10.5826/dpc.1204a165
Background: Atopic dermatitis (AD) has been linked to cardiovascular disease (CVD) in population-based studies, however, their causal relationship is still unclear.
Objective: To evaluate the causal association of AD with risk of cardiovascular outcomes using a Mendelian randomization (MR) approach.
Method: 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: 13 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%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.
text/xml
2160-9381
2141
en
Linfeng  Li
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Mendelian randomization
Association between Atopic Dermatitis and Major Cardiovascular Outcomes: A Two-Sample Mendelian Randomization Study
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-10-30
2022-10-31
2022-11-29
e2022165
Dermatol Pract Concept
Background: Atopic dermatitis (AD) has been linked to cardiovascular disease (CVD) in population-based studies, however, their causal relationship is still unclear.
Objective: To evaluate the causal association of AD with risk of cardiovascular outcomes using a Mendelian randomization (MR) approach.
Method: 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: 13 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%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.
Linfeng  Li
2022/10/31
10.5826/dpc.1204a165
e2022165
Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
2160-9381
Mendelian randomization
en
e2022165
Association between Atopic Dermatitis and Major Cardiovascular Outcomes: A Two-Sample Mendelian Randomization Study
https://dpcj.org/index.php/dpc/article/download/2141/1759
  Association Between Atopic Dermatitis and Major
      Cardiovascular Outcomes: a Two-Sample
           Mendelian Randomization Study
                                        Hongjiao Qi1, Lifeng Wang2, Linfeng Li1


1 Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
2 Department of Dermatology, Beijing Luhe Hospital, Capital Medical university, Beijing, PR China



Key words: atopic dermatitis, cardiovascular disease, Mendelian randomization
Citation: Qi H, Wang L, Li L. Association between Atopic Dermatitis and Major Cardiovascular Outcomes: A Two-Sample Mendelian
Randomization Study. Dermatol Pract Concept. 2022;12(4):e2022165. DOI: https://doi.org/10.5826/dpc.1204a165
Accepted: February 28, 2022; Published: October 2022
Copyright: ©2022 Qi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Linfeng Li, Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China,
Address: 95 Yong’an Road, Xicheng District, Beijing, China. Zip: 100050, Tel: +8613693620186, E-mail: zoonli@sina.com




  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 asso-
                       ciation studies (GWAS). Inverse variance weighted (IVW) method was used as the primary a­ nalysis.
                       ­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 ar-
                       tery 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.




