Abstract
Background
The investigation into unsaturated fatty acids has spanned an extensive period; however, the evidence supporting their therapeutic efficacy in treating acne remains inconclusive. Previous research has predominantly focused on omega-3 and omega-6 fatty acids, with limited exploration of the roles played by monounsaturated fatty acids and specific unsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
Methods
To more comprehensively assess the impacts of diverse unsaturated fatty acids and their subcomponents, we employed Mendelian randomization methodology. Our primary analytical approach was inverse variance weighting (IVW), supplemented by a series of sensitivity analyses to enhance the robustness of our findings. Given the potential for overlapping single nucleotide polymorphisms (SNPs) among the various unsaturated fatty acids under investigation, we incorporated multivariate Mendelian randomization to reduce the risk of false positives. Additionally, Bayesian weighted Mendelian randomization was utilized to confirm the consistency of our results.
Results
Univariate Mendelian randomization indicated that omega-3 and DHA were inversely associated with acne risk, while the omega-6 to omega-3 ratio showed a positive correlation with acne risk. Multivariate Mendelian randomization revealed that only DHA demonstrated a positive association with acne risk, a finding supported by Bayesian weighted Mendelian randomization.
Conclusion
Collectively, these results suggest that our data primarily support the protective influence of DHA against acne.
Keywords: polyunsaturated fatty acids, acne, Mendelian randomization, omega-3, omega-6, docosahexaenoic acid
Introduction
Acne is a chronic inflammatory skin disease that affects the hair follicle sebaceous gland unit due to multiple etiological factors.1 It is estimated that acne impacts approximately 9.4% of the global population, positioning it as the eighth most prevalent ailment worldwide and imposing significant economic burden.2 After healing, it is easy to leave scars and pigmentation, which affects 85% of young people and adolescents. Its impact on social and psychological aspects can even exceed its impact on the body.3–5 A questionnaire-based study revealed that 95% of patients hold the belief that specific food items and beverages can exacerbate acne, while 85.5% of patients associate it with the consumption of fatty or fried foods.3 These findings underscore the public’s recognition of the correlation between diet and acne.6 In contrast to our current understanding of the genetic susceptibility and hormonal factors involved in acne pathogenesis, the precise role of diet in acne development remains elusive.7–9 The incidence of acne has been observed to increase among Japanese Okinawans and Inuits who previously had no history of acne upon adopting a Western diet.10,11 Upon comparing the dietary habits of Okinawans and Inuits with those following a Western diet, it was discovered that the latter exhibited higher intake of ω-6 polyunsaturated fatty acids (PUFA) but lacked ω-3 PUFA, resulting in an excessively high ratio of ω-6/ω-3 PUFA.12 A P Simopoulos highlighted that an elevated ratio of ω-6/ω-3 PUFA promotes inflammation and numerous diseases,13 whereas a Mediterranean diet characterized by a higher proportion of ω-3 PUFA can partially alleviate the severity of acne.14 Subsequently, several scholars demonstrated through randomized controlled trials that providing dietary supplements containing ω-3 PUFA can reduce acne lesions.15
The aforementioned evidence suggests that ω-3 PUFA may possess therapeutic effects on acne; however, the impact of ω-6 PUFA on acne remains uncertain, and there is also a dearth of evidence regarding the effects of other unsaturated fatty acids on acne. Furthermore, the levels of unsaturated fatty acids in the body are influenced by numerous factors (including but not limited to genetic factors and dietary habits),16,17 rendering it exceedingly challenging to provide robust evidence for the causal relationship between unsaturated fatty acids and acne through basic experiments and observational studies.18 Therefore, it is imperative to employ a rational and feasible research methodology to circumvent the limitations encountered in previous studies.
Mendelian randomization (MR) is a robust method that leverages genetic variation, specifically single nucleotide polymorphisms (SNPs), as instrumental variables for inferring causality.19 By adhering to Mendel’s law of independent assortment, alleles are randomly transmitted from parents to offspring during meiosis.20 Consequently, compared to conventional research approaches, MR analysis is less susceptible to confounding factors and reverse causality.
The objective of this study was to assess the causal association between unsaturated fatty acids and acne through MR Analysis, encompassing monounsaturated fatty acids, ω-3 unsaturated fatty acids, ω-6 unsaturated fatty acids, the ratio of ω-6 to ω-3 fatty acids, docosahexaenoic acid (DHA), and linoleic acid (LA).
