Association Between Atopic Dermatitis and Major Cardiovascular Outcomes: a Two-Sample Mendelian Randomization Study

Hongjiao Qi; Lifeng Wang; Linfeng Li

doi:10.5826/dpc.1204a165

. 2022 Oct 1;12(4):e2022165. doi: 10.5826/dpc.1204a165

Association Between Atopic Dermatitis and Major Cardiovascular Outcomes: a Two-Sample Mendelian Randomization Study

Hongjiao Qi ¹, Lifeng Wang ², Linfeng Li ^1,^✉

PMCID: PMC9681179 PMID: 36534570

Abstract

Introduction

Atopic dermatitis (AD) has been linked to cardiovascular disease (CVD) in population-based studies, however, their causal relationship is still unclear.

Objectives

To evaluate the causal association of AD with risk of cardiovascular outcomes using a Mendelian randomization (MR) approach.

Methods

We extracted summary-level data for AD, stroke, heart failure, coronary artery disease (CAD), myocardial infarction, angina pectoris from published, nonoverlapping genome-wide association studies (GWAS). Inverse variance weighted (IVW) method was used as the primary analysis. Alternative methods, including weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier, weighted mode, and leave-out analysis, were performed to examine potential pleiotropy.

Results

Thirteen SNPs (13,287 cases and 41,345 controls) were selected as instrumental variables (IVs). No associations of AD with risks of stroke (odds ratio [OR] = 1.03, 95% confidence interval [CI]: 0.97–1.09, P = 0.3630), heart failure (OR = 1.04, 95%CI: 0.99–1.09, P= 0.119), coronary artery disease (OR = 1.00, 95%CI: 0.96–1.05, P = 0.988), myocardial infarction (OR = 1.00, 95%CI: 1.00-1.00, P = 0.322), and angina pectoris (OR = 1.00, 95%CI: 1.00-1.00, P = 0.369) was found. No significant effect of pleiotropy was detected.

Conclusions

This MR study does not support a causal effect of AD on stroke, heart failure, CAD, myocardial infarction, angina pectoris.

Keywords: atopic dermatitis, cardiovascular disease, Mendelian randomization

Introduction

Atopic dermatitis (AD, atopic eczema, eczema) is a common chronic, inflammatory, relapsing, skin diseases [1]. The prevalence of AD is 15 to 20% among children

And 7% to 14% among adults [2,3]. It is characterized by eczematous lesions, varying degrees of pruritus, and a chronic or relapsing disease course [4]. AD broadly decreases health-related quality of life [5].

Recently, there has been a growing interest in the putative cardiovascular comorbidities of AD in population-based observational studies [6–11]. However, owning to the nature of being susceptible to potential confounders and reverse causation in observational study design [12], it remains unclear whether the elevated risk of CVD in patients with AD is caused by AD or introduced by confounding factors of AD and CVD. Understanding the causal relationship between AD and CVD could have implications for appropriate identification, clinical surveillance, and management of high-risk population. Mendelian randomization (MR) analysis is a novel epidemiological approach to assess the causal relationship between an exposure and an outcome [12], with less susceptibility to unmeasured confounders and reverse causation by using genetic variants (i.e., single nucleotide polymorphisms, SNPs) as instrumental variables (IVs) [13,14].

Objectives

In this study, we explored the causal associations between AD and CVD events using the MR method.

Methods

We carried out a two-sample MR analysis based on summary statistics to investigate the causal relationship between AD and CVD events including stroke, heart failure, CAD, myocardial infarction, and angina pectoris. Single nucleotide polymorphisms (SNPs) were selected as instruments variables because they are randomly allocated and less probable to be affected by confounding or reverse causation^[15]. We used publicly available data, informed patients consents and ethical approvals were available in original genome-wide association studies (GWAS) studies.

Data Sources and Selection of SNPs

Summary-level data for AD were extracted from the EArly Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium, including 13,287 cases and 41,345 controls of mostly European ancestry [16]. Summary-level data stroke were extracted from the MEGASTROKE Consortium, a meta-analysis of 29 GWAS including a total of 40,585 cases and 406,111 non-cases of European ancestry [17]. Summary-level data for heart failure were extracted from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium [18], comprising 47,309 cases and 930,014 non-cases of European ancestry across 26 studies. Summary-level data for CAD from UKBiobank-CardioMetabolic-Consortium CHD working group included 10801 cases and 137914 non-cases of European ancestry [19]. Summary-level data for myocardial infarction from UKBiobank included 4837 cases and 332,362 non-cases of European ancestry. Summary-level data for angina pectoris from UKBiobank included 4,837 cases and 332,362 non-cases of European ancestry.

Statistical Analysis

For each CVD outcome, we carried out two-sample MR analysis to estimate the causal effect of AD, using the “TwoSampleMR” package of R. The inverse-variance weighted (IVW) linear regression was conducted as the primary analysis. IVW is an efficient analysis method which assumes that all genetic variants are valid IVs, and that there is no horizontal pleiotropy [20]. We calculated the odds ratio (OR) with 95% confidence interval (CI) and created the SNP effect scatter plot.

Besides, we assessed the potential violations of the assumptions of MR analysis by performing a number of complementary sensitivity analysis: weighted median approach for examining result robustness when some instruments may be potentially invalid [20], MR-Egger regression for evaluating the directional pleiotropy of instruments [21,22], weighted mode, which generally has low bias and low Type 1 error rate inflation [23], MR Pleiotropy RESidual Sum and Outlier (MR PRESSO) for outlier instrument detection [24], and leave-one-out analysis to evaluate whether the MR estimate was influenced by single proxy SNP. We also calculated the Cochran Q test from the IVW analysis to examine potential horizontal pleiotropy.

All statistical analyses were performed using R software 4.0.3 (R Foundation for Statistical Computing). All statistical tests were two-sided with α=0.05.

Results

Genetic Instruments

Thirteen SNPs were identified as associated with AD (P<5×10⁻⁸), with independent inheritance (r²<0.01), and without linkage disequilibrium (LD) in summary statistics. All of these 13 SNPs were available in GWAS for stroke, heart failure, CAD, myocardial infarction, angina pectoris. Details of the included SNPs are shown in Tables S1, Tables S2, S3, S4, and S5 respectively.

Two-sample MR of AD and CVD

No significant evidence was found for a causal effect of AD on stroke, heart failure, CAD, myocardial infarction, angina pectoris using the IVW analysis (stroke: OR = 1.03, 95%CI: 0.97–1.09, P = 0.363; heart failure: OR = 1.04, 95%CI: 0.99–1.09, P = 0.119; CAD: OR = 1.00, 95%CI: 0.94–1.06, P = 0.961; myocardial infarction: OR = 1.00, 95%CI: 1.00-1.00, P = 0.322; angina pectoris: OR = 1.00, 95%CI: 1.00-1.00, P = 0.369). The results neither weighted median, MR Egger, weighted mode nor MR PRESSO analyses were significant for all of the diseases above (Table 1 and Figures S1, S2, S3, S4, S5).

Table 1.

The Causal Effect of Atopic Dermatitis on Stroke

Type of CVD	Method	OR (95% CI)	P Value	No. of SNPs
Stroke	IVW	1.03 (0.97–1.09)	0.363	13
	Weighted median	0.99 (0.92–1.05)	0.681	13
	MR Egger	0.96 (0.79–1.17)	0.694	13
	Weighted mode	0.97 (0.88–1.07)	0.529	13
	MR PRESSO	1.01 (0.96–1.06)	0.659	13
Heart failure	IVW	1.04 (0.99–1.09)	0.119	13
	Weighted median	1.05 (1.00–1.11)	0.069	13
	MR Egger	1.13 (0.98–1.30)	0.110	13
	Weighted mode	1.06 (0.98–1.14)	0.176	13
	MR PRESSO	1.04 (0.99–1.09)	0.145	13
Coronary artery disease	IVW	1.00 (0.96–1.05)	0.988	13
	Weighted median	0.99 (0.94–1.05)	0.760	13
	MR Egger	0.96 (0.84–1.10)	0.608	13
	Weighted mode	0.98 (0.90–1.07)	0.654	13
	MR PRESSO	1.00 (0.96–1.05)	0.988	13
Myocardial infarction	IVW	1.00 (1.00-1.00)	0.322	13
	Weighted median	1.01 (1.00-1.00)	0.789	13
	MR Egger	1.00 (1.00-1.00	0.724	13
	Weighted mode	1.00 (1.00-1.00)	0.574	13
	MR PRESSO	1.00 (1.00-1.00)	0.328	13
Angina pectoris	IVW	1.00 (1.00-1.00)	0.369	13
	Weighted median	1.01 (1.00-1.00)	0.416	13
	MR Egger	1.00 (1.00-1.00)	0.992	13
	Weighted mode	1.00 (1.00-1.00)	0.627	13
	MR PRESSO	1.00 (1.00-1.00)	0.386	13

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CI = Confidence interval; CVD = cardiovascular disease; IVW = inverse variance–weighted; MR = mendelian randomization; OR = odds ratio; SNP = single-nucleotide polymorphism.

Leave-one-out analysis indicated no influence of single SNP on the risk estimates of AD on stroke, heart failure, CAD, myocardial infarction, angina pectoris. P values of Cochrane Q test and MR Egger intercept for AD on stroke were 0.481 and 0.695, respectively; for AD on heart failure were 0.150 and 0.224, respectively; for AD on CAD were 0.146 and 0.583, respectively; for AD on myocardial infarction were 0.417 and 0.993, respectively; for AD on angina pectoris were 0.080 and 0.752, respectively, suggesting no evidence of potential horizontal pleiotropy and heterogeneity.

