abstract:

Objective: To explore the relationship between sleep habits (sleep duration, sleep efficiency, sleep onset timing) and ischemic stroke, and whether there is an interaction between sleep habits and ischemic stroke susceptibility gene loci. Methods: A questionnaire survey, physical examination, blood biochemical testing and genotyping were conducted among rural residents in Beijing, and the gene loci of ischemic stroke suggested by previous genome-wide association studies (GWAS) were screened. Multivariable generalized linear model was used to analyze the correlation between sleep habits, sleep-gene interaction and ischemic stroke. Results: A total of 4 648 subjects with an average age of (58.5±8.7) years were enrolled, including 1 316 patients with ischemic stroke. Compared with non-stroke patients, stroke patients with sleep duration ≥9 hours, sleep efficiency < 80%, and sleep onset timing earlier than 22:00 accounted for a higher proportion (P < 0.05). There was no significant association between sleep duration and risk of ischemic stroke (OR=1.04, 95%CI: 0.99-1.10, P=0.085). Sleep efficiency was inversely associated with the risk of ischemic stroke (OR=0.18, 95%CI: 0.06-0.53, P=0.002). The risk of ischemic stroke in the subjects with sleep efficiency < 80% was 1.47-fold (95%CI: 1.03-2.10, P=0.033) of that in the subjects with sleep efficiency ≥80%. Falling asleep earlier than 22:00 was associated with 1.26 times greater risk of stroke than falling asleep between 22:00 and 22:59 (95%CI: 1.04-1.52, P=0.017). Multifactorial adjustment model showed that rs579459 on ABO gene had an interaction with sleep time (P for interaction =0.040). When there were two T alleles for rs579459 on the ABO gene, those who fell asleep before 22:00 had 1.56 times (95%CI: 1.20-2.04, P=0.001) the risk of stroke compared with those who fell asleep between 22:00 and 22:59, and there was no significant difference when the number of pathogenic alleles was 0 or 1. In the model adjusted only for gender, age and family structure, sleep duration and the number of T allele rs2634074 on PITX2 gene had an interaction with ischemic stroke (P for interaction=0.033). Conclusion: Decreased sleep efficiency is associated with increased risk of ischemic stroke, and falling asleep earlier than 22:00 is associated with higher risk of ischemic stroke. Sleep onset timing interacted with rs579459 in ABO gene and the risk of ischemic stroke. Sleep duration and PITX2 rs2634074 may have a potential interaction with ischemic stroke risk.

Key words: Gene loci, Sleep, Ischemic stroke, Interaction

中图分类号:

R181

杨若彤,王梦莹,李春男,于欢,王小文,吴俊慧,王斯悦,王伽婷,陈大方,吴涛,胡永华. 缺血性脑卒中全基因组关联研究提示阳性基因位点与睡眠行为的交互作用[J]. 北京大学学报（医学版）, 2022, 54(3): 412-420.

Ruo-tong YANG,Meng-ying WANG,Chun-nan LI,Huan YU,Xiao-wen WANG,Jun-hui WU,Si-yue WANG,Jia-ting WANG,Da-fang CHEN,Tao WU,Yong-hua HU. Interaction between ischemic stroke risk loci identified by genome-wide association studies and sleep habits[J]. Journal of Peking University (Health Sciences), 2022, 54(3): 412-420.

图/表 5

表1

研究对象基本特征"

