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From the Journals

Cardiovascular Genes Linked to Psoriasis Risk

Genetic markers for heart disease surprisingly linked to 22% higher psoriasis risk, challenging conventional understanding of their relationship.

Conexiant

A genetic association study found that genetic predictors of cardiovascular disease may be associated with an increased risk of psoriasis, but not vice versa.

In the study, published in JAMA Cardiology, investigators analyzed genetic data from approximately 3.4 million individuals, including 181,249 cases of coronary artery disease (CAD), 110,182 cases of stroke, and 36,466 cases of psoriasis.

They utilized Mendelian randomization techniques two-sample Mendelian randomization (MR) analyses using summary-level data from large-scale genome-wide association meta-analysis studies (GWAS) for each trait. The analysis focused on individuals of European descent from GWAS meta-analyses involving CAD, stroke, psoriasis, and nine other IMDs.

Genetic instruments used in the study included 109 independent variants for psoriasis, 241 independent variants for CAD, and 47 independent variants for stroke. These instruments were derived from genome-wide significant variants (P < 5 × 10^–8) from respective GWAS meta-analyses.

The primary statistical method for evaluating MR effects was the inverse-variance weighted (IVW) MR. Sensitivity analyses, including MR-Egger, simple median, weighted median, MR-Steiger, MR-Lasso, and MR-PRESSO, were performed to address potential biases and violations of MR assumptions.

Among the study's key findings were:

  • Genetic predictors of CAD were associated with increased psoriasis risk (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 1.04–1.10, P = .003).
  • Genetic predictors of stroke were also associated with increased psoriasis risk (OR = 1.22, 95% CI = 1.05–1.41, P = .01).
  • No significant associations were found between genetic predictors of psoriasis and risk of CAD (OR = 1.01, 95% CI = 0.99–1.03, P = .12) or stroke (OR = 1.00, 95% CI = 0.98–1.02, P = .77).
  • The associations remained significant after adjusting for key confounding factors, including body mass index, waist-to-hip ratio, smoking, blood pressure, hemoglobin A1c, total cholesterol, triglycerides, and low-density lipoprotein cholesterol.
  • No risk-increasing associations were observed between genetic predictors of cardiovascular disease and other common immune-mediated diseases (IMD) such as rheumatoid arthritis and inflammatory bowel disease (IBS).

Additional statistical data from the study included:

  • MR-Steiger directionality testing confirmed statistically significant risk-increasing MR associations for genetic predictors of CAD on psoriasis (P = 1 × 10^–27) and genetic predictors of stroke on psoriasis (P = 1 × 10^–32).
  • In multivariable MR, adjusting for stroke rendered the associations of genetically predicted CAD with psoriasis risk nonsignificant (OR = 1.04, 95% CI = 0.98–1.09, P = .21), and vice versa (OR = 1.14, 95% CI = 0.97–1.35, P = .12).
  • The CAD IVW estimate after inclusion of all key confounders remained significant (OR = 1.06, 95% CI = 1.01–1.11, P = .02), as did the stroke IVW estimate (OR = 1.17, 95% CI = 1.05–1.29, P = .02).

One-sample MR analyses using individual-level data from the UK Biobank (n = 336,806) revealed:

  • The association between genetic predictors of CAD and psoriasis risk was not statistically significant (IVW OR = 1.04, 95% CI = 0.95–1.14, P = .40).
  • The association between genetic predictors of stroke and psoriasis risk was statistically significant (IVW OR = 1.27, 95% CI = 1.06–1.50, P = .03).
  • No statistically significant differences in CAD or stroke MR effects on psoriasis were observed in sex-stratified or HLA-C*06:02-stratified subgroups.
  • Cardiovascular MR effects on psoriasis were not stronger in participants taking β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aspirin, or statins, compared with those who did not take these medications.

The study also investigated the association of genetic predictors of CAD and stroke with none other IMDs, including acne (20,165 cases and 595,231 controls), atopic dermatitis (60,653 cases and 804,329 controls), asthma (19,954 cases and 107,715 controls), celiac disease (4,533 cases and 10,750 controls), Crohn's disease (40,266 cases and 28,072 controls), IBS (59,957 cases and 34,915 controls), multiple sclerosis (47,429 cases and 68,374 controls), rheumatoid arthritis (29,880 cases and 73,758 controls), and ulcerative colitis (33,609 cases and 45,975 controls). No risk-increasing associations were observed for these IMDs.

The investigators noted that their findings challenged two prevailing concepts regarding the link between psoriasis and cardiovascular disease: the notion that the strong association is primarily attributable to the high prevalence of cardiovascular risk factors in psoriasis and the common belief that inflammation from psoriasis exerts a systemic inflammatory effect that predisposes patients with psoriasis to cardiovascular disease.

Limitations of the study included the inability to empirically prove that the second and third instrumental variable assumptions were not violated in MR analyses and potential underpowered analyses for detecting smaller effect sizes between genetic predictors of cardiovascular disease and some common IMDs.

A full conflict of interest disclosures can be found in the study.