Methods
Ethical Statement
According to Article 32 of the Measures for Ethical Review of Life Science and Medical Research Involving Human Beings adopted by the National Science and Technology Ethics Committee of the People’s Republic of China, ethical review can be exempted because the data used in this study do not cause any harm to human beings, do not involve any sensitive personal information or commercial interests, and the databases selected are open and legal.
Research Design
The experiment is based on three fundamental assumptions of Mendelian randomization (MR): 1) a strong correlation between instrumental variables and exposure factors; 2) no correlation between instrumental variables and confounding factors; 3) no direct association between instrumental variables and outcome, with their impact on the outcome being solely mediated through exposure. Single unsaturated fatty acids, ω-3 unsaturated fatty acids, ω-6 unsaturated fatty acids, the ratio of ω-6 to ω-3 fatty acids, docosahexaenoic acid (DHA), and linoleic acid (LA) are employed as exposure factors, while acne is considered as the outcome factor in a two-sample Mendelian randomization design. The research overview is depicted in Figure 1.
Figure 1.
Overview of the research route.
Data Sources
The data on unsaturated fatty acids was obtained from the European Bioinformatics Institute (EBI) database, utilizing a dataset collected in 2022 comprising of 11,506 individuals (N=11506). A subset was randomly selected from the larger cohort of 121,584 participants enrolled in the UK Biobank project. Non-fasting EDTA plasma samples were measured to acquire the data, with an equal division among samples.21 A comprehensive analysis encompassed a total of 11,590,399 SNP. The acne data was sourced from the FinnGen database for the year 2021 (N=212,438), with analysis conducted on over 16,000,000 SNPs. GWAS IDs can be found in Table 1.
Table 1.
The Dataset Used and Its GWAS Database ID
| ACNE | Finn-b-L12_ACNE |
|---|---|
| Omega-3 levels | ebi-a-GCST90092931 |
| Omega-6 levels | ebi-a-GCST90092933 |
| Omega-6/Omega-3 | ebi-a-GCST90092934 |
Instrumental Variable Selection
The SNPs of unsaturated fatty acids extracted from the EBI database underwent a preliminary screening, with only those SNPs having a p-value less than 5×10−8 being included. To ensure the effectiveness and independence of the SNPs, we applied a threshold of r2=0.001 and kb=10000 to remove linkage disequilibrium. Furthermore, in order to mitigate weak instrumental variable (IV) bias, we calculated the F values for all IVs and considered those with F > 10 as strong instrumental variables.22 Additionally, PhenoScanner (httP://www.Phenoscanner.medschl.cam.ac.uk) was utilized to screen all included IVs to confirm their adherence to the assumptions of MR studies.
Statistical Analysis
In this study, we employed the MR analysis method to investigate the causal effect of unsaturated fatty acids on acne. The primary analytical approach utilized was the inverse variance weighted (IVW) method using a random effects model. Additionally, we conducted supplementary analyses using the weighted median method, MR–Egger method, Simple mode method, and Weighted mode method. In cases where discrepancies arose among these five methods, IVW was selected as the reference standard. To ensure robustness and reliability of our findings, we calculated Cochran’s Q statistic to assess potential heterogeneity. Furthermore, we performed an MR-Egger intercept test to estimate horizontal pleiotropy,23 and conducted leave-one-out analysis to examine sensitivity and evaluate whether a single SNP is driving the observed association.
Due to the interdependence of various levels of unsaturated fatty acids, in order to eliminate the potential bias caused by pleiotropy from SNPs highly overlapping with various unsaturated fatty acids in the analysis results, we conducted a multivariable Mendelian randomization (MVMR) analysis again to estimate the “direct” effects of each exposure on the outcome.24,25
Meanwhile, we propose the Bayesian Weighted Mendelian Randomization (BWMR) analysis method as a complementary approach to two-sample MR. On one hand, it accounts for the multi-gene architecture and pleiotropy of diseases or traits that were not considered in conventional MR analysis. On the other hand, it enhances the stability and robustness of the final outcomes.26
The statistical significance of all analysis results was determined using a threshold of p<0.05.
These analyses were conducted utilizing R software (version 4.3.0). MR analysis was performed employing R packages “TwoSampleMR”, “MendelianRandomization”, and “ggplot2”.
