Psoriasis is a known contributor to psychosocial disability and impaired quality of life, with patients exhibiting a 21% greater risk of mortality than the general population. Although it is essential to understand the factors that causally affect risk, researchers noted that evidence for causal relationships between modifiable factors and psoriasis mostly comes from conventional observational studies.
“A limitation of observational studies is that the causality of the associations cannot be inferred, as results may be biased by confounding and reverse causation,” they explained.
Mendelian randomization (MR) is an analytic approach in which genetic variants are used as proxies, or instrumental variables, for putative risk factors. As these genetic variants are randomly assorted at conception, the researchers said, “They are not influenced by reverse causation, and in the absence of pleiotropic associations (associations between genetic variants and disease through alternative pathways), they can provide unconfounded estimates of disease risk.”
A 2-sample MR analysis was conducted to investigate the causality between the risk of psoriasis and several potentially modifiable factors: smoking behavior (initiation and lifetime index), alcohol and coffee consumption, sleep duration, physical activity, education, overall obesity (childhood and adult body mass index [BMI]) and abdominal obesity (waist-to-hip ratio, waist circumference), and hip circumference.
For each modifiable risk factor, effect estimates for each single-nucleotide polymorphism (SNP) used as instruments in the MR analysis were retrieved from several large-scale genome-wide association studies (GWAS). The number of SNPs used as genetic instruments for the examined modifiable factors ranged from 4 to 505, in which the primary method used for assessment was the random-effects inverse variance weighted (IVW).
Findings of the univariate 2-sample MR analysis showed an increased risk of psoriasis for each standard deviation [SD] increase of genetically predicted lifetime smoking index (ORIVW, 2.11; 95% CI, 1.28-3.51), childhood (ORIVW, 1.40; 95% CI, 1.14-1.71) and adult BMI (ORIVW, 1.63; 95% CI, 1.32-2), waist circumference (ORIVW, 1.86; 95% CI, 1.31-2.64), and hip circumference (ORIVW, 1.55; 95% CI, 1.15-2.07).
A protective association was additionally reported between genetically predicted longer sleep duration (ORIVW, 0.56; 95% CI, 0.37-0.84) and increased years of education (ORIVW, 0.78; 95% CI, 0.62-0.98). Moreover, the protective effect of education was found to persist in multivariable MR (MVMR) after adjusting for genetic predictors of lifetime smoking index and adult BMI (ORMVMR-IVW, 0.72; 95% CI, 0.56-0.92). For childhood BMI, the direct effect (not mediated by adult BMI) was null (ORMVMR-IVW, 1.01; 95% CI, 0.79-1.29; P = .96).
The researchers noted that as all analyses were performed using summary-level data derived from the GWAS on Europeans, their findings may not be generalizabile to non-European populations. The inability to explore the causal effect of the examined factors on the severity of psoriasis or various disease subtypes was also noted as a potential limitation.
“Continuation of existing or introduction of new approaches to tackle obesity and smoking are of great importance not only to reduce the incidence of psoriasis but of several diseases as well,” concluded the researchers. “Higher levels of education are also crucial for psoriasis prevention, further enhancing the lengthy list of conditions associated with educational levels and further highlighting the lifelong benefits of education on good health.”
Chalitsios CV, Georgiou A, Bouras E, et al. Investigating modifiable pathways in psoriasis: A Mendelian randomization study. J Am Acad Dermatol. Published online November 9, 2022. doi:10.1016/j.jaad.2022.11.010