Conclusions

To the best of our knowledge, this is the first study to explore the causal relationship between AD and CVD based on an MR approach. Our results did not support a causal effect of AD on CVD.

Previous studies on the link between AD and stroke are controversial. In a Danish matched cohort study, patients with severe AD had an increased risk of ischemic stroke, but after adjustment for socioeconomic status, smoking, comorbidities, and medication use, the risk was similar with controls [6]. In a cohort from the Nurses’ Health Study 2, the risk of stroke was significantly increased in female nurses with AD in the age and models adjusted for demographic, lifestyle risk factors, family history of MI, and postmenopausal hormone replacement use. However, after further controlling for hypertension, hypercholesterolemia, and diabetes, the association between AD and stroke was no longer significant [7]. In a Swedish nationwide case-control study, only severe AD was associated with ischemic stroke [8]. A cross-sectional study conducted among primary care and community settings patients found only adult patients with moderate to severe AD was significantly associated with higher prevalence rates of prior stroke compared to the control: 4.4% versus 2.4% [25]. In a large population-based study including three surveys in US, AD was not associated with stroke in NHANES 2005–2006, but was significantly associated with higher odds of stroke in NHIS 2010 and 2012 in crude models and multivariate models adjusted for demographic, lifestyle factors, hay fever and asthma [9]. A population-based cohort study with data from the UK Clinical Practice Research Datalink reported very modest association between AD and stroke in adjusted models, and the associations were considerably stronger in patients with severe or active AD [10]. Two recent large German studies also found no association between AD and stroke [26,27]. Moreover, a large Canadian cohort even found AD was associated with lower risk of stroke in adjusted model [28].

Though there are only few studies on the link between AD and heart failure, the results are still inconsistent. An US cross-sectional inpatient study reported a significant relationship between AD and heart failure [29]. A cohort study also found positive association between AD and heart failure [10].

CAD is a cause of major morbidity and mortality worldwide. It includes stable ischemic heart disease, MI and unstable angina [30]. Several studies provided estimates for the association of AD with the risk of CAD. The abovementioned study conducted by Silverberg et al. showed AD was associated with significantly higher odds of CAD, the associations attenuated but remained significant in the three adjusted models [9]. But Kwa et al. study reported AD was not significantly associated with CAD [29]. Findings about associations between AD and angina were also mixing. Standl et al. and Silverwood et al. reported a significantly positive association between AD and angina [10,26]. However, AD was not found to be significantly associated with angina in NHANES [9]. The situation is similar to MI. There is a significant association between AD and MI in NHANES, but after controlling risk factor of CVD, the association did not remain significant [9]. Studies of Drucker et al. and Standl et al. also suggested no evidence of the association between AD and MI [7,26,28]. However, Silverwood et al., the NHIS 2010, and a recent cross-sectional study suggested AD was associated with an increased risk of MI, even adjusted for potential confounding factors [9,10,31]. AD and CVD related studies are shown in Table S6.

There are some limitations to the present study. First, the summary-level GWAS data we used were based mainly on people of European ancestry. Therefore, results in this study may not be applicable to other populations. Second, onset age and disease severity of AD might influence the association between AD and comorbidities, but because the limitation of data, we were not able to perform subgroup analyses by age and severity of AD. Third, an important limitation for MR study is potential pleiotropy. In this study, we applied various MR approaches to test for potential pleiotropy, and no evidence of pleiotropy for all the analyses was observed. Moreover, the definitions of AD and comorbidities used in the data is a mixture of self-reported diagnosis together with doctor diagnosed cases, which may cause bias to our findings.

Conclusion

In conclusion, MR study does not support a causal effect of AD on stroke, heart failure, CAD, myocardial infarction, angina pectoris.

Supplementary File

Table 1 .

Leave Out Analysis for the Association Between AD and Stroke.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	1.036604	0.972788	1.104605	0.267451
rs12144049	1.042417	0.972733	1.117092	0.239259
rs12188917	1.041947	0.978455	1.10956	0.200193
rs12334935	1.035133	0.970749	1.103787	0.291931
rs2212434	1.020007	0.955225	1.089182	0.554045
rs2477121	1.034137	0.969395	1.103203	0.308846
rs2918299	1.03132	0.96544	1.101695	0.359834
rs4151657	1.022324	0.959644	1.089097	0.494015
rs479844	1.016297	0.952313	1.08458	0.626072
rs6062486	1.011756	0.961976	1.064113	0.649796
rs61815704	1.030897	0.963773	1.102695	0.375715
rs6419573	1.031928	0.966049	1.1023	0.350428
rs8066625	1.024116	0.959297	1.093315	0.475022
All	1.029013	0.967481	1.094458	0.363285

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OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 2 .

Leave Out Analysis for the Association Between AD and Heart Failure.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	1.045685	0.998383	1.095228	0.058563
rs12144049	1.040601	0.985861	1.098381	0.14888
rs12188917	1.039984	0.989537	1.093003	0.122254
rs12334935	1.049112	1.00675	1.093256	0.022613
rs2212434	1.029703	0.980293	1.081603	0.24335
rs2477121	1.04574	0.998462	1.095256	0.05812
rs2918299	1.03622	0.985465	1.089589	0.16496
rs4151657	1.031931	0.983738	1.082484	0.197717
rs479844	1.028488	0.978571	1.08095	0.268462
rs6062486	1.041393	0.991172	1.09416	0.107756
rs61815704	1.035809	0.984408	1.089894	0.175465
rs6419573	1.037437	0.987373	1.09004	0.145272
rs8066625	1.028608	0.981841	1.077604	0.234802
All	1.037797	0.990541	1.087308	0.118686

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OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 3 .

Leave Out Analysis for the Association Between AD and Coronary Artery Disease.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	0.998822	0.953129	1.046706	0.960658
rs12144049	0.999948	0.950616	1.05184	0.998389
rs12188917	0.994383	0.948679	1.042289	0.814494
rs12334935	1.005797	0.962038	1.051546	0.798973
rs2212434	1.009113	0.964813	1.055448	0.692053
rs2477121	1.001785	0.95586	1.049915	0.940634
rs2918299	1.003518	0.957882	1.051329	0.88243
rs4151657	0.988936	0.951483	1.027864	0.572203
rs479844	0.988138	0.946092	1.032053	0.590661
rs6062486	1.002905	0.957254	1.050733	0.902869
rs61815704	1.008962	0.963617	1.056441	0.703724
rs6419573	0.999903	0.953663	1.048385	0.996795
rs8066625	1.002174	0.956419	1.050117	0.927441
All	1.000338	0.957371	1.045233	0.987967

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OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 4 .

Leave Out Analysis for the Association Between AD and Myocardial Infarction.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	0.999032	0.997552	1.000513	0.199932
rs12144049	0.99909	0.997501	1.000681	0.262249
rs12188917	0.999546	0.998032	1.001061	0.556637
rs12334935	0.999523	0.998046	1.001002	0.527093
rs2212434	0.999239	0.997709	1.000772	0.330301
rs2477121	0.999383	0.997902	1.000866	0.414595
rs2918299	0.999211	0.997712	1.000712	0.302782
rs4151657	0.999099	0.997621	1.00058	0.232923
rs479844	0.999167	0.997629	1.000707	0.288732
rs6062486	0.999378	0.997897	1.000862	0.411388
rs61815704	0.999544	0.997987	1.001104	0.566673
rs6419573	0.999325	0.997826	1.000827	0.378057
rs8066625	0.998984	0.997499	1.00047	0.180141
All	0.99927	0.997827	1.000716	0.322364

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OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 5 .

Leave Out Analysis for the Association Between AD and Angina Pectoris.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	1.000954	0.999344	1.002566	0.245799
rs12144049	1.001062	0.999283	1.002844	0.242133
rs12188917	1.000588	0.998863	1.002316	0.504061
rs12334935	1.001026	0.999524	1.00253	0.180897
rs2212434	1.000258	0.998796	1.001722	0.729742
rs2477121	1.000653	0.998952	1.002356	0.452234
rs2918299	1.000854	0.999161	1.002551	0.323015
rs4151657	1.00054	0.998912	1.00217	0.51587
rs479844	1.000581	0.998834	1.002331	0.514699
rs6062486	1.000607	0.998924	1.002292	0.480047
rs61815704	1.000857	0.999064	1.002653	0.349097
rs6419573	1.000952	0.99932	1.002587	0.253258
rs8066625	1.00064	0.998937	1.002347	0.461454
All	1.000735	0.999134	1.002338	0.368553

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OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 6 .

