Citrullinated and MMP-degraded vimentin is associated with chronic pulmonary diseases and genetic variants in PADI3/PADI4 and CFH in postmenopausal women

Abstract

Citrullinated vimentin has been linked to several chronic and autoimmune diseases, but how citrullinated vimentin is associated with disease prevalence and genetic variants in a clinical setting remains unknown. The aim of this study was to obtain a better understanding of the genetic variants and pathologies associated with citrullinated and MMP-degraded vimentin. Patient Registry data, serum samples and genotypes were collected for a total of 4369 Danish post-menopausal women enrolled in the Prospective Epidemiologic and Risk Factor study (PERF). Circulating citrullinated and MMP-degraded vimentin (VICM) was measured. Genome-wide association studies (GWAS) and phenome wide association studies (PheWAS) with levels of VICM were performed. High levels of VICM were significantly associated with the prevalence of chronic pulmonary diseases and death from respiratory and cardiovascular diseases (CVD). GWAS identified 33 single nucleotide polymorphisms (SNPs) with a significant association with VICM. These variants were in the peptidylarginine deiminase 3/4 (PADI3/PADI4) and Complement Factor H (CFH)/KCNT2 gene loci on chromosome 1. Serum levels of VICM, a marker of citrullinated and MMP-degraded vimentin, were associated with chronic pulmonary diseases and genetic variance in PADI3/PADI4 and CFH/ KCNT2. This points to the potential for VICM to be used as an activity marker of both citrullination and inflammation, identifying responders to targeted treatment and patients likely to experience disease progression.

Figure 1

Association of pre-baseline disease phenotypes with baseline VICM levels identifies a significant relationship between high levels of VICM and chronic pulmonary disease.

Figure 2

Estimated hazard ratios of all-cause mortality by levels of VICM, cause-specific hazard ratios of death due to respiratory disease, CVD, and cancer by levels of VICM. Blue lines are adjusted for age and red lines are adjusted for age, smoking and BMI. Specific hazards can be seen in Supplementary Table S3.

Figure 3

GWAS analysis identifies that VICM levels are associated with genetic variances in PADI3/ PADI4 and CFH/ KCNT2 loci. PADI3/4 peptidylarginine deiminase 3/4, CFH complement factor H, KCNT2 potassium sodium-activated channel subfamily T member 2.