Casual association between childhood body mass index and risk of psoriasis: A Mendelian randomization study

Observational studies have suggested that childhood body mass index (BMI) is associated with the risk of psoriasis. However, their causal relationship remains unclear. In this investigation, we aimed to determine whether an association exists between childhood BMI and psoriasis.


| INTRODUC TI ON
Psoriasis is a lifelong inflammatory skin disorder that manifests as erythema, scaly papules, and plaques and causes stinging, irritation, burning sensations, and tingling. 1It is likely that the interaction between genetic and environmental factors contributes to the development of psoriasis, with environmental factors playing a crucial role in genetically predisposed individuals. 2,3The prevalence of psoriasis in children is approximately 0.5%, with an approximately linear increase from 1 to 18 years of age.Some data suggest that about one-third to one-half of adult psoriasis patients have their first onset in childhood.The peak onset of psoriasis in children has been reported between the ages of 2 and 8 years, while some scholars believe that the peak age of onset varies by gender, with female children having an earlier onset than males, and studies have not yet reached a consensus.Compared to adult psoriasis, about one-third of children have a family history of psoriasis, and some scholars have found that about 30%-50% of first-degree relatives of children with psoriasis have psoriasis. 4In a study of psoriasis in children, some scholars found that the lesions on the extremities of children with psoriasis were the most prevalent sites, while scalp was the most prevalent site in adults, and the vulva and buttocks were more likely to be involved.It has also been reported that Koebner's phenomenon is more common in children than in adults with psoriasis. 5t tissue is believed to be crucial in inflammatory responses and immunity. 6It also produces hormone-active substances and chemokines. 7Being overweight or obese may increase the risk of developing psoriasis, and being overweight has been suggested as a potential factor in the development of psoriasis. 8Studies conducted through observation have shown a correlation between a high body mass index (BMI) and an increased incidence of psoriasis, suggesting that obesity could be an index of risk for psoriasis. 9However, it remains unclear whether adolescent adiposity is causally related to an increased likelihood of developing psoriasis.
Mendelian randomization (MR) employs genetic variants as instrumental variables (IVs) to determine if an observable correlation between increased risk and an outcome represents a causative relationship.Two-sample MR can estimate causal relationships when the results and exposure data originate from separate samples. 10To date, no MR studies have been used to assess the association between BMI and psoriasis incidence in children.Therefore, we used MR analysis to investigate whether there is a causative link between BMI and psoriasis incidence in children.

| Data sources and genetic variant selection
We searched the MR Base database (http://www.mrbase.org/),containing statistical aggregate data from a large number of genome-wide association studies (GWAS).The exposure data were derived from open-access summary statistics datasets of GWAS systematic reviews for childhood BMI in people of European descent (n = 39 620). 11To enhance inference, we employed a two-sample MR study that used genetic variants associated with childhood BMI as the IVs, based on a genome-wide significance p-value threshold of 5.00E-08.We extracted 16 single-nucleotide polymorphisms (SNPs) associated with childhood BMI from the GWAS to use as IVs.The sample for the analysis comprised a total of 337 159 individuals, of which 3871 were cases and 333 288 were controls.

| Statistical analysis for Mendelian randomization
In MR assessment, genetic variants serve as surrogates for exposure variables and are not regarded as potential confounding variables. 12r methodology consisted of three steps: examining the separate relationship of SNPs with childhood BMI; exploring the relationship between each SNP and the probability of developing psoriasis; combining the results above to assess the causal link between childhood BMI and psoriasis using MR analysis. 13Using 16 SNPs as IVs, we performed a two-sample MR analysis to assess the causal relationship between childhood BMI and psoriasis.Tables 1 and 2 present the results obtained from the statistical summaries of various GWAS.
Inverse variance weighting (IVW) applied the systematic review methodology integrating the predicted Wald percentages of attributable effects obtained through various SNPs, accurately estimating the correlated influence of the exposure's impact on outcomes when every inherited mutation meets the IV assumptions. 14Incorporating many different mutations into an MR assessment may increase the statistical ability, but it may also include multifaceted variations in genes that fail to qualify as legitimate IVs. 15 We used both the weighted median and MR-Egger regret methods to consider pleiotropy, that is, the linkage of genuine variation with multiple variables.MR-Egger models resist inaccurate instruments, assessing and compensating for asymmetrical pleiotropy by including data summary predictions from various genetic variants.MR-Egger conducts a Conclusion: According to the findings of the MR analysis, an increased childhood BMI may be linked to a higher likelihood of psoriasis.