Results
Description of Instrumental Variables
The genome-wide significance threshold (p<5×10−8) was applied to filter the data, followed by linkage disequilibrium (LD) testing and harmonization. SNPs with an F statistic value greater than 10 were retained to ensure strong correlation with each respective unsaturated fatty acid. PhenoScanner was utilized to identify any potential confounding factors associated with the SNPs, but no significant associations were found. Supplementary Table S1 provides detailed information on the retained SNPs and their corresponding statistical data.
Results of Univariate Mendelian Randomization Analysis
As depicted in Figure 2, higher levels of ω6/ω3 were positively associated with the risk of acne (OR=1.2598, 95% CI: 1.0113–1.5692, p=0.0393). Conversely, elevated levels of ω3 (OR=0.7817, 95% confidence interval CI: 0.6186–0.9878, p=0.0391) and DHA (OR=0.6618, 95% CI: 0.4986–0.8784, p=0.0043) exhibited an inverse association with acne risk.
Figure 2.
All single-factor analysis of variance for unsaturated fatty acids.
Among these associations observed between different groups (ie, the ω6/ω3 group and the DHA group), it is noteworthy that only the Simple mode results did not reach statistical significance; however, they align with the IVW results otherwise.
Regarding the ω3 group specifically, only MR Egger results failed to achieve statistical significance while other methods yielded consistent outcomes as compared to IVW analysis; this further enhances the credibility of our findings.
Detailed results of causal effect tests are shown in Supplementary Table S2.
The further sensitivity analysis revealed no evidence of horizontal pleiotropy; however, heterogeneity was observed for ω3 (Q=73.069, P=0.003<0.05) and DHA (Q=58.689, P=0.005<0.05). Given the adoption of a random-effects model in this study and the fact that heterogeneity did not compromise the stability of the results, we maintain confidence in their reliability. Leave-one-out analysis demonstrated that significant findings were not driven by any individual SNP and remained robust overall. Supplementary Table S3 presents the results pertaining to horizontal pleiotropy and heterogeneity, while Supplementary Documents showcase leave-one-out outcomes (Figure S1) and scatter plots (Figure S2).
Multivariate MR Analysis Results
In order to assess the direct impact of each exposure on the outcome, we incorporated univariate Mendelian randomization (MR) positive results for ω6/ω3, ω3, and DHA into the multivariable MR analysis. The findings revealed that ω6/ω3 did not exhibit a significant effect on acne, whereas ω3 and DHA continued to exert an influence on acne risk. Interestingly, the result for ω3 contradicted the univariate MR analysis, suggesting a positive association between higher levels of ω3 and increased acne risk (OR=4.059, 95% CI: 1.156–14.256, p=0.029). Conversely, the result for DHA aligned with the univariate MR analysis and indicated a negative correlation between elevated levels of DHA and acne risk (OR=0.183, 95% CI: 0.063–0.530, p=0.002). Despite slight discrepancies between MVMR and univariate results observed in this study, MVMR provided additional evidence to evaluate the relationship between unsaturated fatty acids and acne. More details can be found in Figure 3 illustrating MVMR results, and Supplementary Table S4 presenting relevant data.
Figure 3.
Results of multivariate Mendelian randomization analysis.
Bayesian Weighted MR Analysis Results
The Bayesian weighted meta-regression analysis indicated no significant association between the ω6/ω3 ratio and acne risk, as well as ω3 levels. However, higher DHA levels exhibited a negative correlation with acne (OR=0.668, 95% CI: 0.502–0.944, p=0.020). Please refer to Supplementary Table S5 for detailed data.
Discussion
Compared to previous studies investigating the impact of unsaturated fatty acids on acne, our study goes beyond examining the overall effects of ω3 or ω6. We place greater emphasis on understanding the individual roles and interactions of specific components such as DHA, EPA, and LA. Employing univariable MR analysis, we assess the effects of different unsaturated fatty acids on acne while also incorporating multivariable MR to account for potential interactions among positive unsaturated fatty acids in order to observe their “direct” effects. Finally, Bayesian weighted MR is introduced to validate our findings. By leveraging the strengths of various MR analysis methods and integrating existing databases, this study ultimately concludes that DHA exhibits a negative correlation with acne risk, whereas other unsaturated fatty acids do not demonstrate statistical significance.