Characteristics of Population-Based Studies Reporting the Association Between AD and CVD

							CVD main results
Study	Study design and Period	Setting	Age, sample size (proportion of males)	Diagnosis of AD	Outcome definition	Statistical analysis	CAD	Angina	MI	HF	Stroke
Andersen, 20161	Cohort, (1997–2012)	Denmark	≥15 yrs, Mild: 26,898, Severe: 2,527 (46.1%), Control: 145372	Hospital diagnosis of AD, ICD-8, ICD-10 codes	ICD-8, ICD-10 codes	Poisson regression			Adjusted¹ IRR: Mild: 0.82 (0.66–1.02), Severe: 1.39 (0.95–2.03); Fully adjusted² IRR Mild: 0.73 (0.59–0.91), Severe: 1.06 (0.72–1.56)		Adjusted^a IRR: Mild 0.92 (0.78–1.11), Severe: 1.51 (1.08–2.10); Fully adjusted^b IRR Mild: 0.82 (0.68–0.98), Severe: 1.19 (0.85–1.65)
Drucker, 20162	Cross-sectional, (1989–2009)	USA	Total :78702, AD: 7916 (0%)	Self-reported clinician diagnosed eczema (AD)	self-reported, confirmed by medical record, letter or interview	Logistic regression			Adjusted³ OR: 0.97 (0.69–1.36); MV-adjusted⁴ OR 0.94 (0.67–1.32); MV-adjusted⁵ OR 0.91 (0.65–1.28)		Adjusted^c OR: 1.38 (1.03–1.85); MV-adjusted^d OR 1.35 (1.00–1.80); MV-adjusted^e OR 1.31 (0.98–1.76)
Drucker, 20173	Cross-sectional, (2009 onwards)	Canada	30–74 yrs, Total: 259119, AD: 21379 (25%)	Self-reported a diagnosis of eczema	Self-reported a diagnosis of MI, stroke	Logistic regression			Adjusted⁶ OR: 0.83 (0.72–0.95), MV-adjusted⁷ model 1 OR: 0.80 (0.69–0.92); MV-adjusted⁸ model 2 OR: 0.87 (0.75–1.00)		Adjusted^f OR: 0.81 (0.68–0.97); MV-adjusted^g model 1 OR: 0.75 (0.62–0.89); MV-adjusted^h model 2 OR: 0.79 (0.66–0.95)
Egeberg, 20164	Cross-sectional, (1995–2012)	Denmark	≥18 yrs, AD: 7937 (38.2%), Control: 79370	Clinical diagnosis of AD ICD-10 codes	Administrative code	Logistic regression			Adjusted⁹ OR: overall: 1.1 (0.92–1.33), mild: 0.88 (0.63–1.23); severe: 1.23 (0.98–1.54)		Adjustedⁱ OR: overall: 1.52 (1.32–1.74), mild: 1.23 (0.94–1.60); severe: 1.45 (1.19–1.77)
Ivert, 20195	Case-control, (1968–2016)	Sweden	≥15 yrs, AD: 104832, Non-severe: 95274 (33.8%), Severe: 9558 (35.7%), Control: 1022435	ICD-8: ICD-9: ICD-10: codes	ICD codes	Conditional logistic regression		All cases: all crude¹⁰ OR: 1.18 (1.13–1.23), all fully adjusted¹¹ OR: 1.13 (1.08–1.19), Men crude^j OR: 1.15 (1.08–1.22), Men fully adjusted^k OR: 1.10 (1.03–1.18), Women crude^j OR: 1.21 (1.14–1.28), Women fully adjusted^k OR: 1.16 (1.09–1.24). Non-severe cases: all crude^j OR: 1.16 (1.10–1.21), All fully adjusted OR: 1.13 (1.08–1.19), Men crude^j OR: 1.15 (1.07–1.23), Men fully adjusted^k OR: 1.12 (1.04–1.20), Women crude^j OR: 1.17 (1.09–1.25), Women fully adjusted^k OR: 1.15 (1.08–1.24). Severe cases: all crude^j OR: 1.27 (1.15–1.40), All fully adjusted OR: 1.11 (1.00–1.24), Men crude^j OR: 1.16 (1.00–1.34), Men fully adjusted^k OR: 1.04 (0.89–1.21), Women crude^j OR: 1.38 (1.20–1.57), Women fully adjusted^k OR: 1.19 (1.04–1.37)	All cases: all crude^j OR: 1.10 (1.04–1.15), all fully adjusted^k OR: 1.07 (1.02–1.12), Men crude^j OR: 1.15 (1.07–1.22), Men fully adjusted^k OR: 1.12 (1.05–1.20), Women crude^j OR: 1.03 (0.96–1.11), Women fully adjusted^k OR: 1.01 (0.94–1.08). Non-severe cases: all crude^j OR: 1.08 (1.03–1.14), All fully adjusted^k OR: 1.07 (1.02–1.13), Men crude^j OR: 1.16 (1.08–1.24), Men fully adjusted^k OR: 1.15 (1.07–1.23), Women crude^j OR: 0.99 (0.92–1.08), Women fully adjusted^k OR: 0.98 (0.91–1.07). Severe cases: all crude^j OR: 1.14 (1.03–1.27), All fully adjusted^k OR: 1.03 (0.92–1.15), Men crude^j OR: 1.09 (0.94–1.26), Men fully adjusted^k OR: 1.01 (0.87–1.18), Women crude^j OR: 1.20 (1.03–1.40), Women fully adjusted^k OR: 1.06 (0.91–1.24)		All cases: all crude^j OR: 1.07 (1.02–1.13), all fully adjusted^k OR: 1.04 (0.99–1.09). Men crude^j OR: 1.13 (1.05–1.22), Men fully adjusted^k OR: 1.09 (1.01–1.17). Women crude^j OR: 1.03 (0.96–1.10), Women fully adjusted^k OR: 1.00 (0.93–1.07). Non-severe cases: all crude^j OR: 1.02 (0.97–1.08), All fully adjusted^k OR: 1.00 (0.94–1.06), Men crude^j OR: 1.09 (1.01–1.19), Men fully adjusted^k OR: 1.06 (0.98–1.16), Women crude^j OR: 0.96 (0.89–1.04), Women fully adjusted^k OR: 0.95 (0.88–1.02). Severe cases: all crude^j OR: 1.32 (1.19–1.47), All fully adjusted^k OR: 1.19 (1.07–1.33), Men crude^j OR: 1.32 (1.11–1.56), Men fully adjusted^k OR: 1.20 (1.01–1.43), Women crude^j OR: 1.33 (1.15–1.53), Women fully adjusted^k OR: 1.19 (1.03–1.37)
Jung, 20216	Cohort, (2005–2016)	Korea	Total: 2780356 (49.6%), AD: 285468	ICD-10: one of the AD diagnostic codes and underwent two AD-related tests	prescribed medication ≥2 times (outpatient) or ≥1 time hospitalized, ICD-10 codes	Cox regression		Adjusted¹² HR: 5.99 (4.96–7.25), Mild: 2.88 (1.07–7.75), Mod: 6.49 (1.61–26.18), Severe: 6.16 (5.0–7.47)	Adjusted^l HR: 9.43 (7.28–12.20), Mild: 5.50 (2.41–12.57), Mod: 3.92 (0.55–28.15), Severe: 10.13 (7.7–13.17)		Adjusted^l HR: 10.61 (8.65–13.03), Mild: 10.35 (4.85–22.08), Mod: 12.72 (3.15–51.35), Severe 10.56 (8.59–12.98)
Kwa 20177	Cross-sectional, (2002–2012)	USA	≥18 yrs, Total: 72651487, AD-E 164868	ICD-9 codes	Pre-coded by Association for Healthcare Research and Quality (AHRQ)	Logistic regression.	Crude OR: 0.75 (0.74–0.77), Propensity¹³ OR: 0.67 (0.66–0.69).		Crude OR: 0.56 (0.53–0.58), PSM^m OR: 0.52 (0.49–0.55)	Crude OR: 1.10 (1.07–1.13), PSM^m OR: 1.03 (1.01–1.06)	Crude OR: 0.74 (0.71–0.77), PSM^m OR: 0.71 (0.67–0.74)
Nishida, 20198	Cohort, (1988–2009)	Japan	aged 40–79 yrs, Total: 85,099 (41.7%)	self-reported	ICD-10 codes	Cox proportional hazard regression	Frequency of Eczema: Often/Seldom or Sometimes: Adjusted¹⁴ HR: 1.39 (1.12–1.72), MV-adjusted¹⁵ HR: 1.30 (1.05–1.61)			Often/Seldom or Sometimes: Adjustedⁿ HR: 1.14 (0.88–1.48), MV-adjusted^o HR: 1.11 (0.85–1.43)	Often/Seldom or Sometimes: Total stroke: Adjustedⁿ HR: 1.03 (0.87–1.22), MV-adjusted^o HR: 0.98 (0.83–1.17). Ischemic stroke: Adjustedⁿ HR: 1.01 (0.80–1.27), MV-adjusted^o HR: 0.96 (0.76–1.21). Hemorrhagic stroke: Adjustedⁿ HR: 1.07 (0.82–1.38), MV-adjusted^o HR: 1.04 (0.81–1.35)
Radtke, 20169	Cross-sectional, (2009 onwards)	Germany	>18 yrs, Total: 1349671, AD: 48140	ICD-10 codes	ICD-10 codes	Chi-square	Ischemic heart disease: Prevalence rate: (with/without AD): 0.83 (0.80–0.86)
Rhee, 202110	Cohort, (2009–2018)	Korea	>20 yrs, Total: 9548939, AD: 18557 (48.6%)	ICD-10 code, ≥3 times of physician diagnosis within 1 year	ICD-10 codes	Cox proportional hazards regression			Unadjusted HR: 1.51 (1.40–1.63), Adjusted¹⁶ HR: 1.21 (1.12–1.31), MV-adjusted¹⁷ HR: 1.14 (1.06–1.24)
Riis, 201611	Cohort, (1977–2013)	Denmark	Danishi born 1947–1977. Total 53210, AD: 4814 (45%)	Two clinical diagnoses of ICD-8 or ICD-10 codes	Clinical diagnoses of ICD-8 or ICD-10 codes	Cox proportional hazards regression			Crude HR: all: 1.79 (1.25–2.57), Men: 2.03 (1.32–3.12), Women: 1.39 (0.72–2.69), Mild: 1.62 (1.04–2.51), Severe: 2.38 (1.26–4.50), Adjusted¹⁸ HR: 1.74 (1.21–2.49); Men: 2.01 (1.31–3.08), Women: 1.28 (0.66–2.48), Mild: 1.58 (1.02–2.45); Severe: 2.40 (1.27–4.45)
Shalom, 201912	cross-sectional, (1998–2016)	Israel	AD: 116816 patients (2.7% of total), Control: 116812	At least one documented diagnosis	“CHS Chronic Disease Register”	Logistic regression	Ischemic heart disease: AD n (%): 2252 (1.9) General population n (%): 2290 (2.0), p=0.568			AD n (%): 538 (0.5) General population n (%): 572 (0.5), p=0.306	AD n (%): 538 (0.5) General population n (%): 572 (0.5), p=0.306