Review | Dermatol Pract Concept. 2022;12(4):e2022165                                                                                  1
Introduction                                                     cases and 406,111 non-cases of European ancestry [17].
                                                                 Summary-level data for heart failure were extracted from
Atopic dermatitis (AD, atopic eczema, eczema) is a common        the Heart Failure Molecular Epidemiology for Therapeutic
chronic, inflammatory, relapsing, skin diseases [1]. The prev-   Targets (HERMES) Consortium [18], comprising 47,309
alence of AD is 15 to 20% among children                         cases and 930,014 non-cases of European ancestry across
    And 7% to 14% among adults [2,3]. It is characterized        26 studies. Summary-level data for CAD from UKBiobank-­
by eczematous lesions, varying degrees of pruritus, and a        CardioMetabolic-Consortium CHD working group in-
chronic or relapsing disease course [4]. AD broadly decreases    cluded 10801 cases and 137914 non-cases of European
health-related quality of life [5].                              ancestry [19]. Summary-level data for myocardial infarction
    Recently, there has been a growing interest in the puta-     from UKBiobank included 4837 cases and 332,362 non-
tive cardiovascular comorbidities of AD in population-based      cases of European ancestry. Summary-level data for angina
observational studies [6-11]. However, owning to the nature      pectoris from UKBiobank included 4,837 cases and 332,362
of being susceptible to potential confounders and reverse        non-cases of European ancestry.
causation in observational study design [12], it remains un-
clear whether the elevated risk of CVD in patients with AD is    Statistical Analysis
caused by AD or introduced by confounding factors of AD          For each CVD outcome, we carried out two-sample MR anal-
and CVD. Understanding the causal relationship between           ysis to estimate the causal effect of AD, using the “TwoSam-
AD and CVD could have implications for appropriate iden-         pleMR” package of R. The inverse-variance weighted (IVW)
tification, clinical surveillance, and management of high-risk   linear regression was conducted as the primary analysis.
population. Mendelian randomization (MR) analysis is a           IVW is an efficient analysis method which assumes that all
novel epidemiological approach to assess the causal relation-    genetic variants are valid IVs, and that there is no horizon-
ship between an exposure and an outcome [12], with less sus-     tal pleiotropy [20]. We calculated the odds ratio (OR) with
ceptibility to unmeasured confounders and reverse causation      95% confidence interval (CI) and created the SNP effect
by using genetic variants (i.e., single nucleotide polymor-      scatter plot.
phisms, SNPs) as instrumental variables (IVs) [13,14].              Besides, we assessed the potential violations of the as-
                                                                 sumptions of MR analysis by performing a number of com-
Objectives                                                       plementary sensitivity analysis: weighted median approach
                                                                 for examining result robustness when some instruments
In this study, we explored the causal associations between       may be potentially invalid [20], MR-Egger regression for
AD and CVD events using the MR method.                           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
Methods
                                                                 Outlier (MR PRESSO) for outlier instrument detection [24],
We carried out a two-sample MR analysis based on sum-            and leave-one-out analysis to evaluate whether the MR esti-
mary statistics to investigate the causal relationship between   mate was influenced by single proxy SNP. We also calculated
AD and CVD events including stroke, heart failure, CAD,          the Cochran Q test from the IVW analysis to examine poten-
myocardial infarction, and angina pectoris. Single nucleotide    tial horizontal pleiotropy.
polymorphisms (SNPs) were selected as instruments vari-             All statistical analyses were performed using R software
ables because they are randomly allocated and less probable      4.0.3 (R Foundation for Statistical Computing). All statisti-
to be affected by confounding or reverse causation[15]. We       cal tests were two-sided with α=0.05.
used publicly available data, informed patients consents and
ethical approvals were available in original genome-wide as-
                                                                 Results
sociation studies (GWAS) studies.
                                                                 Genetic Instruments
Data Sources and Selection of SNPs                               Thirteen SNPs were identified as associated with AD
Summary-level data for AD were extracted from the EArly          (P<5×10-8), with independent inheritance (r2<0.01), and
Genetics and Lifecourse Epidemiology (EAGLE) eczema              without linkage disequilibrium (LD) in summary statistics.
consortium, including 13,287 cases and 41,345 controls of        All of these 13 SNPs were available in GWAS for stroke,
mostly European ancestry [16]. Summary-level data stroke         heart failure, CAD, myocardial infarction, angina pectoris.
were extracted from the MEGASTROKE Consortium,                   Details of the included SNPs are shown in Tables S1, Tables
a meta-analysis of 29 GWAS including a total of 40,585           S2, S3, S4, and S5 respectively.




2                                                                            Review | Dermatol Pract Concept. 2022;12(4):e2022165
Two-sample MR of AD and CVD                                       were 0.417 and 0.993, respectively; for AD on angina pec-
No significant evidence was found for a causal effect of AD       toris were 0.080 and 0.752, respectively, suggesting no evi-
on stroke, heart failure, CAD, myocardial infarction, angina      dence of potential horizontal pleiotropy and heterogeneity.
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:            Conclusions
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-         To the best of our knowledge, this is the first study to explore
1.00, P = 0.322; angina pectoris: OR = 1.00, 95%CI: 1.00-         the causal relationship between AD and CVD based on an
1.00, P = 0.369). The results neither weighted median, MR         MR approach. Our results did not support a causal effect of
Egger, weighted mode nor MR PRESSO analyses were sig-             AD on CVD.
nificant for all of the diseases above (Table 1 and Figures S1,      Previous studies on the link between AD and stroke are
S2, S3, S4, S5).                                                  controversial. In a Danish matched cohort study, patients
   Leave-one-out analysis indicated no influence of single        with severe AD had an increased risk of ischemic stroke,
SNP on the risk estimates of AD on stroke, heart failure,         but after adjustment for socioeconomic status, smoking, co-
CAD, myocardial infarction, angina pectoris. P values of Co-      morbidities, and medication use, the risk was similar with
chrane Q test and MR Egger intercept for AD on stroke were        controls [6]. In a cohort from the Nurses’ Health Study
0.481 and 0.695, respectively; for AD on heart failure were       2, the risk of stroke was significantly increased in female
0.150 and 0.224, respectively; for AD on CAD were 0.146           nurses with AD in the age and models adjusted for demo-
and 0.583, respectively; for AD on myocardial infarction          graphic, lifestyle risk factors, family history of MI, and