BMI, children, GWAS, Mendelian randomization, psoriasis
weighted linear regression analysis of the gene-outcome correlations on the gene-exposure values, with the trend reflecting an estimation of the effect that is causal, and the point of intersection represents an approximation of the median horizontally multifaceted impact throughout genomic variants. 15The weighted median estimation offers an accurate assessment of the causal effect, even when as much as 50% of the available data for the assessment as a result of non-valid IV genetic variants. 16The weighted median evaluator makes predictions with higher accuracy than the MR-Egger method. 17

| Heterogeneity and sensitivity test
We implemented a "leave-one-out" approach to examine the potential influence of individual SNPs on the causal association.[21]

| Instrumental variables for Mendelian randomization
We identified 16 SNPs from GWAS on childhood BMI that fulfilled all requirements for being independently causally related to childhood BMI at the genome-wide level (Table 1; Figure 1).None of the nine positive associations between SNPs and psoriasis attained statistical significance (Table 1; Table S1).As indicated by the R 2 statistic, the genetic variants used as IVs accounted for 1.4% of the variance in the exposure.Each variant presented an F-statistic greater than 30, corresponding to p-values of 5.00E-08, making weak instrumental bias negligible given the "weak IV" threshold was set at F < 10.

| Heterogeneity and sensitivity test
No heterogeneity was found in the causal effect estimates for each SNP, as indicated by Cochran's Q test (Table 2).The I 2 values also suggested low heterogeneity, lending further confidence to the MR estimations (Tables 1 and 2).Moreover, the stability of the IVW estimation was not affected by the removal of any individual SNPs, demonstrating the robustness of our findings.We inspected the asymmetry of the funnel plots, which might suggest the presence of directional pleiotropy thatcould bias the MR results.However, neither the funnel plot nor the MR-Egger regression indicated evidence of asymmetry (Figure 3).Therefore, our results validate the reliability of MR estimation and suggest that directional pleiotropy did not bias our findings.
Based on the results from the "Leave-one-out" approach, none of the SNPs decisively influenced the causal inferences (Figure 4).relationship between childhood obesity and psoriasis remains unclear, although childhood obesity is regarded as a risk factor 8 (Table 3).We investigated this relationship using three MR statistical techniques (IVW, weighted median, and MR-Egger regression). 16r study suggests a potential causal link between childhood BMI and psoriasis.Although the MR estimations obtained from IVW, weighted median, and MR-Egger regression were not entirely consistent, both IVW and weighted median methods provide evidence suggesting that obesity and psoriasis may share a common genetic background. 23In response to inflammatory agents such as TNFand IL-1, leptin levels in adipose tissue increase, mediating obesityassociated inflammation and playing a role in the development of psoriasis.Reduced levels of lipocalin in obese psoriasis patients result in a chronic inflammatory state.Lipocalin has anti-inflammatory and insulin-sensitizing properties, and reduced levels of lipocalin in obese psoriasis patients lead to a chronic inflammatory state. 24ese psoriasis patients can reduce the severity of their disease with weight loss interventions. 25Mendelian randomization studies imply that a higher BMI is associated with an increased risk of developing psoriasis. 26The direct causal connection between adolescent BMI and the development of psoriasis has not been reported.

MR method
MR is a method that reduces the bias inherent in observational studies and is sensitive to distortion from multiplication, where a single genetic variant may be correlated with multiple phenotypes,