Silverberg, 201513	Cross-sectional, (2005–2006)	USA (NHANES)	≥20 yrs, Total: 4970 AD: 3.1% of total	self-reported	self-reported doctor diagnosis	Logistic regression	Crude OR: 2.57 (1.45–4,53), Model 1 adjusted¹⁹ OR: 2.11 (1.14–3.91) Model 2 adjusted²⁰ OR: 2.46 (1.37–4.43) Model 3 adjusted²¹ OR: 1.96 (1.02–3.77)	Crude OR: 1.87 (0.98–3.57), Model 1 adjusted^s OR: 1.63 (0.84–3.15) Model 2 adjusted^t OR: 1.91 (0.98–3.69) Model 3 adjusted^u OR: 1.35 (0.55–3.28)	Crude OR: 2.59 (1.35–4.96), Model 1 adjusted^s OR: 2.33 (1.22–4.46); Model 2 adjusted^t OR: 2.58 (1.31–5.06) Model 3 adjusted^u OR: 1.98 (0.96–4.12)	Crude OR: 2,37 (1.27–4.41), Model 1 adjusted^s OR: 2.01 (1.03–3.94) Model 2 adjusted^t OR: 2.25 (1.17–4.32) Model 3 adjusted^u OR: 1.01 (0.40–2.57)	Crude OR: 0.76 (0.31–1.86), Model 1 adjusted^s OR: 0.71 (0.29–1.74) Model 2 adjusted^t OR: 0.74 (0.30–1.82) Model 3 adjusted^u OR: 0.61 (0.21–1.80)
	Cross-sectional, (2010)	USA, (NHIS)	≥18 yrs, Total: 27157, AD: 10.2% of total	self-reported	self-reported doctor diagnosis	Logistic regression	Crude OR: 1.48 (1.22–1.80), Model 1 adjusted^s OR: 1.38 (1.13–1.69) Model 2 adjusted^t OR: 1.41 (1.16–1.71) Model 3 adjusted²² OR: 1.38 (1.12–1.70)	Crude OR: 1.87 (1.44–2.42), Model 1 adjusted^s OR: 1.79 (1.37–2.35) Model 2 adjusted^t OR: 1.58 (1.21–2.05) Model 3 adjusted^v OR: 1.73 (1.30–2.31)	Crude OR: 1.73 (1.39–2.16), Model 1 adjusted^s OR: 1.72 (1.36–2.17) Model 2 adjusted^t OR: 1.65 (1.32–2.06) Model 3 adjusted^v OR: 1.48 (1.15–1.90		Crude OR: 1.61 (1.27–2.05), Model 1 adjusted^s OR: 1.61 (1.25–2.07) Model 2 adjusted^t OR: 1.53 (1.19–1.96) Model 3 adjusted^v OR: 1.39 (1.05–1.83)
	Cross-sectional, (2012)	USA (NHIS)	≥18 yrs, Total: 34525, AD: 7.2% of total	self-reported doctor diagnosis	self-reported doctor diagnosis	Logistic regression	Crude OR: 1.36 (1.09–1.69), Model 1 adjusted^s OR: 1.50 (1.18–1.90) Model 2 adjusted^t OR: 1.31 (1.06–1.64) Model 3 adjusted^v OR: 1.32 (1.04–1.66)	Crude OR: 1.73 (1.18–2.54), Model 1 adjusted^s OR: 1.81 (1.21–2.70) Model 2 adjusted^t OR: 1.58 (1.09–2.30) Model 3 adjusted^v OR: 1.77 (1.20–2.61)	Crude OR: 1.33 (1.03–1.70), Model 1 adjusted^s OR: 1.44 (1.11–1.87) Model 2 adjusted^t OR: 1.29 (1.01–1.66) Model 3 adjusted^v OR: 1.26 (0.96–1.64)		Crude OR: 1.63 (1.27–2.09), Model 1 adjusted^s OR: 1.75 (1.35–2.28) Model 2 adjusted^t OR: 1.52 (1.19–1.95) Model 3 adjusted^v OR: 1.73 (1.33–2.25)
Silverwood, 201814	Cohort, (1998–2015)	UK	≥18 yrs, AD: 387439 (36.1%) Match group: 1528477	At least one diagnosis code and two treatment codes on separate dates, ICD-10 codes	ICD-9 or ICD-10 codes	Cox regression		(Unstable angina) Unadjusted: HR: 1.22 (1.14–1.31) Mild: 1.22 (1.11–1.33) Mod: 1.20 (1.08–1.34) Severe: 1.47 (1.10–1.97), Adjusted²³ HR: 1.25 (1.11–1.41) Mild: 1.25 (1.10–1.43) Mod: 1.22 (1.06–1.42) Severe: 1.48 (1.08–2.03), Mediation model²⁴ HR: 1.17 (1.03–1.32), Mild: 1.19 (1.04–1.37), Mod: 1.11 (0.96–1.29), Severe: 1.41 (1.02–1.95)	Unadjusted HR: 1.10 (1.05–1.15) Mild: 1.03 (0.96–1.09) Mod: 1.15 (1.07–1.23) Severe: 1.46 (1.21–1.74) Adjusted^w HR: 1.06 (0.98–1.15) Mild: 1.00 (0.91–1.10) Mod: 1.11 (1.01–1.23) Severe 1.41 (1.15–1.71), Mediation model^x HR: 1.04 (0.96–1.13), Mild: 1.00 (0.91–1.10), Mod: 1.07 (0.97–1.18), Severe: 1.37 (1.12–1.68)	Unadjusted HR: 1.21 (1.16–1.26) Mild: 1.12 (1.05–1.19) Mod: 1.27 (1.19–1.35) Severe: 1.71 (1.43–2.05) Adjusted^w HR 1.19 (1.10–1.30) Mild: 1.12 (1.02–1.23) Mod: 1.25 (1.14–1.38) Severe: 1.69 (1.38–2.06), Mediation model^x HR: 1.17 (1.08–1.28), Mild: 1.12 (1.02–1.24), Mod: 1.20 (1.09–1.33), Severe: 1.67 (1.36–2.05)	Unadjusted: HR 1.07 (1.03–1.12) Mild: 1.03 (0.98–1.09) Mod: 1.11 (1.04–1.18) Severe: 1.19 (1.00–1.42) Adjusted^w HR: 1.10 (1.02–1.19) Mild: 1.07 (0.98–1.16) Mod: 1.14 (1.04–1.25) Severe: 1.22 (1.01–1.48), Mediation model^x HR: 1.08 (1.00–1.16), Mild: 1.06 (0.97–1.15), Mod: 1.09 (1.00–1.20), Severe: 1.20 (0.99–1.46)
Standl, 201715	Cross-sectional, (2012–2014)	Germany (AOK PLUS)	≥40 yrs, Total: 1180678, AD: 36606 (36.24%)	At least two clinical diagnoses of ICD-10 codes	ICD-10 codes	Linear regression		Model 1 adjusted²⁵ RR: All: 1.34 (1.28–1.41), Mild: 1.20 (1.10–1.31), Mod:1.33 (1.25–1.42), Severe: 1.60 (1.45–1.77), Model 2 Adjusted²⁶: RR: All: 1.32 (1.26–1.38), Mild: 1.18 (1.08–1.29), Mod: 1.31 (1.23–1.39), Severe: 1.57 (1.43–1.74)	Model 1 adjusted^y RR: All: 0.98 (0.90–1.05), Mild AD: 0.94 (0.82–1.08), Mod: 0.95 (0.85–1.05), Severe: 1.12 (0.94–1.32), Model 2 Adjusted^z RR: All 0.98 (0.91–1.06), Mild: 0.95 (0.82–1.09), Mod: 0.95 (0.86–1.06), Severe: 1.12 (0.94–1.33)		Model 1 adjusted^y: RR: All: 1.06 (1.01–1.11), Mild: 1.03 (0.94–1.12), Mod:1.06 (0.99–1.13), Severe: 1.08 (0.96–1.21), Model 2 Adjusted^z RR: All: 1.05 (1.00–1.11), Mild: 1.03 (0.94–1.12), Mod:1.05 (0.99–1.13), Severe: 1.08 (0.96–1.21)
Standl, 201715	Cohort, (2005–2014)	Germany (AOK PLUS)	≥40 yrs, Total: 121413, AD: 33816 (35%)	At least two clinical diagnoses of ICD-10 codes	ICD-10 codes	Linear regression		Model 1 adjusted^y: RR: All: 1.18 (1.13–1.23), Mild: 0.94 (0.85–1.04), Mod:1.21 (1.13–1.29), Severe: 1.38 (1.26–1.50), Model 2 adjusted^z: RR: All: 1.17 (1.12–1.23), Mild: 0.93 (0.84–1.03), Mod: 1.20 (1.12–1.28), Severe: 1.37 (1.25–1.49)	Model 1 adjusted^y RR: All: 1.05 (0.98–1.12), Mild: 0.91 (0.79–1.04), Mod: 1.10 (1.01–1.20), Severe: 1.07 (0.94–1.22), Model 2^z Adjusted RR: All: 1.05 (0.99–1.12), Mild AD: 0.92 (0.80–1.05), Mod: 1.11 (1.02–1.21), Severe: 1.08 (0.95–1.22)		Model 1 adjusted^y RR: All: 1.03 (0.98–1.07), Mild: 0.92 (0.84–1.01), Mod: 1.06 (1.00–1.13), Severe: 1.07 (0.98–1.17), Model 2 Adjusted^z: RR: All: 1.02 (0.98–1.07), Mild: 0.92 (0.84–1.01), Mod: 1.05 (0.99–1.12), Severe: 1.06 (0.98–1.16)
Su, 201416	Cohort, (2005–2009)	Taiwan	≥20 yrs, Total: 40646, AD: 20323 (38.1%)	ICD-9 codes, (newly diagnosed)	ICD-9 codes	Cox’s proportional hazard s regression			Adjusted²⁷ HR: 1.31 (0.88–1.95)	Adjusted^aa 1.46 (1.10–1.93)	(Ischemic stroke) Crude HR: 1.29 (1.09–1.54), Adjusted^aa HR: 1.33 (1.12–1.59)
Sung, 201717	Cohorts, (2000–2011)	Taiwan	Total: 75515, AD: 15103 (45.8%)	Outpatitents received at least three consensus diagoses, ICD-9 codes	Brain computed tomography or magnetic resonance imaging and at least three consensus diagnosis	Cox’ proportional hazard regression					Crude HR: All stroke: 1.25 (1.13–1.39), Ischemic stroke: 1.30 (1.17–1.46), Hemorrhagic stroke: 1.00 (0.76–1.32), Adjusted²⁸ HR: 1.17 (1.06–1.30), Ischemic stroke: 1.21 (1.08–1.36), Hemorrhagic stroke : 0.97 (0.74–1.29)
Treudler, 201718	Cross-sectional, (2011–2014)	Germany	Logistic regression: Total: 4340, AD: 168	Physician-diagnosed AD (ever)	Physician diagnosis	Logistic regression	OR: 1.6 (0.8–3.0)		OR: 0.5 (0.2–1.6)		OR: 1.3 (0.6–2.9)
Tsai, 201619	Cohort (2000–2011)	Taiwan	≥20 yrs. Total: 470440, AD: 235220 (41.87%)	ICD-9 codes, (at least two medical visits)	New diagnosis of stroke, ICD-9 codes	Cox’s proportional hazard regression					Stroke: crude HR: 1.27 (1.23–1.3), Adjusted²⁹ HR: Stroke: 1.13 (1.10–1.16), Ischemic stroke: 1.30 (1.27–1.34), Adjusted^cc HR: 1.16 (1.12–1.19)
Varbo, 201720	Cohort, (2003–2014)	Denmark	Total: 84601, AD: 8484	self-reported	ICD-8 ICD-10 codes (two independent doctors)	Cox proportional hazard regression					Ischemic stroke: Adjusted³⁰ HR: 1.24 (1.01–1.52), MV-adjusted³¹ HR: 1.19 (0.96–1.48)