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




Review | Dermatol Pract Concept. 2022;12(4):e2022165                                                                            3
postmenopausal hormone replacement use. However, after              There are some limitations to the present study. First, the
further controlling for hypertension, hypercholesterolemia,      summary-level GWAS data we used were based mainly on
and diabetes, the association between AD and stroke was no       people of European ancestry. Therefore, results in this study
longer significant [7]. In a Swedish nationwide case-control     may not be applicable to other populations. Second, onset
study, only severe AD was associated with ischemic stroke        age and disease severity of AD might influence the associa-
[8]. A cross-sectional study conducted among primary care        tion between AD and comorbidities, but because the limita-
and community settings patients found only adult patients        tion of data, we were not able to perform subgroup analyses
with moderate to severe AD was significantly associated          by age and severity of AD. Third, an important limitation for
with higher prevalence rates of prior stroke compared to the     MR study is potential pleiotropy. In this study, we applied
control: 4.4% versus 2.4% [25]. In a large population-based      various MR approaches to test for potential pleiotropy, and
study including three surveys in US, AD was not associated       no evidence of pleiotropy for all the analyses was observed.
with stroke in NHANES 2005-2006, but was significantly           Moreover, the definitions of AD and comorbidities used in
associated with higher odds of stroke in NHIS 2010 and           the data is a mixture of self-reported diagnosis together with
2012 in crude models and multivariate models adjusted for        doctor diagnosed cases, which may cause bias to our findings.
demographic, lifestyle factors, hay fever and asthma [9]. A
population-based cohort study with data from the UK Clin-
ical Practice Research Datalink reported very modest asso-       Conclusion
ciation between AD and stroke in adjusted models, and the
                                                                 In conclusion, MR study does not support a causal effect
associations were considerably stronger in patients with se-
                                                                 of AD on stroke, heart failure, CAD, myocardial infarction,
vere or active AD [10]. Two recent large German studies also
                                                                 angina pectoris.
found no association between AD and stroke [26,27]. More-
over, a large Canadian cohort even found AD was associated
with lower risk of stroke in adjusted model [28].                References
    Though there are only few studies on the link between
                                                                 1. Puar N, Chovatiya R, Paller AS. New treatments in atopic der-
AD and heart failure, the results are still inconsistent. An
                                                                    matitis. Ann Allergy Asthma Immunol. 2021;126(1):21–31.
US cross-sectional inpatient study reported a significant           DOI: 10.1016/j.anai.2020.08.016. PMID: 32818591.
relationship between AD and heart failure [29]. A cohort         2. Bylund S, von Kobyletzki LB, Svalstedt M, Svensson A.
study also found positive association between AD and heart          Prevalence and Incidence of Atopic Dermatitis: A System-
­failure [10].                                                      atic Review. Acta Derm Venereol.2020;100(12):adv00160.
                                                                    DOI:10.2340/00015555–3510. PMID: 32412646.
    CAD is a cause of major morbidity and mortality world-
                                                                 3. Sacotte R, Silverberg JI. Epidemiology of adult atopic dermatitis.
wide. It includes stable ischemic heart disease, MI and un-
                                                                    Clin Dermatol. 2018;36(5):595–605. DOI: 10.1016/j.clinderma-
stable angina [30]. Several studies provided estimates for          tol.2018.05.007. PMID: 30217272.
the association of AD with the risk of CAD. The abovemen-        4. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lan-
tioned study conducted by Silverberg et al. showed AD was           cet. 2020;396(10247):345–360. DOI:10.1016/s0140-6736(20)
associated with significantly higher odds of CAD, the asso-         31286–1. PMID: 32738956.
                                                                 5. Drucker AM, Wang AR, Li W-Q, Sevetson E, Block JK, Qureshi
ciations attenuated but remained significant in the three ad-
                                                                    AA. The Burden of Atopic Dermatitis: Summary of a Report
justed models [9]. But Kwa et al. study reported AD was not
                                                                    for the National Eczema Association. J Invest Dermatol. 2017
significantly associated with CAD [29]. Findings about as-          Jan;137(1):26–30. DOI: 10.1016/j.jid.2016.07.012. PMID:
sociations between AD and angina were also mixing. Standl           27616422.
et al. and Silverwood et al. reported a significantly positive   6. Andersen YMF, Egeberg A, Gislason GH, Hansen PR, Skov L,
association between AD and angina [10,26]. However, AD              Thyssen JP. Risk of myocardial infarction, ischemic stroke, and
                                                                    cardiovascular death in patients with atopic dermatitis. J Al-
was not found to be significantly associated with angina in
                                                                    lergy Clin Immunol. 2016;138(1):310–312.e3. DOI: 10.1016/j.
NHANES [9]. The situation is similar to MI. There is a sig-
                                                                    jaci.2016.01.015. PMID: 26971689.
nificant association between AD and MI in NHANES, but            7. Drucker AM, Li WQ, Cho E, et al. Atopic dermatitis is not
after controlling risk factor of CVD, the association did not       independently associated with nonfatal myocardial infarc-
remain significant [9]. Studies of Drucker et al. and Standl        tion or stroke among US women. Allergy. 2016;71(10):1496–
et al. also suggested no evidence of the association between        1500. DOI:10.1111/all.12957. PMID: 27291834. PMCID:
                                                                    PMC5023476.
AD and MI [7,26,28]. However, Silverwood et al., the NHIS
                                                                 8. Ivert LU, Johansson EK, Dal H, Lindelöf B, Wahlgren C-F, Brad-
2010, and a recent cross-sectional study suggested AD was
                                                                    ley M. Association Between Atopic Dermatitis and Cardiovas-
associated with an increased risk of MI, even adjusted for          cular Disease: A Nationwide Register-based Case-control Study
potential confounding factors [9,10,31]. AD and CVD re-             from Sweden. Acta Derm Venereol. 2019;99(10):865–870. DOI:
lated studies are shown in Table S6.                                10.2340/00015555–3235. PMID: 31197387.



