Causal Association Study between Sleep Duration and Heart Failure

doi:10.12114/j.issn.1007-9572.2023.0331

Abstract

Abstract:

Background

The correlation between sleep duration and heart failure has been established, yet the majority of studies are observational in nature, rendering causal inference difficult due to confounding variables.

Objective

To explore the causal relationship between both inadequate and excessive sleep durations and heart failure using two-sample Mendelian randomization (MR) .

Methods

The research data was derived from the genome-wide association study (GWAS) summary database, wherein inadequate sleep duration consisted of 106 192 samples and excessive sleep duration consisted of 34 184 samples. Appropriate single nucleotide polymorphisms (SNPs) were selected as instrumental variables, and two-sample Mendelian randomization analyses were conducted using inverse variance weighted (IVW), weighted median, Weighted mode and MR-Egger regression to evaluate the causal relationship between sleep duration and heart failure, as measured by the odds ratio. Sensitivity analyses were performed using heterogeneity testing, horizontal pleiotropic test, and leave-one-out analysis.

Results

23 SNPs were identified as being associated with inadequate sleep duration, while 5 SNPs were associated with exessive sleep duration. The IVW analysis revealed that inadequate sleep duration was a risk factor for heart failure [OR (95%CI) =2.347 (1.209-4.555), P=0.012]. After removal of SNPs with multiple testing correction, demonstrated the robustness of MR results.

Conclusion

There is a positive causal relationship between short sleep duration and heart failure, that is, short sleep duration increases the risk of heart failure.

Key words: Sleep, Sleep duration, Heart failure, Mendelian randomization, Causal inference

摘要：

背景

睡眠时间与心力衰竭相关，但大多数研究为观察性研究，由于混杂因素过多难以进行因果关联的推断。

目的

采用两样本孟德尔随机化（MR）方法评估睡眠时间过短和睡眠时间过长与心力衰竭的因果关联。

方法

研究数据来自全基因组关联分析（GWAS）汇总数据库，其中睡眠时间过短包含106 192例样本，睡眠时间过长34 184例样本，分别选取合适的单核苷酸多态性（SNPs）作为工具变量，采用逆方差加权法（IVW）、加权中位数法和MR-Egger回归法等进行两样本MR分析，以OR值评估睡眠时间与心力衰竭之间的因果关联。采用异质性检验、水平多效性检验、leave-one-out检验等进行敏感性分析。

结果

筛选到与睡眠时间过短相关的SNPs有23个，与睡眠时间过长相关的SNPs有5个，IVW结果显示睡眠时间过短是心力衰竭发生的危险因素[OR（95%CI）=2.347（1.209~4.555），P=0.012]；剔除存在水平多效性的SNP后进行敏感性分析，表明MR结果具有稳健性。

结论

睡眠时间过短与心力衰竭存在正向因果关联，即睡眠时间过短会增加心力衰竭的患病风险。

关键词: 睡眠, 睡眠时间, 心力衰竭, 孟德尔随机化, 因果推断

CLC Number:

R163

LIU Zhenyu,WEI Yunpeng,WANG Jiangmin, et al. Causal Association Study between Sleep Duration and Heart Failure[J]. Chinese General Practice, 2025, 28(27): 3441-3446. DOI: 10.12114/j.issn.1007-9572.2023.0331.
刘振宇,魏云鹏,王江敏等. 睡眠时间与心力衰竭的因果关联研究[J]. 中国全科医学, 2025, 28(27): 3441-3446. DOI: 10.12114/j.issn.1007-9572.2023.0331.