Open in a new tab

AD: atopic dermatitis, CVD: cardiovascular disease, CAD: coronary artery disease, MI: myocardial infarction, HF: heart failure, yrs: years old, ICD: International Classification of Diseases, RR: incident rate ratios, OR: odds ratio, HR: hazard ratio, RR: risk ratio. MV: multivariate, BMI: body mass index

Adjusted for age and sex

Adjusted for age and sex, socioeconomic status, smoking, comorbidities, and medication use

Adjusted for age

⁴

Adjusted for age, race, BMI, physical activity, alcohol, smoking, family history of MI, hormone replacement use

⁵

Adjusted for age, race, BMI, physical activity, alcohol, smoking, family history of MI, hormone replacement use, history of hypertension, hypercholesterolemia and diabete

⁶

Adjusted for age and sex

⁷

Adjusted for age, sex, ethnic background, body mass index, smoking 100 cigarettes, weekly alcohol intake, average daily sleep, weekly physical activity and history of asthma

⁸

The analysis for each outcome is additionally adjusted for all three other outcomes (hypertension, type 2 diabetes, MI, stroke)

⁹

Adjusted for age, sex, socioeconomic status, and number of dermatology visits

¹⁰

Adjusted for age and sex

¹¹

Adjusted for cardiovascular comorbidities (diabetes mellitus, hyperlipidemia, hypertension) and years of education

¹²

Adjusted for sex, age, and other CVD and metabolic diseases

¹³

Adjusted for age, sex, race, mean annual household income, insurance status, number of chronic conditions, and hospital region

¹⁴

Adjusted for age and sex

¹⁵

Adjusted for age, sex, BMI, history of hypertension, diabetes, alcohol, smoking, perceived mental stress, daily walking time, participation in sports, sleep duration, education

¹⁶

Adjusted for age and sex

¹⁷

Adjusted for age and sex, smoking, alcohol, physical activity, low socioeconomic status, BMI, hypertension, diabetes mellitus, and dyslipidemia

¹⁸

Adjusted for birth-year categories, gender, educational level and history of diabetes, hypertension, hyperlipidaemia or stroke

¹⁹

Adjusted for age, highest level of education in the household, ethnicity, and sex

²⁰

Adjusted for 1-year history of asthma and hay fever

²¹

Adjusted for BMI, history of ever smoking cigarettes, consumption of alcohol in the past year, and vigorous activity in the past 30 days

²²

Adjusted for BMI, history of ever smoking cigarettes, consumption of alcohol in the past year, and vigorous activity in the past week

²³

Adjusted for current calendar period (1997–99, 2000–04, 2005–09, 2010–15), time since diagnosis (0–4, 5–9, 10–14, 15–19, ≥20 years), index of multiple deprivation at cohort entry, and time-varying asthma

²⁴

Adjusted additionally for BMI and smoking at cohort entry, and time-varying hyperlipidaemia, hypertension, depression, anxiety, diabetes, and severe alcohol use

²⁵

Adjusted for sex and cubic age

²⁶

Adjusted for sex, cubic age, and socioeconomic status of region and access to health care

²⁷

Adjusted for age, sex, comorbidities and medication

²⁸

Adjusted for AD, age, sex, and comorbidity

²⁹

Adjusted for age, gender, treatment, and comorbidity

³⁰

Adjusted for age and sex

³¹

Adjusted for age, sex, smoking, lipid-lowering therapy, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, diabetes, alcohol consumption, systolic and diastolic blood pressure, BMI, physical activity, atrial fibrillation

Figure 1

Scatter plot for Mendelian randomization analysis for AD on stroke.

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Figure 2

Scatter plot for Mendelian randomization analysis for AD on heart failure.

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Figure 3

Scatter plot for Mendelian randomization analysis for AD on CAD.

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Figure 4

Scatter plot for Mendelian randomization analysis for AD on myocardial infarction.

dp1204a165s010.tif^{(214KB, tif)}

Figure 5

Scatter plot for Mendelian randomization analysis for AD on angina pectoris.

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Footnotes

Funding: None.

Competing interests: None.

Authorship: All authors have contributed significantly to this publication.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table 1 .

Leave Out Analysis for the Association Between AD and Stroke.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	1.036604	0.972788	1.104605	0.267451
rs12144049	1.042417	0.972733	1.117092	0.239259
rs12188917	1.041947	0.978455	1.10956	0.200193
rs12334935	1.035133	0.970749	1.103787	0.291931
rs2212434	1.020007	0.955225	1.089182	0.554045
rs2477121	1.034137	0.969395	1.103203	0.308846
rs2918299	1.03132	0.96544	1.101695	0.359834
rs4151657	1.022324	0.959644	1.089097	0.494015
rs479844	1.016297	0.952313	1.08458	0.626072
rs6062486	1.011756	0.961976	1.064113	0.649796
rs61815704	1.030897	0.963773	1.102695	0.375715
rs6419573	1.031928	0.966049	1.1023	0.350428
rs8066625	1.024116	0.959297	1.093315	0.475022
All	1.029013	0.967481	1.094458	0.363285

Open in a new tab

OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 2 .

Leave Out Analysis for the Association Between AD and Heart Failure.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	1.045685	0.998383	1.095228	0.058563
rs12144049	1.040601	0.985861	1.098381	0.14888
rs12188917	1.039984	0.989537	1.093003	0.122254
rs12334935	1.049112	1.00675	1.093256	0.022613
rs2212434	1.029703	0.980293	1.081603	0.24335
rs2477121	1.04574	0.998462	1.095256	0.05812
rs2918299	1.03622	0.985465	1.089589	0.16496
rs4151657	1.031931	0.983738	1.082484	0.197717
rs479844	1.028488	0.978571	1.08095	0.268462
rs6062486	1.041393	0.991172	1.09416	0.107756
rs61815704	1.035809	0.984408	1.089894	0.175465
rs6419573	1.037437	0.987373	1.09004	0.145272
rs8066625	1.028608	0.981841	1.077604	0.234802
All	1.037797	0.990541	1.087308	0.118686

Open in a new tab

OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 3 .

Leave Out Analysis for the Association Between AD and Coronary Artery Disease.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	0.998822	0.953129	1.046706	0.960658
rs12144049	0.999948	0.950616	1.05184	0.998389
rs12188917	0.994383	0.948679	1.042289	0.814494
rs12334935	1.005797	0.962038	1.051546	0.798973
rs2212434	1.009113	0.964813	1.055448	0.692053
rs2477121	1.001785	0.95586	1.049915	0.940634
rs2918299	1.003518	0.957882	1.051329	0.88243
rs4151657	0.988936	0.951483	1.027864	0.572203
rs479844	0.988138	0.946092	1.032053	0.590661
rs6062486	1.002905	0.957254	1.050733	0.902869
rs61815704	1.008962	0.963617	1.056441	0.703724
rs6419573	0.999903	0.953663	1.048385	0.996795
rs8066625	1.002174	0.956419	1.050117	0.927441
All	1.000338	0.957371	1.045233	0.987967

Open in a new tab

OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 4 .

