Genetic liability to acne is associated with increased risk of inflammatory bowel disease: A Mendelian randomization study

To the Editor: Isotretinoin, an effective mediation prescribed for severe acne, has been suspected to trigger inflammatory bowel disease (IBD).1Reddy D. Siegel C.A. Sands B.E. Kane S. Possible association between isotretinoin and inflammatory bowel disease.Am J Gastroenterol. 2006; 101: 1569-1573Crossref PubMed Scopus (89) Google Scholar However, with more recent evidence that supports a null association between isotretinoin exposure and IBD risk,2Wright S. Strunk A. Garg A. Risk of new-onset inflammatory bowel disease among patients with acne vulgaris exposed to isotretinoin.J Am Acad Dermatol. 2021; 84: 41-45Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar there is growing speculation whether IBD may be part of the consequence of the acne itself rather than the side effect of isotretinoin treatment. Only 1 population-based study has previously touched on this hypothesis, indicating a direct effect of acne on IBD.3Alhusayen R.O. Juurlink D.N. Mamdani M.M. et al.Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.J Invest Dermatol. 2013; 133: 907-912Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar As the causal association is difficult to establish depending solely on classical observational designs, we performed a 2-sample Mendelian randomization (MR) study to test the hypothesis that acne would increase the risk of IBD. MR leverages randomly allocated genetic variants as instruments (Fig 1), which could infer the causal effect of an exposure on an outcome by minimizing confounding and reverse causality.We constructed genetic instruments for acne vulgaris using 46 independent, genome-wide significant single-nucleotide polymorphisms identified from the hitherto largest meta-analysis of genome-wide association studies, comprising 20,165 acne cases and 595,231 controls of European ancestry.4Mitchell B.L. Saklatvala J.R. Dand N. et al.Genome-wide association meta-analysis identifies 29 new acne susceptibility loci.Nat Commun. 2022; 13: 702Crossref PubMed Scopus (4) Google Scholar Detailed information on the instruments and their selection strategies is presented in Supplementary Table (available via Mendeley at https://doi.org/10.17632/gdznn3m5ch.1). Summary statistics for IBD (25,042 cases and 34,915 controls) and its 2 common subtypes, ulcerative colitis (UC) (12,366 cases and 33,609 controls) and Crohn’s disease (12,194 cases and 28,072 controls) were retrieved from a recent genome-wide association studies meta-analysis with participants of European ancestry.5de Lange K.M. Moutsianas L. Lee J.C. et al.Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017; 49: 256-261Crossref PubMed Scopus (486) Google Scholar All genetic associations were adjusted for age, sex, and principal components.We performed the primary analysis using the inverse-variance weighted (IVW) method, followed by sensitivity analyses robust to pleiotropy, including weighted median estimator, MR–pleiotropy residual sum and outlier, and multivariable MR adjusting for body mass index (a potential pleiotropic factor). We also checked horizontal pleiotropy and heterogeneity using the MR-Egger intercept and Cochran Q statistic, respectively. The Steiger test was applied to ensure the correctness of the causal direction.Our results showed that the genetic liability to acne is positively associated with IBD risk (PIVW = .009) (Fig 2). Subtype-specific association was observed for UC (PIVW = .009) but not for Crohn’s disease (PIVW = .379). Pleiotropy-robust methods yielded similar results. Although some evidence of heterogeneity was reported, the MR-Egger did not indicate directional pleiotropy. There is no clear evidence of sample overlap between the genome-wide association studies of acne and IBD.Fig 2MR results for the causal effect of acne on IBD. The MR estimates are presented as OR for IBD per 1 unit increase in the log odds scale of acne. CD, Crohn’s disease; IBD, inflammatory bowel disease; IVW, inverse-variance weighted; MR, Mendelian randomization; OR, odds ratio; PRESSO, pleiotropy residual sum and outlier; UC, ulcerative colitis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Consistent with the inference from the earlier cohort study,3Alhusayen R.O. Juurlink D.N. Mamdani M.M. et al.Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.J Invest Dermatol. 2013; 133: 907-912Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar our MR analysis demonstrated that acne has a potential causal effect on the risk of IBD, specifically UC, among the European population. The mechanism underlying the different effects for IBD subtypes is unclear but is in line with the understanding that UC and Crohn’s disease have distinct pathophysiological features. The application of MR technology enables us to investigate the independent role of acne, overcoming the typical confounding of behavioral factors such as drug use, which are difficult to collect accurately, in observational studies. Our novel findings raise the call for viewing acne as a systemic inflammatory condition and encourage further research to explore the biologic mechanism linking acne and IBD. To the Editor: Isotretinoin, an effective mediation prescribed for severe acne, has been suspected to trigger inflammatory bowel disease (IBD).1Reddy D. Siegel C.A. Sands B.E. Kane S. Possible association between isotretinoin and inflammatory bowel disease.Am J Gastroenterol. 