Items	Total (n= 4 648)	Participants without IS (n= 3 332)	Participants with IS (n= 1 316)	P
Age/years, $\bar x \pm s$	58.5±8.7	57.5±8.7	60.8±8.3	< 0.001
Male, n (%)	2 112 (45.4)	1 384 (41.5)	728 (55.3)	< 0.001
Married, n (%)	4 060 (87.4)	2 934 (88.0)	1 126 (85.6)	< 0.001
Junior high school education or above, n (%)	2 574 (55.4)	1 962 (58.9)	612 (46.5)	< 0.001
Annual household income /10 000 yuan, $\bar x \pm s$	3.0±4.4	3.2±4.5	2.5±4.2	< 0.001
Smoker, n (%)	1 303 (28.0)	910 (27.3)	393 (29.9)	< 0.001
Drinker, n (%)	1 307 (28.1)	971 (29.1)	336 (25.5)	< 0.001
Adequate exercise, n (%)	892 (19.2)	673 (20.2)	219 (16.6)	0.006
Vegetables≥300 g/d and fruits≥200 g/d, n (%)	2 988 (64.3)	2 149 (64.5)	839 (63.8)	0.634
BMI/(kg/m²), $\bar x \pm s$	26.2±3.5	26.1±3.6	26.3±3.4	0.126
Total cholesterol/(mmol/L), $\bar x \pm s$	3.0±1.1	3.1±1.1	2.9±1.1	0.001
Hypertension, n (%)	3 328 (71.6)	2 182 (65.5)	1 146 (87.1)	< 0.001
Diabetes, n (%)	2 449 (52.7)	1 826 (54.8)	623 (47.4)	< 0.001
Coronary heart disease, n (%)	1 034 (22.3)	668 (20.1)	366 (27.8)	< 0.001
Family medical history, n (%)
IS	2 887 (62.1)	1 769 (53.1)	1 118 (85.0)	< 0.001
Diabetes	3 696 (79.5)	2 838 (85.2)	858 (65.2)	< 0.001
Coronary heart disease	2 299 (49.5)	1 743 (52.3)	556 (42.3)	< 0.001
Sleep duration/h, n (%)				< 0.001
< 7	1 031 (22.2)	758 (22.8)	273 (20.7)
7.0-8.9	2 393 (51.5)	1 768 (53.1)	625 (47.5)
≥9	1 224 (26.3)	806 (24.2)	418 (31.8)
Sleep efficiency/%, n (%)				0.015
≥80	4 378 (94.2)	3 156 (94.7)	1 222 (92.9)
< 80	270 (5.8)	176 (5.3)	94 (7.1)
Sleep onset timing, n (%)				< 0.001
< 22:00	1 111 (23.9)	688 (20.7)	423 (32.1)
22:00-22:59	1 844 (39.7)	1 354 (40.6)	490 (37.2)
23:00-23:59	1 058 (22.8)	822 (24.7)	236 (17.9)
≥24:00	635 (13.7)	468 (14.1)	167 (12.7)

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Sleep behaviors	Model 1		Model 2
Sleep behaviors	OR (95%CI)	P	OR (95%CI)	P
Sleep duration/h	1.04 (0.99, 1.08)	0.115	1.04 (0.99, 1.10)	0.085
< 7	1.04 (0.90, 1.29)	0.407	1.01 (0.83, 1.24)	0.895
7.0-8.9	1.00		1.00
≥9	1.22 (1.04, 1.43)	0.016	1.17 (0.98, 1.40)	0.081
Sleep efficiency/%	0.10 (0.04, 0.26)	< 0.001	0.18 (0.06, 0.53)	0.002
≥80	1.00		1.00
< 80	1.71 (1.25, 2.34)	0.001	1.47 (1.03, 2.10)	0.033
Sleep onset timing
< 22:00	1.44 (1.22, 1.71)	< 0.001	1.26 (1.04, 1.52)	0.017
22:00-22:59	1.00			1.00
23:00-23:59	0.86 (0.72, 1.04)	0.118	0.93 (0.76, 1.15)	0.517
≥24:00	0.86 (0.67, 1.10)	0.223	0.86 (0.66, 1.13)	0.291