Leave Out Analysis for the Association Between AD and Myocardial Infarction.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	0.999032	0.997552	1.000513	0.199932
rs12144049	0.99909	0.997501	1.000681	0.262249
rs12188917	0.999546	0.998032	1.001061	0.556637
rs12334935	0.999523	0.998046	1.001002	0.527093
rs2212434	0.999239	0.997709	1.000772	0.330301
rs2477121	0.999383	0.997902	1.000866	0.414595
rs2918299	0.999211	0.997712	1.000712	0.302782
rs4151657	0.999099	0.997621	1.00058	0.232923
rs479844	0.999167	0.997629	1.000707	0.288732
rs6062486	0.999378	0.997897	1.000862	0.411388
rs61815704	0.999544	0.997987	1.001104	0.566673
rs6419573	0.999325	0.997826	1.000827	0.378057
rs8066625	0.998984	0.997499	1.00047	0.180141
All	0.99927	0.997827	1.000716	0.322364

Open in a new tab

OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 5 .

Leave Out Analysis for the Association Between AD and Angina Pectoris.

Leave out analysis
SNP	OR	lci	uci	p
rs10790275	1.000954	0.999344	1.002566	0.245799
rs12144049	1.001062	0.999283	1.002844	0.242133
rs12188917	1.000588	0.998863	1.002316	0.504061
rs12334935	1.001026	0.999524	1.00253	0.180897
rs2212434	1.000258	0.998796	1.001722	0.729742
rs2477121	1.000653	0.998952	1.002356	0.452234
rs2918299	1.000854	0.999161	1.002551	0.323015
rs4151657	1.00054	0.998912	1.00217	0.51587
rs479844	1.000581	0.998834	1.002331	0.514699
rs6062486	1.000607	0.998924	1.002292	0.480047
rs61815704	1.000857	0.999064	1.002653	0.349097
rs6419573	1.000952	0.99932	1.002587	0.253258
rs8066625	1.00064	0.998937	1.002347	0.461454
All	1.000735	0.999134	1.002338	0.368553

Open in a new tab

OR: odds ratio; lcl: lower confidence intervals; ucl: upper confidence intervals

Table 6 .

Characteristics of Population-Based Studies Reporting the Association Between AD and CVD

