Causal associations between CD40/CD40L and aortic diseases: A mendelian randomization study

Abstract

Background: CD40 and CD40L have been reported as associated with aortic dissection (AD) and aortic aneurysm (AA), but the causality of the associations has not been established yet.Methods: We conducted a two-sample Mendelian randomization (MR) study to assess the causal inference between CD40/CD40L and aortic diseases including AD and AA. The instrumental variables (IVs) for CD40 and CD40L were selected from a high-quality protein quantitative trait loci dataset released by a genomic study involving 30,931 individuals of European ancestry. The genome-wide association studies summary statistics for AD and AA were from the FinnGen Release 7, with 288638 controls for all outcomes of interests, 680 cases for AD and 6,092 cases for AA, also from European ancestry. For AA subtypes, there were 5,881 cases of thoracic AA (TAA) and 2,434 cases of abdominal AA (AAA) respectively. Inverse-variance weighted and Wald ratio were applied for calculating causal estimates. Horizontal pleiotropy and heterogeneity were assessed using MR-Egger regression analysis and Cochran Q test, respectively. Leave-one-out analyses were further performed.Results: Three single-nucleotide polymorphisms (SNPs) for CD40 and one SNP for CD40L were selected as IVs. We found genetic proxied CD40 levels inversely associated with the risk of AD (odds ratio [OR]: 0.777, 95% confidence interval [CI]: 0.618–0.978, p = 0.031) and AA (OR: 0.905, 95% CI: 0.837–0.978, p = 0.012), consistent across TAA (both p < 0.050). There were trends of increased risks of AD and AA in the presence of CD40L while not reaching statistical significance. No significant horizontal pleiotropy or heterogeneity was observed.Conclusion: Our MR study provides evidence supporting the causal association between CD40 and the reduced risks of both AD and AA.

Pathogenesis and management of abdominal aortic aneurysm

“… 43 Multiple Mendelian randomization analyses suggest causative roles for raised LDL-C and lipoprotein(a) and reduced high-density lipoprotein cholesterol (HDL-C) in AAA pathogenesis. 45 , 73 , 74 Mendelian randomization analyses also suggest causal roles for high pulse pressure 75 and diastolic blood pressure, 45 smoking initiation and heaviness, 45 and the CD40 inflammatory pathway, 76 but not raised systolic blood pressure 45 or C-reactive protein 77 in AAA. Counterintuitively, increased IL-1 signaling has been suggested to increase the risk of AAA, possibly by stimulating an increase in LDL-C which may in part explain the lack of benefit of IL-1 blocking antibody in a small trial in AAA participants (ClinicalTrials.gov Identifier: NCT02007252).…”

“… 120 , 121 A Mendelian randomization analysis found genetic predicted CD40 levels were inversely associated with AAA (OR 0.91, 95% CI 0.84, 0.98). 76 Thus, blocking inflammation has been proposed as a treatment to limit AAA growth. There are however multiple challenges to targeting inflammation as a treatment for AAA.…”

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

“…In the context of GWAS, various SNPs have been discovered to be associated with either a decreased or elevated risk of ATAA progression. In addition, several novel genes, including CD40 [ 36 ], ESR1 [ 233 ], COQB1 [ 109 ], ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4) , and GLRX [ 33 ] have been identified in the context of ATAA.…”