2006; 101: 1569-1573Crossref PubMed Scopus (89) Google Scholar However, with more recent evidence that supports a null association between isotretinoin exposure and IBD risk,2Wright S. Strunk A. Garg A. Risk of new-onset inflammatory bowel disease among patients with acne vulgaris exposed to isotretinoin.J Am Acad Dermatol. 2021; 84: 41-45Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar there is growing speculation whether IBD may be part of the consequence of the acne itself rather than the side effect of isotretinoin treatment. Only 1 population-based study has previously touched on this hypothesis, indicating a direct effect of acne on IBD.3Alhusayen R.O. Juurlink D.N. Mamdani M.M. et al.Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.J Invest Dermatol. 2013; 133: 907-912Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar As the causal association is difficult to establish depending solely on classical observational designs, we performed a 2-sample Mendelian randomization (MR) study to test the hypothesis that acne would increase the risk of IBD. MR leverages randomly allocated genetic variants as instruments (Fig 1), which could infer the causal effect of an exposure on an outcome by minimizing confounding and reverse causality. We constructed genetic instruments for acne vulgaris using 46 independent, genome-wide significant single-nucleotide polymorphisms identified from the hitherto largest meta-analysis of genome-wide association studies, comprising 20,165 acne cases and 595,231 controls of European ancestry.4Mitchell B.L. Saklatvala J.R. Dand N. et al.Genome-wide association meta-analysis identifies 29 new acne susceptibility loci.Nat Commun. 2022; 13: 702Crossref PubMed Scopus (4) Google Scholar Detailed information on the instruments and their selection strategies is presented in Supplementary Table (available via Mendeley at https://doi.org/10.17632/gdznn3m5ch.1). Summary statistics for IBD (25,042 cases and 34,915 controls) and its 2 common subtypes, ulcerative colitis (UC) (12,366 cases and 33,609 controls) and Crohn’s disease (12,194 cases and 28,072 controls) were retrieved from a recent genome-wide association studies meta-analysis with participants of European ancestry.5de Lange K.M. Moutsianas L. Lee J.C. et al.Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017; 49: 256-261Crossref PubMed Scopus (486) Google Scholar All genetic associations were adjusted for age, sex, and principal components. We performed the primary analysis using the inverse-variance weighted (IVW) method, followed by sensitivity analyses robust to pleiotropy, including weighted median estimator, MR–pleiotropy residual sum and outlier, and multivariable MR adjusting for body mass index (a potential pleiotropic factor). We also checked horizontal pleiotropy and heterogeneity using the MR-Egger intercept and Cochran Q statistic, respectively. The Steiger test was applied to ensure the correctness of the causal direction. Our results showed that the genetic liability to acne is positively associated with IBD risk (PIVW = .009) (Fig 2). Subtype-specific association was observed for UC (PIVW = .009) but not for Crohn’s disease (PIVW = .379). Pleiotropy-robust methods yielded similar results. Although some evidence of heterogeneity was reported, the MR-Egger did not indicate directional pleiotropy. There is no clear evidence of sample overlap between the genome-wide association studies of acne and IBD. Consistent with the inference from the earlier cohort study,3Alhusayen R.O. Juurlink D.N. Mamdani M.M. et al.Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.J Invest Dermatol. 2013; 133: 907-912Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar our MR analysis demonstrated that acne has a potential causal effect on the risk of IBD, specifically UC, among the European population. The mechanism underlying the different effects for IBD subtypes is unclear but is in line with the understanding that UC and Crohn’s disease have distinct pathophysiological features. The application of MR technology enables us to investigate the independent role of acne, overcoming the typical confounding of behavioral factors such as drug use, which are difficult to collect accurately, in observational studies. Our novel findings raise the call for viewing acne as a systemic inflammatory condition and encourage further research to explore the biologic mechanism linking acne and IBD. None disclosed. The authors thank the investigators of original genome-wide association studies for sharing summary statistics.