Chromosome	rsID	Gene	n	MAF	Risk allele	OR (95%CI)	P	P′
1	rs225132	ERRFI1	4 448	0.34	T	1.09 (0.99, 1.21)	0.083	1.000
1	rs10489177	C1orf156	4 421	0.32	G	1.27 (1.15, 1.41)	< 0.001^*	< 0.001^*
2	rs780094	GCKR	3 440	0.47	G	1.03 (0.92, 1.14)	0.629	1.000
2	rs2292832	miR-149	3 394	0.32	T	1.04 (0.93, 1.17)	0.462	1.000
3	rs16851055	SPSB4	4 380	0.20	G	1.16 (1.03, 1.31)	0.015^*	0.405
4	rs2200733	PITX2	3 345	0.48	T	1.03 (0.93, 1.15)	0.534	1.000
4	rs2634074	PITX2	4 199	0.40	T	1.23 (1.12, 1.36)	< 0.001^*	< 0.001^*
5	rs1428155	GLRA1	3 405	0.32	C	1.03 (0.92, 1.15)	0.597	1.000
5	rs2910164	miR-146a	4 402	0.47	G	0.97 (0.88, 1.07)	0.557	1.000
6	rs556621	HCG27	3 377	0.50	A	1.07 (0.97, 1.19)	0.178	1.000
7	rs662	PON1	3 400	0.37	A	1.12 (1.00, 1.25)	0.042^*	1.000
7	rs3735590	PON1	3 444	0.14	C	1.11 (0.96, 1.30)	0.169	1.000
9	rs579459	ABO	4 418	0.34	T	1.29 (1.17, 1.42)	< 0.001^*	< 0.001^*
9	rs2383207	CDKN2B-AS1	3 438	0.33	A	1.03 (0.92, 1.15)	0.590	1.000
9	rs505922	ABO	4 419	0.48	C	0.96 (0.88, 1.06)	0.446	1.000
10	rs11196288	HABP2	4 391	0.36	G	1.03 (0.93, 1.14)	0.593	1.000
11	rs660599	MMP-12	3 438	0.12	T	0.95 (0.81, 1.11)	0.518	1.000
12	rs12425791	NINJ2	4 409	0.25	A	0.99 (0.89, 1.11)	0.868	1.000
12	rs11614913	MIR-196A2	4 328	0.50	C	0.98 (0.89, 1.08)	0.702	1.000
12	rs10849373	NINJ2	4 423	0.14	G	1.51 (1.28, 1.79)	< 0.001^*	< 0.001^*
12	rs11833579	NINJ2	4 378	0.34	A	1.06 (0.95, 1.17)	0.301	1.000
14	rs1952706	PTCSC3	3 867	0.49	C	0.97 (0.87, 1.07)	0.496	1.000
14	rs2787417	PTCSC3	4 362	0.49	T	0.95 (0.86, 1.04)	0.280	1.000
14	rs934075	PTCSC3	4 415	0.49	G	0.97 (0.88, 1.06)	0.481	1.000
16	rs12445022	JPH3	4 441	0.10	A	1.06 (0.91, 1.23)	0.457	1.000
16	rs879324	ZFHX3	3 433	0.34	T	1.08 (0.97, 1.20)	0.177	1.000
16	rs7193343	ZFHX3	4 428	0.41	T	1.14 (1.03, 1.26)	0.008^*	0.216