F I G U R E 4
Leave-one-out of single-nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and their risk of psoriasis.Each black point represents result of the inverse variance weighting (IVW) Mendelian randomization (MR) method applied to estimate the causal effect of childhood BMI on psoriasis excluding particular SNP from the analysis.Each red point depicts the IVW estimate using all SNPs.No single SNP is strongly driving the overall effect of childhood BMI on psoriasis in this leave-one-out sensitivity analysis.
resulting in potentially biased causal estimates. 27Including various variations in MR study can boost the power of statistics. 28However, it also increases the likelihood of including pleiotropic variants that are not valid IVs, necessitating sensitivity analyses. 29We used the weighted median estimator and the MR-Egger regression to account for pleiotropy, detect horizontal pleiotropy, and evaluate the causal effect of exposure on the outcome in its presence.Although the findings were not consistent across all three methods, the results of the weighted median estimator were similar to those of the IVW method, adding confidence to these associations.The results of our study support prior observational research and provide the chance to investigate the processes underpinning the association between childhood adiposity and psoriasis risk.
At present, the treatment of psoriasis in children is primarily relies on topical medications, and for moderate to severe cases, phototherapy or systemic treatment may be considered. 30Psoriasis in children often presents as a chronic and recurring condition with numerous comorbidities, such as obesity and metabolic syndrome.
These comorbidities significantly impact the physical and mental health of both children and their parents. 31Biological agents provide a targeted and effective treatment option by selectively acting on specific signal transduction molecules and pathways involved in T-cell activation.These agents are well-tolerated and demonstrate high efficacy. 31Patients with psoriasis often exhibit low levels of lipocalin.Given the association of lipocalin levels with psoriasis, obesity, and metabolic syndrome, it represents a potential target for TA B L E 3 Literature review of BMI and psoriasis risk in pediatric patients.

Conclusions Reference
To explore whether psoriasis in children is similarly associated with cardiometabolic risk status Pediatric psoriasis was positively associated with overweight/obesity and waist height ratio >0.The study has several restrictions, such as the small effect of genetic variants on BMI and the classification biases associated with psoriasis patients. 33In addition, the study was conducted on individuals of European ancestry, emphasizing the need for additional MR studies on other populations to determine causality.
Despite these limitations, the study has virtues, including MR, which has never been used to assess juvenile BMI as a psoriasis risk indicator.In addition, this research estimated gene exposure and gene outcome interactions for the mutations, making it the first to investigate the possible link between childhood BMI and psoriasis.
In the context of my conclusion, the MR analysis reveals that childhood BMI may be, in a causal manner, linked to a higher likelihood of psoriasis, highlighting the possibility of a role of childhood obesity in the onset of psoriasis.These results suggest avenues for future research into the mechanisms underlying the association between childhood adiposity and psoriasis.

| CON CLUS ION
In summary, our study indicated that high childhood BMI might be causally associated with increased risk of psoriasis, which supports the childhood weight control for the prevention and treatment of psoriasis.Further researches are needed to explore the underlying mechanisms of this causal relationship.

F I G U R E 1 F I G U R E 2 F I G U R E 3
of a possible link.Our MR analysis, which might be more precise than the MR-Egger regression, indicates that childhood BMI could contribute to the risk of psoriasis.Therefore, this investigation corroborates previous observational studies.Kim et al. demonstrated that individuals with a BMI of 30 units had a considerably higher risk of psoriasis than those with a BMI of 18.5-23.0unites (HR = 1.09, 95% confidence interval: 1.06-1.11).22Szentkereszty-Kovács et al. found that the leptin receptor (rs1137101) and brain-derived neurotrophic factor (rs925946) gene alterations are present in those individuals with psoriasis, Forest plot of the causal effects of single-nucleotide polymorphisms associated with childhood body mass index on psoriasis.The significance of red lines are Mendelian randomization (MR) results of MR-Egger test and inverse variance weighting method.Scatter plots of genetic associations with childhood body mass index against the genetic associations with psoriasis.The slopes of each line represent the causal association for each method.The blue line represents the inverse-variance weighted estimate, the green line represents the weighted median estimate, and the dark blue line represents the Mendelian randomization (MR)-Egger estimate.Funnel plot to assess heterogeneity.The blue line represents the inverse-variance weighted estimate, and the dark blue line represents the Mendelian randomization (MR)-Egger estimate.
innovative drug development.While biologics have emerged as the mainstay treatment for psoriasis, they may also lead to new clinical challenges, including eczema flare-ups, arthritis, or septic sweat glands.Therefore, personalized and precision medicine should prioritize research efforts toward identifying biomarkers that can predict and prevent potential paradoxical reactions, aiming to halt the progression of psoriasis.32

-value
MR estimates from each method of assessing the causal effect of children BMI on the risk of psoriasis.
Abbreviations: Beta, beta coefficient; BMI, body mass index; MR, Mendelian randomization; SE, standard error; SNP, single-nucleotide polymorphism.TA B L E 1 MR estimates from each method of assessing the causal effect of children BMI on the risk of psoriasis.TA B L E 2 a I 2 = (Q − df)/Q.