							CVD main results
Study	Study design and Period	Setting	Age, sample size (proportion of males)	Diagnosis of AD	Outcome definition	Statistical analysis	CAD	Angina	MI	HF	Stroke
Andersen, 20161	Cohort, (1997–2012)	Denmark	≥15 yrs, Mild: 26,898, Severe: 2,527 (46.1%), Control: 145372	Hospital diagnosis of AD, ICD-8, ICD-10 codes	ICD-8, ICD-10 codes	Poisson regression			Adjusted¹ IRR: Mild: 0.82 (0.66–1.02), Severe: 1.39 (0.95–2.03); Fully adjusted² IRR Mild: 0.73 (0.59–0.91), Severe: 1.06 (0.72–1.56)		Adjusted^a IRR: Mild 0.92 (0.78–1.11), Severe: 1.51 (1.08–2.10); Fully adjusted^b IRR Mild: 0.82 (0.68–0.98), Severe: 1.19 (0.85–1.65)
Drucker, 20162	Cross-sectional, (1989–2009)	USA	Total :78702, AD: 7916 (0%)	Self-reported clinician diagnosed eczema (AD)	self-reported, confirmed by medical record, letter or interview	Logistic regression			Adjusted³ OR: 0.97 (0.69–1.36); MV-adjusted⁴ OR 0.94 (0.67–1.32); MV-adjusted⁵ OR 0.91 (0.65–1.28)		Adjusted^c OR: 1.38 (1.03–1.85); MV-adjusted^d OR 1.35 (1.00–1.80); MV-adjusted^e OR 1.31 (0.98–1.76)
Drucker, 20173	Cross-sectional, (2009 onwards)	Canada	30–74 yrs, Total: 259119, AD: 21379 (25%)	Self-reported a diagnosis of eczema	Self-reported a diagnosis of MI, stroke	Logistic regression			Adjusted⁶ OR: 0.83 (0.72–0.95), MV-adjusted⁷ model 1 OR: 0.80 (0.69–0.92); MV-adjusted⁸ model 2 OR: 0.87 (0.75–1.00)		Adjusted^f OR: 0.81 (0.68–0.97); MV-adjusted^g model 1 OR: 0.75 (0.62–0.89); MV-adjusted^h model 2 OR: 0.79 (0.66–0.95)
Egeberg, 20164	Cross-sectional, (1995–2012)	Denmark	≥18 yrs, AD: 7937 (38.2%), Control: 79370	Clinical diagnosis of AD ICD-10 codes	Administrative code	Logistic regression			Adjusted⁹ OR: overall: 1.1 (0.92–1.33), mild: 0.88 (0.63–1.23); severe: 1.23 (0.98–1.54)		Adjustedⁱ OR: overall: 1.52 (1.32–1.74), mild: 1.23 (0.94–1.60); severe: 1.45 (1.19–1.77)
Ivert, 20195	Case-control, (1968–2016)	Sweden	≥15 yrs, AD: 104832, Non-severe: 95274 (33.8%), Severe: 9558 (35.7%), Control: 1022435	ICD-8: ICD-9: ICD-10: codes	ICD codes	Conditional logistic regression		All cases: all crude¹⁰ OR: 1.18 (1.13–1.23), all fully adjusted¹¹ OR: 1.13 (1.08–1.19), Men crude^j OR: 1.15 (1.08–1.22), Men fully adjusted^k OR: 1.10 (1.03–1.18), Women crude^j OR: 1.21 (1.14–1.28), Women fully adjusted^k OR: 1.16 (1.09–1.24). Non-severe cases: all crude^j OR: 1.16 (1.10–1.21), All fully adjusted OR: 1.13 (1.08–1.19), Men crude^j OR: 1.15 (1.07–1.23), Men fully adjusted^k OR: 1.12 (1.04–1.20), Women crude^j OR: 1.17 (1.09–1.25), Women fully adjusted^k OR: 1.15 (1.08–1.24). Severe cases: all crude^j OR: 1.27 (1.15–1.40), All fully adjusted OR: 1.11 (1.00–1.24), Men crude^j OR: 1.16 (1.00–1.34), Men fully adjusted^k OR: 1.04 (0.89–1.21), Women crude^j OR: 1.38 (1.20–1.57), Women fully adjusted^k OR: 1.19 (1.04–1.37)	All cases: all crude^j OR: 1.10 (1.04–1.15), all fully adjusted^k OR: 1.07 (1.02–1.12), Men crude^j OR: 1.15 (1.07–1.22), Men fully adjusted^k OR: 1.12 (1.05–1.20), Women crude^j OR: 1.03 (0.96–1.11), Women fully adjusted^k OR: 1.01 (0.94–1.08). Non-severe cases: all crude^j OR: 1.08 (1.03–1.14), All fully adjusted^k OR: 1.07 (1.02–1.13), Men crude^j OR: 1.16 (1.08–1.24), Men fully adjusted^k OR: 1.15 (1.07–1.23), Women crude^j OR: 0.99 (0.92–1.08), Women fully adjusted^k OR: 0.98 (0.91–1.07). Severe cases: all crude^j OR: 1.14 (1.03–1.27), All fully adjusted^k OR: 1.03 (0.92–1.15), Men crude^j OR: 1.09 (0.94–1.26), Men fully adjusted^k OR: 1.01 (0.87–1.18), Women crude^j OR: 1.20 (1.03–1.40), Women fully adjusted^k OR: 1.06 (0.91–1.24)		All cases: all crude^j OR: 1.07 (1.02–1.13), all fully adjusted^k OR: 1.04 (0.99–1.09). Men crude^j OR: 1.13 (1.05–1.22), Men fully adjusted^k OR: 1.09 (1.01–1.17). Women crude^j OR: 1.03 (0.96–1.10), Women fully adjusted^k OR: 1.00 (0.93–1.07). Non-severe cases: all crude^j OR: 1.02 (0.97–1.08), All fully adjusted^k OR: 1.00 (0.94–1.06), Men crude^j OR: 1.09 (1.01–1.19), Men fully adjusted^k OR: 1.06 (0.98–1.16), Women crude^j OR: 0.96 (0.89–1.04), Women fully adjusted^k OR: 0.95 (0.88–1.02). Severe cases: all crude^j OR: 1.32 (1.19–1.47), All fully adjusted^k OR: 1.19 (1.07–1.33), Men crude^j OR: 1.32 (1.11–1.56), Men fully adjusted^k OR: 1.20 (1.01–1.43), Women crude^j OR: 1.33 (1.15–1.53), Women fully adjusted^k OR: 1.19 (1.03–1.37)
Jung, 20216	Cohort, (2005–2016)	Korea	Total: 2780356 (49.6%), AD: 285468	ICD-10: one of the AD diagnostic codes and underwent two AD-related tests	prescribed medication ≥2 times (outpatient) or ≥1 time hospitalized, ICD-10 codes	Cox regression		Adjusted¹² HR: 5.99 (4.96–7.25), Mild: 2.88 (1.07–7.75), Mod: 6.49 (1.61–26.18), Severe: 6.16 (5.0–7.47)	Adjusted^l HR: 9.43 (7.28–12.20), Mild: 5.50 (2.41–12.57), Mod: 3.92 (0.55–28.15), Severe: 10.13 (7.7–13.17)		Adjusted^l HR: 10.61 (8.65–13.03), Mild: 10.35 (4.85–22.08), Mod: 12.72 (3.15–51.35), Severe 10.56 (8.59–12.98)
Kwa 20177	Cross-sectional, (2002–2012)	USA	≥18 yrs, Total: 72651487, AD-E 164868	ICD-9 codes	Pre-coded by Association for Healthcare Research and Quality (AHRQ)	Logistic regression.	Crude OR: 0.75 (0.74–0.77), Propensity¹³ OR: 0.67 (0.66–0.69).		Crude OR: 0.56 (0.53–0.58), PSM^m OR: 0.52 (0.49–0.55)	Crude OR: 1.10 (1.07–1.13), PSM^m OR: 1.03 (1.01–1.06)	Crude OR: 0.74 (0.71–0.77), PSM^m OR: 0.71 (0.67–0.74)
Nishida, 20198	Cohort, (1988–2009)	Japan	aged 40–79 yrs, Total: 85,099 (41.7%)	self-reported	ICD-10 codes	Cox proportional hazard regression	Frequency of Eczema: Often/Seldom or Sometimes: Adjusted¹⁴ HR: 1.39 (1.12–1.72), MV-adjusted¹⁵ HR: 1.30 (1.05–1.61)			Often/Seldom or Sometimes: Adjustedⁿ HR: 1.14 (0.88–1.48), MV-adjusted^o HR: 1.11 (0.85–1.43)	Often/Seldom or Sometimes: Total stroke: Adjustedⁿ HR: 1.03 (0.87–1.22), MV-adjusted^o HR: 0.98 (0.83–1.17). Ischemic stroke: Adjustedⁿ HR: 1.01 (0.80–1.27), MV-adjusted^o HR: 0.96 (0.76–1.21). Hemorrhagic stroke: Adjustedⁿ HR: 1.07 (0.82–1.38), MV-adjusted^o HR: 1.04 (0.81–1.35)
Radtke, 20169	Cross-sectional, (2009 onwards)	Germany	>18 yrs, Total: 1349671, AD: 48140	ICD-10 codes	ICD-10 codes	Chi-square	Ischemic heart disease: Prevalence rate: (with/without AD): 0.83 (0.80–0.86)
Rhee, 202110	Cohort, (2009–2018)	Korea	>20 yrs, Total: 9548939, AD: 18557 (48.6%)	ICD-10 code, ≥3 times of physician diagnosis within 1 year	ICD-10 codes	Cox proportional hazards regression			Unadjusted HR: 1.51 (1.40–1.63), Adjusted¹⁶ HR: 1.21 (1.12–1.31), MV-adjusted¹⁷ HR: 1.14 (1.06–1.24)
Riis, 201611	Cohort, (1977–2013)	Denmark	Danishi born 1947–1977. Total 53210, AD: 4814 (45%)	Two clinical diagnoses of ICD-8 or ICD-10 codes	Clinical diagnoses of ICD-8 or ICD-10 codes	Cox proportional hazards regression			Crude HR: all: 1.79 (1.25–2.57), Men: 2.03 (1.32–3.12), Women: 1.39 (0.72–2.69), Mild: 1.62 (1.04–2.51), Severe: 2.38 (1.26–4.50), Adjusted¹⁸ HR: 1.74 (1.21–2.49); Men: 2.01 (1.31–3.08), Women: 1.28 (0.66–2.48), Mild: 1.58 (1.02–2.45); Severe: 2.40 (1.27–4.45)
Shalom, 201912	cross-sectional, (1998–2016)	Israel	AD: 116816 patients (2.7% of total), Control: 116812	At least one documented diagnosis	“CHS Chronic Disease Register”	Logistic regression	Ischemic heart disease: AD n (%): 2252 (1.9) General population n (%): 2290 (2.0), p=0.568			AD n (%): 538 (0.5) General population n (%): 572 (0.5), p=0.306	AD n (%): 538 (0.5) General population n (%): 572 (0.5), p=0.306
Silverberg, 201513	Cross-sectional, (2005–2006)	USA (NHANES)	≥20 yrs, Total: 4970 AD: 3.1% of total	self-reported	self-reported doctor diagnosis	Logistic regression	Crude OR: 2.57 (1.45–4,53), Model 1 adjusted¹⁹ OR: 2.11 (1.14–3.91) Model 2 adjusted²⁰ OR: 2.46 (1.37–4.43) Model 3 adjusted²¹ OR: 1.96 (1.02–3.77)	Crude OR: 1.87 (0.98–3.57), Model 1 adjusted^s OR: 1.63 (0.84–3.15) Model 2 adjusted^t OR: 1.91 (0.98–3.69) Model 3 adjusted^u OR: 1.35 (0.55–3.28)	Crude OR: 2.59 (1.35–4.96), Model 1 adjusted^s OR: 2.33 (1.22–4.46); Model 2 adjusted^t OR: 2.58 (1.31–5.06) Model 3 adjusted^u OR: 1.98 (0.96–4.12)	Crude OR: 2,37 (1.27–4.41), Model 1 adjusted^s OR: 2.01 (1.03–3.94) Model 2 adjusted^t OR: 2.25 (1.17–4.32) Model 3 adjusted^u OR: 1.01 (0.40–2.57)	Crude OR: 0.76 (0.31–1.86), Model 1 adjusted^s OR: 0.71 (0.29–1.74) Model 2 adjusted^t OR: 0.74 (0.30–1.82) Model 3 adjusted^u OR: 0.61 (0.21–1.80)
	Cross-sectional, (2010)	USA, (NHIS)	≥18 yrs, Total: 27157, AD: 10.2% of total	self-reported	self-reported doctor diagnosis	Logistic regression	Crude OR: 1.48 (1.22–1.80), Model 1 adjusted^s OR: 1.38 (1.13–1.69) Model 2 adjusted^t OR: 1.41 (1.16–1.71) Model 3 adjusted²² OR: 1.38 (1.12–1.70)	Crude OR: 1.87 (1.44–2.42), Model 1 adjusted^s OR: 1.79 (1.37–2.35) Model 2 adjusted^t OR: 1.58 (1.21–2.05) Model 3 adjusted^v OR: 1.73 (1.30–2.31)	Crude OR: 1.73 (1.39–2.16), Model 1 adjusted^s OR: 1.72 (1.36–2.17) Model 2 adjusted^t OR: 1.65 (1.32–2.06) Model 3 adjusted^v OR: 1.48 (1.15–1.90		Crude OR: 1.61 (1.27–2.05), Model 1 adjusted^s OR: 1.61 (1.25–2.07) Model 2 adjusted^t OR: 1.53 (1.19–1.96) Model 3 adjusted^v OR: 1.39 (1.05–1.83)
	Cross-sectional, (2012)	USA (NHIS)	≥18 yrs, Total: 34525, AD: 7.2% of total	self-reported doctor diagnosis	self-reported doctor diagnosis	Logistic regression	Crude OR: 1.36 (1.09–1.69), Model 1 adjusted^s OR: 1.50 (1.18–1.90) Model 2 adjusted^t OR: 1.31 (1.06–1.64) Model 3 adjusted^v OR: 1.32 (1.04–1.66)	Crude OR: 1.73 (1.18–2.54), Model 1 adjusted^s OR: 1.81 (1.21–2.70) Model 2 adjusted^t OR: 1.58 (1.09–2.30) Model 3 adjusted^v OR: 1.77 (1.20–2.61)	Crude OR: 1.33 (1.03–1.70), Model 1 adjusted^s OR: 1.44 (1.11–1.87) Model 2 adjusted^t OR: 1.29 (1.01–1.66) Model 3 adjusted^v OR: 1.26 (0.96–1.64)		Crude OR: 1.63 (1.27–2.09), Model 1 adjusted^s OR: 1.75 (1.35–2.28) Model 2 adjusted^t OR: 1.52 (1.19–1.95) Model 3 adjusted^v OR: 1.73 (1.33–2.25)
Silverwood, 201814	Cohort, (1998–2015)	UK	≥18 yrs, AD: 387439 (36.1%) Match group: 1528477	At least one diagnosis code and two treatment codes on separate dates, ICD-10 codes	ICD-9 or ICD-10 codes	Cox regression		(Unstable angina) Unadjusted: HR: 1.22 (1.14–1.31) Mild: 1.22 (1.11–1.33) Mod: 1.20 (1.08–1.34) Severe: 1.47 (1.10–1.97), Adjusted²³ HR: 1.25 (1.11–1.41) Mild: 1.25 (1.10–1.43) Mod: 1.22 (1.06–1.42) Severe: 1.48 (1.08–2.03), Mediation model²⁴ HR: 1.17 (1.03–1.32), Mild: 1.19 (1.04–1.37), Mod: 1.11 (0.96–1.29), Severe: 1.41 (1.02–1.95)	Unadjusted HR: 1.10 (1.05–1.15) Mild: 1.03 (0.96–1.09) Mod: 1.15 (1.07–1.23) Severe: 1.46 (1.21–1.74) Adjusted^w HR: 1.06 (0.98–1.15) Mild: 1.00 (0.91–1.10) Mod: 1.11 (1.01–1.23) Severe 1.41 (1.15–1.71), Mediation model^x HR: 1.04 (0.96–1.13), Mild: 1.00 (0.91–1.10), Mod: 1.07 (0.97–1.18), Severe: 1.37 (1.12–1.68)	Unadjusted HR: 1.21 (1.16–1.26) Mild: 1.12 (1.05–1.19) Mod: 1.27 (1.19–1.35) Severe: 1.71 (1.43–2.05) Adjusted^w HR 1.19 (1.10–1.30) Mild: 1.12 (1.02–1.23) Mod: 1.25 (1.14–1.38) Severe: 1.69 (1.38–2.06), Mediation model^x HR: 1.17 (1.08–1.28), Mild: 1.12 (1.02–1.24), Mod: 1.20 (1.09–1.33), Severe: 1.67 (1.36–2.05)	Unadjusted: HR 1.07 (1.03–1.12) Mild: 1.03 (0.98–1.09) Mod: 1.11 (1.04–1.18) Severe: 1.19 (1.00–1.42) Adjusted^w HR: 1.10 (1.02–1.19) Mild: 1.07 (0.98–1.16) Mod: 1.14 (1.04–1.25) Severe: 1.22 (1.01–1.48), Mediation model^x HR: 1.08 (1.00–1.16), Mild: 1.06 (0.97–1.15), Mod: 1.09 (1.00–1.20), Severe: 1.20 (0.99–1.46)
Standl, 201715	Cross-sectional, (2012–2014)	Germany (AOK PLUS)	≥40 yrs, Total: 1180678, AD: 36606 (36.24%)	At least two clinical diagnoses of ICD-10 codes	ICD-10 codes	Linear regression		Model 1 adjusted²⁵ RR: All: 1.34 (1.28–1.41), Mild: 1.20 (1.10–1.31), Mod:1.33 (1.25–1.42), Severe: 1.60 (1.45–1.77), Model 2 Adjusted²⁶: RR: All: 1.32 (1.26–1.38), Mild: 1.18 (1.08–1.29), Mod: 1.31 (1.23–1.39), Severe: 1.57 (1.43–1.74)	Model 1 adjusted^y RR: All: 0.98 (0.90–1.05), Mild AD: 0.94 (0.82–1.08), Mod: 0.95 (0.85–1.05), Severe: 1.12 (0.94–1.32), Model 2 Adjusted^z RR: All 0.98 (0.91–1.06), Mild: 0.95 (0.82–1.09), Mod: 0.95 (0.86–1.06), Severe: 1.12 (0.94–1.33)		Model 1 adjusted^y: RR: All: 1.06 (1.01–1.11), Mild: 1.03 (0.94–1.12), Mod:1.06 (0.99–1.13), Severe: 1.08 (0.96–1.21), Model 2 Adjusted^z RR: All: 1.05 (1.00–1.11), Mild: 1.03 (0.94–1.12), Mod:1.05 (0.99–1.13), Severe: 1.08 (0.96–1.21)
Standl, 201715	Cohort, (2005–2014)	Germany (AOK PLUS)	≥40 yrs, Total: 121413, AD: 33816 (35%)	At least two clinical diagnoses of ICD-10 codes	ICD-10 codes	Linear regression		Model 1 adjusted^y: RR: All: 1.18 (1.13–1.23), Mild: 0.94 (0.85–1.04), Mod:1.21 (1.13–1.29), Severe: 1.38 (1.26–1.50), Model 2 adjusted^z: RR: All: 1.17 (1.12–1.23), Mild: 0.93 (0.84–1.03), Mod: 1.20 (1.12–1.28), Severe: 1.37 (1.25–1.49)	Model 1 adjusted^y RR: All: 1.05 (0.98–1.12), Mild: 0.91 (0.79–1.04), Mod: 1.10 (1.01–1.20), Severe: 1.07 (0.94–1.22), Model 2^z Adjusted RR: All: 1.05 (0.99–1.12), Mild AD: 0.92 (0.80–1.05), Mod: 1.11 (1.02–1.21), Severe: 1.08 (0.95–1.22)		Model 1 adjusted^y RR: All: 1.03 (0.98–1.07), Mild: 0.92 (0.84–1.01), Mod: 1.06 (1.00–1.13), Severe: 1.07 (0.98–1.17), Model 2 Adjusted^z: RR: All: 1.02 (0.98–1.07), Mild: 0.92 (0.84–1.01), Mod: 1.05 (0.99–1.12), Severe: 1.06 (0.98–1.16)
Su, 201416	Cohort, (2005–2009)	Taiwan	≥20 yrs, Total: 40646, AD: 20323 (38.1%)	ICD-9 codes, (newly diagnosed)	ICD-9 codes	Cox’s proportional hazard s regression			Adjusted²⁷ HR: 1.31 (0.88–1.95)	Adjusted^aa 1.46 (1.10–1.93)	(Ischemic stroke) Crude HR: 1.29 (1.09–1.54), Adjusted^aa HR: 1.33 (1.12–1.59)
Sung, 201717	Cohorts, (2000–2011)	Taiwan	Total: 75515, AD: 15103 (45.8%)	Outpatitents received at least three consensus diagoses, ICD-9 codes	Brain computed tomography or magnetic resonance imaging and at least three consensus diagnosis	Cox’ proportional hazard regression					Crude HR: All stroke: 1.25 (1.13–1.39), Ischemic stroke: 1.30 (1.17–1.46), Hemorrhagic stroke: 1.00 (0.76–1.32), Adjusted²⁸ HR: 1.17 (1.06–1.30), Ischemic stroke: 1.21 (1.08–1.36), Hemorrhagic stroke : 0.97 (0.74–1.29)
Treudler, 201718	Cross-sectional, (2011–2014)	Germany	Logistic regression: Total: 4340, AD: 168	Physician-diagnosed AD (ever)	Physician diagnosis	Logistic regression	OR: 1.6 (0.8–3.0)		OR: 0.5 (0.2–1.6)		OR: 1.3 (0.6–2.9)
Tsai, 201619	Cohort (2000–2011)	Taiwan	≥20 yrs. Total: 470440, AD: 235220 (41.87%)	ICD-9 codes, (at least two medical visits)	New diagnosis of stroke, ICD-9 codes	Cox’s proportional hazard regression					Stroke: crude HR: 1.27 (1.23–1.3), Adjusted²⁹ HR: Stroke: 1.13 (1.10–1.16), Ischemic stroke: 1.30 (1.27–1.34), Adjusted^cc HR: 1.16 (1.12–1.19)
Varbo, 201720	Cohort, (2003–2014)	Denmark	Total: 84601, AD: 8484	self-reported	ICD-8 ICD-10 codes (two independent doctors)	Cox proportional hazard regression					Ischemic stroke: Adjusted³⁰ HR: 1.24 (1.01–1.52), MV-adjusted³¹ HR: 1.19 (0.96–1.48)