In this study, univariate Mendelian randomization analysis demonstrated a protective effect of higher levels of ω3 and DHA against acne, while an increased ratio of ω6/ω3 was associated with an elevated risk of developing acne. These findings align with previous studies reporting a higher incidence of acne in populations consuming a Western diet characterized by a greater proportion of ω6.10,11 Notably, it should be emphasized that pure ω6 does not exert a causal effect on acne due to the fact that polyunsaturated fatty acids (PUFAs) ω6 and ω3 obtained from natural sources are primarily linoleic acid (LA) and alpha-linolenic acid (ALA), respectively. Both PUFAs follow the same metabolic pathway and exhibit competitive inhibition, influencing the conversion efficiency from LA to arachidonic acid (AA) as well as ALA to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), depending on substrate concentrations.27 Consequently, an elevated ratio of ω6/ω3 may impact ALA metabolism efficiency and reduce EPA and DHA production.28 This observation is consistent with our research results suggesting that direct effects of ω6 on acne occurrence are absent; instead, it lowers the conversion efficiency from ALA to anti-inflammatory DHA and EPA by competing for the same enzyme site, thereby increasing the risk of developing acne. Subsequent sensitivity analysis identified rs174564 as a key SNP located near fatty acid desaturase 2 (FADS2), which plays an indispensable role in initiating desaturation processes involved in converting ALA into EPA and DHA.29–31 Previous MR studies have indicated that upregulation of rs174564 gene expression can mitigate inflammatory responses despite its distinct location from acne; nevertheless, it still exhibits anti-inflammatory effects.32 This further strengthens the reliability of our findings.
After controlling for the confounding effects of highly correlated single nucleotide polymorphisms (SNPs) between groups in terms of ω6/ω3, ω3, and docosahexaenoic acid (DHA) using multivariable Mendelian randomization (MR) analysis,25 our findings still demonstrate a causal relationship between DHA and acne, while the statistical significance of ω6/ω3 is no longer observed. This provides robust evidence to support further investigation into effective unsaturated fatty acids and corroborates our previous results from univariable MR analysis indicating that pure ω6 does not exhibit statistical significance, whereas the ratio of ω6/ω3 poses a risk effect. Moreover, the contradictory outcome regarding ω3 compared to univariable MR analysis remains unexplained at this stage and may necessitate additional experimental validation.
To address the uncertainty arising from the limited impact of single nucleotide polymorphisms (SNPs) in complex genetic structures, which may result in overlooking certain instances of horizontal pleiotropy in Mendelian randomization (MR) analysis, as well as biases introduced by sample duplication in meta-analysis data, we employed Bayesian Weighted Mendelian Randomization (BWMR) for validation.26 The findings further substantiated our assertion that only DHA exhibits statistical significance and is inversely associated with acne.
Given the current absence of EPA data in the GWAS database, we are currently unable to establish a causal relationship between EPA and acne. We anticipate further research in this area in the future.
Finally, although we have made considerable efforts to address the limitations of this study, certain insurmountable challenges remain. The database utilized in our analysis did not include Asian and African populations, which may result in our conclusions being unable to support the effectiveness of DHA for these groups. Furthermore, during the manual removal of SNPs, some variants may have been inadvertently overlooked due to constraints in the authors’ knowledge.
Conclusion
The Mendelian randomization results we obtained lend support to the protective effect of supplemental DHA on acne, thereby potentially contributing to the integration of dietary supplements into clinical practice. The role of ω3 presents certain contradictions, and despite our diligent efforts to elucidate them, we remain uncertain about the underlying reasons behind these results necessitating further experimentation for comprehensive analysis.
Declarations
The data utilized in this study were obtained from publicly accessible databases and have received the necessary approvals from the respective ethics review committees, along with informed consent from participants. All original studies have been granted approval by the ethics review committees and accompanied by participant informed consent forms. As individual-level data was not employed in this study, there is no requirement for a new round of ethics review committee approval.
Abbreviations
DHA, Docosahexaenoic acid; EPA, Eicosapentaenoic acid; IVW, Inverse variance weighting; SNP, Single nucleotide polymorphisms; PUFA, Polyunsaturated fatty acids; MR, Mendelian randomization; LA, Linoleic acid; EBI, European Bioinformatics Institute; GWAS, Genome-wide association study; MVMR, Multivariable Mendelian randomization; BWMR, Bayesian Weighted Mendelian Randomization; LD, Linkage disequilibrium.
Disclosure
The authors report no conflicts of interest in this work.
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