Higher genetically predicted triglyceride levels were associated with psoriasis in a Mendelian randomization study published in Medicine, although the findings do not establish whether measured triglyceride levels or triglyceride-lowering therapy affect psoriasis risk, severity, or treatment response.
The researchers conducted a two-sample Mendelian randomization analysis using genome-wide association study summary statistics from European-ancestry samples drawn from the IEU OpenGWAS database. The analysis included 114,999 samples in the total fatty acid data set, 441,016 samples in the triglyceride data set, and 216,752 samples in the psoriasis outcome data set.
Genome-wide significant single nucleotide polymorphisms were used as instrumental variables. Inverse-variance weighted analysis served as the primary method, with MR-Egger regression, weighted median, weighted mode, and simple mode analyses used as supplementary methods.
In the primary inverse-variance weighted analysis, genetically predicted triglyceride levels were associated with psoriasis. The researchers reported an odds ratio of 1.17, which they described as showing that triglycerides were a risk factor for psoriasis. Among the supplementary methods, the weighted median and weighted mode analyses were also statistically significant, whereas the MR-Egger and simple mode analyses were not.
In sensitivity analyses, the researchers reported heterogeneity among the triglyceride-associated variants. The primary analysis used a fixed-effects inverse-variance weighted model. The MR-Egger horizontal pleiotropy test was not statistically significant, which the researchers interpreted as no evidence of horizontal pleiotropy, and leave-one-out analysis indicated that no single variant drove the result.
By contrast, the primary inverse-variance weighted analysis did not show a statistically significant association between genetically predicted total fatty acid levels and psoriasis. Among the supplementary methods, MR-Egger regression reached statistical significance, while the weighted median, weighted mode, and simple mode analyses did not. The researchers concluded that total fatty acids were not a causal factor for psoriasis.
In a third analysis, the researchers reported that genetically predicted total fatty acid levels were associated with triglyceride levels, which they interpreted as supporting a causal relationship between fatty acids and triglycerides. However, the paper stated that 64 single nucleotide polymorphisms were associated with total fatty acids but described the fatty acid–to–triglyceride analysis as using 296 single nucleotide polymorphisms, the same number reported for the triglyceride instruments. The discrepancy was not explained in the text. The study did not include a formal mediation analysis to test a fatty acid–triglyceride–psoriasis pathway.
The study evaluated genetic proxies for lipid traits and a psoriasis genome-wide association study phenotype rather than measured lipid levels, psoriasis severity, flare frequency, or response to lipid-lowering therapy. It assessed total fatty acids rather than individual fatty acid species and was restricted to European-ancestry data. The researchers did not report instrument-strength statistics, the number of psoriasis cases within the outcome sample, or analyses testing the reverse direction of effect.
The researchers noted that this was the first Mendelian randomization analysis of these relationships and wrote that larger genome-wide association study data sets and updated analyses are needed to further verify the causal relationships among triglycerides, fatty acids, and psoriasis. They added that analyzing the fatty acid composition and nutritional status of patients with psoriasis may be necessary to clarify the role of lipid metabolism in the disease.
The researchers wrote that larger genome-wide association study data sets and updated Mendelian randomization analyses are needed to further verify the relationships among triglycerides, fatty acids, and psoriasis. They added that future studies may need to evaluate fatty acid composition and nutritional status among patients with psoriasis to clarify the role of lipid metabolism in disease pathogenesis.
Disclosures: The researchers reported no funding and no conflicts of interest.
Source: Medicine