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Adjusted for age and sex

Adjusted for age and sex, socioeconomic status, smoking, comorbidities, and medication use

Adjusted for age

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Adjusted for age, race, BMI, physical activity, alcohol, smoking, family history of MI, hormone replacement use

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Adjusted for age, race, BMI, physical activity, alcohol, smoking, family history of MI, hormone replacement use, history of hypertension, hypercholesterolemia and diabete

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Adjusted for age and sex

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Adjusted for age, sex, ethnic background, body mass index, smoking 100 cigarettes, weekly alcohol intake, average daily sleep, weekly physical activity and history of asthma

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The analysis for each outcome is additionally adjusted for all three other outcomes (hypertension, type 2 diabetes, MI, stroke)

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Adjusted for age, sex, socioeconomic status, and number of dermatology visits

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Adjusted for age and sex

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Adjusted for cardiovascular comorbidities (diabetes mellitus, hyperlipidemia, hypertension) and years of education

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Adjusted for sex, age, and other CVD and metabolic diseases

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Adjusted for age, sex, race, mean annual household income, insurance status, number of chronic conditions, and hospital region

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Adjusted for age and sex

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Adjusted for age, sex, BMI, history of hypertension, diabetes, alcohol, smoking, perceived mental stress, daily walking time, participation in sports, sleep duration, education

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Adjusted for age and sex

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Adjusted for age and sex, smoking, alcohol, physical activity, low socioeconomic status, BMI, hypertension, diabetes mellitus, and dyslipidemia

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Adjusted for birth-year categories, gender, educational level and history of diabetes, hypertension, hyperlipidaemia or stroke

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Adjusted for age, highest level of education in the household, ethnicity, and sex

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Adjusted for 1-year history of asthma and hay fever

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Adjusted for BMI, history of ever smoking cigarettes, consumption of alcohol in the past year, and vigorous activity in the past 30 days

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Adjusted for BMI, history of ever smoking cigarettes, consumption of alcohol in the past year, and vigorous activity in the past week

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Adjusted additionally for BMI and smoking at cohort entry, and time-varying hyperlipidaemia, hypertension, depression, anxiety, diabetes, and severe alcohol use

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Adjusted for sex and cubic age

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Adjusted for sex, cubic age, and socioeconomic status of region and access to health care

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Adjusted for age, sex, comorbidities and medication

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Adjusted for AD, age, sex, and comorbidity

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Adjusted for age, gender, treatment, and comorbidity

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Adjusted for age and sex

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Figure 1

Scatter plot for Mendelian randomization analysis for AD on stroke.

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Figure 2

Scatter plot for Mendelian randomization analysis for AD on heart failure.

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Figure 3

Scatter plot for Mendelian randomization analysis for AD on CAD.

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Figure 4

Scatter plot for Mendelian randomization analysis for AD on myocardial infarction.

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Figure 5

Scatter plot for Mendelian randomization analysis for AD on angina pectoris.

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PERMALINK

Association Between Atopic Dermatitis and Major Cardiovascular Outcomes: a Two-Sample Mendelian Randomization Study

Hongjiao Qi

Lifeng Wang

Linfeng Li

Abstract

Introduction

Objectives

Methods

Results

Conclusions

Introduction

Objectives

Methods

Data Sources and Selection of SNPs

Statistical Analysis

Results

Genetic Instruments

Two-sample MR of AD and CVD

Table 1.

Conclusions

Conclusion

Supplementary File

Table 1 .

Table 2 .

Table 3 .

Table 4 .

Table 5 .

Table 6 .

Footnotes

References

Associated Data

Supplementary Materials

Table 1 .

Table 2 .

Table 3 .

Table 4 .

Table 5 .

Table 6 .

ACTIONS

PERMALINK

RESOURCES

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