Figures/Tables 7

References 24

[4]	刘振宇，王江敏，魏云鹏，等. 北京市海淀区居民睡眠时间与糖尿病患病的相关性研究[J]. 现代预防医学，2022，49（18）：3451-3456. DOI：10.20043/j.cnki.MPM.202203360.
[5]	BOCK J M，VUNGARALA S，COVASSIN N，et al. Sleep duration and hypertension：epidemiological evidence and underlying mechanisms[J]. Am J Hypertens，2022，35（1）：3-11. DOI：10.1093/ajh/hpab146.
[6]	AGGARWAL S，LOOMBA R S，ARORA R R，et al. Associations between sleep duration and prevalence of cardiovascular events[J]. Clin Cardiol，2013，36（11）：671-676. DOI：10.1002/clc.22160.
[7]	WANNAMETHEE S G，PAPACOSTA O，LENNON L，et al. Self-reported sleep duration，napping，and incident heart failure：prospective associations in the British regional heart study[J]. J Am Geriatr Soc，2016，64（9）：1845-1850. DOI：10.1111/jgs.14255.
[8]	ZHUANG S，HUANG S E，HUANG Z，et al. Prospective study of sleep duration，snoring and risk of heart failure[J]. Heart，2023：heartjnl-hear2022-321799. DOI：10.1136/heartjnl-2022-321799.
[9]	HEMANI G，ZHENG J，ELSWORTH B，et al. The MR-Base platform supports systematic causal inference across the human phenome[J]. eLife，2018，7：e34408. DOI：10.7554/eLife.34408.
[10]	ZHAO J Q，YANG F K，ZHUO C G，et al. Association of sleep duration with atrial fibrillation and heart failure：a Mendelian randomization analysis[J]. Front Genet，2021，12：583658. DOI：10.3389/fgene.2021.583658.
[11]	LIANG Y Y，CHEN J，PENG M G，et al. Association between sleep duration and metabolic syndrome：linear and nonlinear Mendelian randomization analyses[J]. J Transl Med，2023，21（1）：90. DOI：10.1186/s12967-023-03920-2.
[12]	ZHOU F X，LI S J，XU H L. Insomnia，sleep duration，and risk of anxiety：a two-sample Mendelian randomization study[J]. J Psychiatr Res，2022，155：219-225. DOI：10.1016/j.jpsychires.2022.08.012.
[13]	SUDLOW C，GALLACHER J，ALLEN N，et al. UK biobank：an open access resource for identifying the causes of a wide range of complex diseases of middle and old age[J]. PLoS Med，2015，12（3）：e1001779. DOI：10.1371/journal.pmed.1001779.
[14]	DASHTI H S，JONES S E，WOOD A R，et al. Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates[J]. Nat Commun，2019，10（1）：1100. DOI：10.1038/s41467-019-08917-4.
[15]	SHAH S，HENRY A，ROSELLI C，et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure[J]. Nat Commun，2020，11（1）：163. DOI：10.1038/s41467-019-13690-5.
[16]	FENG R Y，LU M N，XU J W，et al. Pulmonary embolism and 529 human blood metabolites：genetic correlation and two-sample Mendelian randomization study[J]. BMC Genom Data，2022，23（1）：69. DOI：10.1186/s12863-022-01082-6.
[17]	BURGESS S，DAVEY SMITH G，DAVIES N M，et al. Guidelines for performing Mendelian randomization investigations：update for summer 2023[J]. Wellcome Open Res，2019，4：186. DOI：10.12688/wellcomeopenres.15555.3.
[18]	BOWDEN J，DAVEY SMITH G，BURGESS S. Mendelian randomization with invalid instruments：effect estimation and bias detection through egger regression[J]. Int J Epidemiol，2015，44（2）：512-525. DOI：10.1093/ije/dyv080.
[19]	VERBANCK M，CHEN C Y，NEALE B，et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J]. Nat Genet，2018，50（5）：693-698. DOI：10.1038/s41588-018-0099-7.
[20]	CHEN X R，ZHOU M Q，WANG J Y，et al. Associations of objective sleep duration and physical activity with risk of heart failure：a prospective cohort study[J]. Gen Hosp Psychiatry，2024，90：141-149. DOI：10.1016/j.genhosppsych.2024.08.005.
[21]	ZOU C F，WANG Z Q，HUANG W Y，et al. Linear and non-linear Mendelian randomization analyses of sex-specific associations between sleep duration and hyperuricemia[J]. Front Nutr，2022，9：920791. DOI：10.3389/fnut.2022.920791.
[1]	SAVARESE G，BECHER P M，LUND L H，et al. Global burden of heart failure：a comprehensive and updated review of epidemiology[J]. Cardiovasc Res，2023，118（17）：3272-3287. DOI：10.1093/cvr/cvac013.
[2]	SAVARESE G，LUND L H. Global public health burden of heart failure[J]. Card Fail Rev，2017，3（1）：7-11. DOI：10.15420/cfr.2016:25:2.
[3]	HIRSHKOWITZ M，WHITON K，ALBERT S M，et al. National sleep foundation's updated sleep duration recommendations：final report[J]. Sleep Health，2015，1（4）：233-243. DOI：10.1016/j.sleh.2015.10.004.
[22]	CESPEDES E M，HU F B，REDLINE S，et al. Comparison of self-reported sleep duration with actigraphy：results from the hispanic community health study/study of latinos sueño ancillary study[J]. Am J Epidemiol，2016，183（6）：561-573. DOI：10.1093/aje/kwv251.
[23]	ZHANG Y Q，PELOQUIN C E，DUBREUIL M，et al. Sleep apnea and the risk of incident gout：a population-based，body mass index-matched cohort study[J]. Arthritis Rheumatol，2015，67（12）：3298-3302. DOI：10.1002/art.39330.
[24]	SCHIPPER S B J，VAN VEEN M M，ELDERS P J M，et al. Sleep disorders in people with type 2 diabetes and associated health outcomes：a review of the literature[J]. Diabetologia，2021，64（11）：2367-2377. DOI：10.1007/s00125-021-05541-0.