4                                                                           Review | Dermatol Pract Concept. 2022;12(4):e2022165
 9. Silverberg JI. Association between adult atopic dermatitis,                 Epidemiol. 2016;40(4):304–314. DOI:10.1002/gepi.21965.
    cardiovascular disease, and increased heart attacks in three                PMID: 27061298. PMCID: PMC4849733.
    population-based studies. Allergy. 2015;70(10):1300–1308.             21.   Bowden J, Del Greco M F, Minelli C, Davey Smith G, Shee-
    DOI:10.1111/all.12685. PMID: 26148129.                                      han NA, Thompson JR. Assessing the suitability of summary
10. Silverwood RJ, Forbes HJ, Abuabara K, et al. Severe and pre-                data for two-sample Mendelian randomization analyses using
    dominantly active atopic eczema in adulthood and long term risk             MR-Egger regression: the role of the I2 statistic. Int J Epide-
    of cardiovascular disease: population based cohort study. BMJ.              miol. 2016;45(6):1961–1974. DOI: 10.1093/ije/dyw220. PMID:
    2018;361:k1786. DOI: 10.1136/bmj.k1786. PMID: 29792314.                     27616674. PMCID: PMC5446088.
    PMCID: PMC6190010.                                                    22.   Burgess S, Thompson SG. Interpreting findings from Mendelian
11. Jung HJ, Lee DH, Park MY, Ahn J. Cardiovascular comorbidi-                  randomization using the MR-Egger method. Eur J Epidemiol.
    ties of atopic dermatitis: using National Health Insurance data             2017;32(5):377–389. DOI:10.1007/s10654-017-0255-x. PMID:
    in Korea. Allergy Asthma Clin Immunol. 2021;17(1):94. DOI:                  28527048. PMCID: PMC5506233.
    10.1186/s13223-021-00590-x. PMID: 34551806. PMCID:                    23.   Burgess S, Foley CN, Allara E, Staley JR, Howson JMM. A robust
    PMC8456522.                                                                 and efficient method for Mendelian randomization with hundreds
12. Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic                 of genetic variants. Nat Commun. 2020;11(1):376. DOI:10.1038/
    epidemiology contribute to understanding environmental de-                  s41467-019-14156-4. PMID: 31953392. PMCID: PMC6969055.
    terminants of disease? Int J Epidemiol. 2003;32(1):1–22. DOI:         24.   Verbanck M, Chen C-Y, Neale B, Do R. Detection of widespread
    10.1093/ije/dyg070. PMID: 12689998.                                         horizontal pleiotropy in causal relationships inferred from Men-
13. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G.                 delian randomization between complex traits and diseases. Nat
    Mendelian randomization: using genes as instruments for making              Genet. 2018;50(5):693–698. DOI:10.1038/s41588-018-0099-7.
    causal inferences in epidemiology. Stat Med. 2008;27(8):1133–               PMID: 29686387. PMCID: PMC6083837.
    1163. DOI:10.1002/sim.3034. PMID: 17886233.                           25.   Shalom G, Dreiher J, Kridin K, et al. Atopic dermatitis and the
14. Katikireddi SV, Green MJ, Taylor AE, Davey Smith G, Munafò                  metabolic syndrome: a cross-sectional study of 116 816 patients.
    MR. Assessing causal relationships using genetic proxies for ex-            J Eur Acad Dermatol Venereol. 2019;33(9):1762–1767. DOI:
      posures: an introduction to Mendelian randomization. Addic-               10.1111/jdv.15642. PMID: 31045273.
      tion. 2018;113(4):764–774. DOI:10.1111/add.14038. PMID:             26.   Standl M, Tesch F, Baurecht H, et al. Association of Atopic