rs579459 number of pathogenic alleles	Model 1				Model 2
rs579459 number of pathogenic alleles	0(n=784)	1(n=435)	2(n=201)	P_int	0(n=784)	1(n=1435)	2(n=2201)	P_int
Sleep duration/ h	1.11 (0.97, 1.27)	1.04 (0.96, 1.12)	1.02(0.96, 1.08)	0.889	1.15(0.99, 1.34)	1.03(0.94, 1.13)	1.03 (0.96, 1.11)	0.668
< 7	0.82 (0.47, 1.37)	1.12 (0.81, 1.55)	1.15(0.89, 1. 48)		0.65 (0.35, 1.18)	1.07(0.74, 1.53)	1.14(0.86, 1.51)
7.0 ~8.9	1.00	1.00	1.00		1.00	1.00	1.00
≥9	1.72 (1.08, 2.72)	1.29 (0.96, 1.72)	1.06(0.84, 1.33)		1.97 (1.15, 3.39)	1.15(0.83, 1.61))	1.10 (0.85, 1.42)
Sleep efficiency/%	0.57 (0.07, 5.72)	0.04 (0.01, 0.23)	0.06 (0.01, 0.26)	0.576	0.87(0.07, 13.53)	0.06（0.01, 0.38)	0.16 (0.03, 0.86)	0.661
≥80	1.00	1.00	1.00		1.00	1.00	1.00
< 80	0.70(0.26, 1.74)	2.32 (1.35, 4.02)	1.55(0.97, 2.46)		0.62(0.21, 1.74)	1.85 (1.00, 3.43)	1.27 (0.75, 2.15)
Sleep onset timing
< 22:00	0.78 (0.47, 1.28)	1.21(0.89, 1.66)	1.83 (1.44, 2.32)	0.007	0.65 (0.35, 1.17)	1.02 (0.72, 1.45)	1.56(1.20, 2.04)0.040	0.040
22:00 -22:59	1.00	1.00	1.00		1.00	1.00	1.00
23:00 -23:59	0.84 (0.50, 1.40)	0.91 (0.65, 1.27)	0.85 (0.65, 1.10)	0.782	0.70 (0.38, 1.25)	1.00 (0.69, 1.44)	0.97 (0.72, 1.29)	0.310
≥24：00	1.63 (0.83, 3.10)	0.72 (0.45, 1.11)	0.84 (0.59, 1.19)	0.719	1.45 (0.67, 3.07)	0.72 (0.44, 1.17)	0.88 (0.59, 1.29)	0.954

rs2634074 number of pathogenic alleles	Model 1				Model 2
rs2634074 number of pathogenic alleles	0(n=935)	1(n=1469)	2(n=1795)	P_int	0(n=935)	1(n=1469)	2(n=1795)	P_int
Sleep duration /h	1.14 (1.02, 1.28)	1.08 (0.99, 1.17)	0.97 (0.90, 1.03)	0.033	1.15 (1.02, 1.31)	1.09 (0.99, 1.20)	0.97 (0.90, 1.05)	0.060
< 7	0.74 (0.45, 1.20)	1.01 (0.72, 1.42)	1.18 (0.90, 1.55)		0.73 (0.43, 1.24)	0.94 (0.64, 1.37)	1.11 (0.82, 1.50)
7.0 -8.9	1.00	1.00	1.00		1.00	1.00	1.00
≥9	1.66 (1.12, 2.45)	1.19 (0.89, 1.60)	1.01 (0.79, 1.30)		1.71 (1.10, 2.65)	1.18 (0.85, 1.64)	1.00 (0.75, 1.33)
Sleep efficiency /%	0.08 (0.01, 0.73)	0.24 (0.05, 1.27)	0.04 (0.01, 0.24)	0.532	0.14 (0.01, 1.58)	0.61 (0.09, 4.49)	0.03 (0.00, 0.23)	0.230
≥80	1.00	1.00	1.00		1.00	1.00	1.00
< 80	1.62 (0.71, 3.62)	1.58 (0.90, 2.74)	1.76 (1.04, 2.96)		1.35 (0.54, 3.32)	1.22 (0.64, 2.29)	1.84 (1.02, 3.33)
Sleep onsettiming
< 22:00	1.00 (0.65, 1.54)	1.58 (1.16, 2.17)	1.52 (1.17, 1.98)	0.606	0.80 (0.49, 1.29)	1.22 (0.85, 1.74)	1.45 (1.08, 1.94)	0.223
22:00 -22:59	1.00	1.00	1.00		1.00	1.00	1.00
23:00 -23:59	1.13 (0.71, 1.77)	0.86 (0.62, 1.20)	0.78 (0.58, 1.05)	0.398	1.30 (0.78, 2.14)	0.85 (0.58, 1.22)	0.88 (0.64, 1.22)	0.505
≥24：00	0.99 (0.52, 1.81)	1.01 (0.66, 1.54)	0.76 (0.50, 1.13)	0.785	0.86 (0.42, 1.70)	0.93 (0.58, 1.49)	0.83 (0.53, 1.29)	0.625

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