SNP	CHR	位置	EA	OA	EAF	β	SE	P值
rs11763750	7	2080114	G	A	0.814 346	0.007 212	0.001 234	5.10E-09
rs1229762	7	114218582	C	T	0.335 499	-0.007 239	0.001 017	1.00E-12
rs12518468	5	7249696	T	C	0.671 544	-0.005 885	0.001 021	8.50E-09
rs12567114	1	98527951	G	A	0.724 600	0.006 325	0.001 077	4.10E-09
rs12661667	6	41792545	C	T	0.736 505	-0.006 022	0.001 087	2.80E-08
rs12963463	18	53099093	C	T	0.299 425	0.007 114	0.001 060	1.90E-11
rs13107325	4	103188709	C	T	0.925 472	-0.013 268	0.001 828	2.50E-13
rs1380703	2	57941287	A	G	0.616 469	-0.006 764	0.001 005	1.60E-11
rs1607227	11	28808617	G	T	0.704 938	0.006 369	0.001 055	1.50E-09
rs17005118	4	82288564	G	A	0.735 064	-0.006 482	0.001 087	2.50E-09
rs17388803	15	48027204	A	C	0.894 352	-0.009 826	0.001 587	6.50E-10
rs2014830	3	50172397	C	T	0.698 128	0.005 786	0.001 050	2.70E-08
rs205024	17	11227352	C	T	0.616 724	0.005 510	0.000 986	2.70E-08
rs2186122^*	1	66470206	A	T	0.438 434	-0.005 670	0.000 972	4.80E-09
rs2517827	6	29832846	C	A	0.688 933	-0.005 929	0.001 036	5.70E-09
rs2820313	1	201870221	A	G	0.658 888	-0.006 006	0.001 010	2.30E-09
rs2863957	2	114089551	C	A	0.781 508	0.010 190	0.001 161	2.60E-18
rs3776864	5	102327868	A	C	0.667 210	0.005 724	0.001 019	1.70E-08
rs4585442	5	135508381	A	G	0.688 977	-0.006 347	0.001 036	8.10E-10
rs5757675	22	39838892	G	T	0.259 528	0.006 455	0.001 099	2.70E-09
rs59779556	16	56227965	T	G	0.553 827	0.005 491	0.000 966	2.00E-08
rs60882754^*	8	52886619	A	T	0.938 985	0.011 304	0.002 001	1.80E-08
rs7524118	1	34736052	T	C	0.291 624	-0.005 762	0.001 054	4.90E-08
rs7939345	11	47980568	T	G	0.207 569	0.006 498	0.001 182	4.00E-08
rs9321171	6	129848635	C	T	0.540 122	0.005 354	0.000 966	4.20E-08
rs9367621^*	6	55040290	T	A	0.431 040	0.005 445	0.000 970	1.60E-08