      28921935. PMCID: PMC5873430.                                              Dermatitis with Cardiovascular Risk Factors and Diseases. J
15.   Didelez V, Sheehan N. Mendelian randomization as an instru-               Invest Dermatol. 2017;137(5):1074–1081. DOI: 10.1016/j.
      mental variable approach to causal inference. Stat Methods Med            jid.2016.11.031. PMID: 28011146.
      Res. 2007;16(4):309–330. DOI: 10.1177/0962280206077743.             27.   Treudler R, Zeynalova S, Walther F, Engel C, Simon JC. Atopic
      PMID: 17715159.                                                           dermatitis is associated with autoimmune but not with car-
16.   Paternoster L, Standl M, Waage J, et al. Multi-ancestry                   diovascular comorbidities in a random sample of the general
      genome-wide association study of 21,000 cases and 95,000                  population in Leipzig, Germany. J Eur Acad Dermatol Vene-
      controls identifies new risk loci for atopic dermatitis. Nat              reol. 2018;32(2):e44–e46. DOI: 10.1111/jdv.14495. PMID:
      Genet. 2015;47(12):1449–1456. DOI:10.1038/ng.3424. PMID:                  28758257.
      26482879. PMCID: PMC4753676.                                        28.   Drucker AM, Qureshi AA, Dummer TJB, Parker L, Li WQ.
17.   Malik R, Chauhan G, Traylor M, et al. Multiancestry                       Atopic dermatitis and risk of hypertension, type 2 diabetes, myo-
      genome-wide association study of 520,000 subjects identifies              cardial infarction and stroke in a cross-sectional analysis from
      32 loci associated with stroke and stroke subtypes. Nat Genet.            the Canadian Partnership for Tomorrow Project. Br J Derma-
      2018;50(4):524–537. DOI:10.1038/s41588-018-0058-3. PMID:                  tol. 2017;177(4):1043–1051. DOI: 10.1111/bjd.15727. PMID:
      29531354. PMCID: PMC5968830.                                              28617976.
18.   Shah S, Henry A, Roselli C, et al. Genome-wide association and      29.   Kwa MC, Silverberg JI. Association Between Inflammatory Skin
      Mendelian randomisation analysis provide insights into the                Disease and Cardiovascular and Cerebrovascular Co-Morbidities
      pathogenesis of heart failure. Nat Commun. 2020;11(1):163.                in US Adults: Analysis of Nationwide Inpatient Sample Data. Am
      DOI:10.1038/s41467-019-13690-5. PMID: 31919418. PMCID:                    J Clin Dermatol. 2017;18(6):813–823. DOI: 10.1007/s40257-
      PMC6952380.                                                               017-0293-x. PMID: 28534318.
19.   Nelson CP, Goel A, Butterworth AS, et al. Association analyses      30.   Shahjehan RD, Bhutta BS. Coronary Artery Disease. 2022 Feb 9.
      based on false discovery rate implicate new loci for coronary ar-         In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publish-
      tery disease. Nat Genet. 2017;49(9):1385–1391. DOI:10.1038/               ing; 2022 Jan–. PMID: 33231974..
      ng.3913. PMID: 28714975.                                            31.   Rhee T-M, Choi E-K, Han K-D, Lee S-R, Oh S. Impact of the
20.   Bowden J, Davey Smith G, Haycock PC, Burgess S. Consis-                   Combinations of Allergic Diseases on Myocardial Infarction and
      tent Estimation in Mendelian Randomization with Some In-                  Mortality. J Allergy Clin Immunol Pract. 2021;9(2):872–880.e4.
      valid Instruments Using a Weighted Median Estimator. Genet                DOI: 10.1016/j.jaip.2020.09.008. PMID: 32961311.




Review | Dermatol Pract Concept. 2022;12(4):e2022165                                                                                             5