SNP	CHR	位置	EA	OA	EAF	β	SE	P值
rs11763750	7	2080114	G	A	0.814 346	0.007 212	0.001 234	5.10E-09
rs1229762	7	114218582	C	T	0.335 499	-0.007 239	0.001 017	1.00E-12
rs12518468	5	7249696	T	C	0.671 544	-0.005 885	0.001 021	8.50E-09
rs12567114	1	98527951	G	A	0.724 600	0.006 325	0.001 077	4.10E-09
rs12661667	6	41792545	C	T	0.736 505	-0.006 022	0.001 087	2.80E-08
rs12963463	18	53099093	C	T	0.299 425	0.007 114	0.001 060	1.90E-11
rs13107325	4	103188709	C	T	0.925 472	-0.013 268	0.001 828	2.50E-13
rs1380703	2	57941287	A	G	0.616 469	-0.006 764	0.001 005	1.60E-11
rs1607227	11	28808617	G	T	0.704 938	0.006 369	0.001 055	1.50E-09
rs17005118	4	82288564	G	A	0.735 064	-0.006 482	0.001 087	2.50E-09
rs17388803	15	48027204	A	C	0.894 352	-0.009 826	0.001 587	6.50E-10
rs2014830	3	50172397	C	T	0.698 128	0.005 786	0.001 050	2.70E-08
rs205024	17	11227352	C	T	0.616 724	0.005 510	0.000 986	2.70E-08
rs2186122^*	1	66470206	A	T	0.438 434	-0.005 670	0.000 972	4.80E-09
rs2517827	6	29832846	C	A	0.688 933	-0.005 929	0.001 036	5.70E-09
rs2820313	1	201870221	A	G	0.658 888	-0.006 006	0.001 010	2.30E-09
rs2863957	2	114089551	C	A	0.781 508	0.010 190	0.001 161	2.60E-18
rs3776864	5	102327868	A	C	0.667 210	0.005 724	0.001 019	1.70E-08
rs4585442	5	135508381	A	G	0.688 977	-0.006 347	0.001 036	8.10E-10
rs5757675	22	39838892	G	T	0.259 528	0.006 455	0.001 099	2.70E-09
rs59779556	16	56227965	T	G	0.553 827	0.005 491	0.000 966	2.00E-08
rs60882754^*	8	52886619	A	T	0.938 985	0.011 304	0.002 001	1.80E-08
rs7524118	1	34736052	T	C	0.291 624	-0.005 762	0.001 054	4.90E-08
rs7939345	11	47980568	T	G	0.207 569	0.006 498	0.001 182	4.00E-08
rs9321171	6	129848635	C	T	0.540 122	0.005 354	0.000 966	4.20E-08
rs9367621^*	6	55040290	T	A	0.431 040	0.005 445	0.000 970	1.60E-08

SNP	CHR	位置	EA	OA	EAF	β	SE	P值
rs10899257	11	76415209	G	A	0.855 527	-0.005 638	0.001 031	4.60E-08
rs147114641	17	43748492	C	A	0.774 030	0.005 689	0.000 868	4.90E-11
rs17817288#	16	53807764	A	G	0.518 127	0.004 188	0.000 727	8.90E-09
rs3751046	11	122828342	A	G	0.852 658	-0.005 775	0.001 027	2.00E-08
rs6737318	2	114083120	A	G	0.778 159	-0.006 380	0.000 877	3.40E-13
rs7534398^*	1	7767464	T	A	0.798 618	-0.005 079	0.000 908	2.10E-08
rs75458655	11	118115331	C	T	0.977 027	-0.016 731	0.002 423	5.40E-12

SNP	CHR	位置	EA	OA	EAF	β	SE	P值
rs10899257	11	76415209	G	A	0.855 527	-0.005 638	0.001 031	4.60E-08
rs147114641	17	43748492	C	A	0.774 030	0.005 689	0.000 868	4.90E-11
rs17817288#	16	53807764	A	G	0.518 127	0.004 188	0.000 727	8.90E-09
rs3751046	11	122828342	A	G	0.852 658	-0.005 775	0.001 027	2.00E-08
rs6737318	2	114083120	A	G	0.778 159	-0.006 380	0.000 877	3.40E-13
rs7534398^*	1	7767464	T	A	0.798 618	-0.005 079	0.000 908	2.10E-08
rs75458655	11	118115331	C	T	0.977 027	-0.016 731	0.002 423	5.40E-12

暴露因素	方法	SNPs	OR（95%CI）	P值
睡眠时间不足
	MR Egger	23	57.304（2.415~1 359.486）	0.021
	Weighted median	23	1.655（0.710~3.857）	0.244
	Inverse variance weighted	23	2.347（1.209~4.555）	0.012
	Weighted mode	23	1.334（0.349~5.102）	0.677
睡眠时间过长
	MR Egger	5	0.213（0.001~49.025）	0.616
	Weighted median	5	0.508（0.066~3.901）	0.515
	Inverse variance weighted	5	0.774（0.141~4.249）	0.768
	Weighted mode	5	0.381（0.033~4.415）	0.484