# Anti–early antigen Epstein-Barr virus titer and atherosclerosis in relation to vascular endothelial growth factor (VEGF) polymorphism rs3025039 among older Japanese individuals

## TL;DR

This study found that higher levels of an antibody linked to active Epstein-Barr virus infection are associated with atherosclerosis, but only in people with a specific genetic variant.

## Contribution

The study reveals a genetic factor influencing the link between Epstein-Barr virus and atherosclerosis, introducing a new concept in understanding viral infection-related cardiovascular disease.

## Key findings

- Higher EBV EA-IgG titer was linked to atherosclerosis only in individuals with the VEGF rs3025039 CC genotype.
- The association between EBV EA-IgG titer and atherosclerosis was stronger in rs3025039 (T) allele carriers.
- A significant interaction was found between rs3025039 genotype and EBV EA-IgG titer in relation to atherosclerosis.

## Abstract

Epstein-Barr (EB) virus infection stimulates the production of vascular endothelial growth factor (VEGF), which contributes to the progression of angiogenesis. Angiogenesis plays an important role in the development of atherosclerosis. Since serum anti-early antigen EB virus IgG (EBV EA-IgG) titer is a sign of active EB virus infection, EBV EA-IgG titer could be associated with atherosclerosis. The number of minor (T) alleles in VEGF polymorphism rs3025039 has been reported to be inversely associated with serum VEGF concentration, suggesting that rs3025039 might have a strong influence on the association between EBV EA-IgG titer and atherosclerosis. By focusing on the role of VEGF in the development of atherosclerosis, this study aimed to investigate the association between active EB virus infection and atherosclerosis.

A cross-sectional study of 2,661 older Japanese individuals aged 60–89 years who participated in annual health check-ups during 2017–2019 was conducted. Logistic regression was used to evaluate the association between EBV EA-IgG titer and atherosclerosis in relation to rs3025039 genotype. The influence of rs3025039 (T) allele carrier status on the association between EBV EA-IgG titer and atherosclerosis was also evaluated by using logistic regression.

Among rs3025039 CC-homozygotes, with the lowest EBV EA-IgG titer tertile as the reference, the multivariable odds ratio (95% confidence interval) was 1.11 (0.82, 1.50) for the medium tertile and 1.07 (0.78, 1.47) for the high tertile. Among rs3025039 (T) allele carriers, the corresponding values were 1.44 (0.88, 2.36) and 1.88 (1.15, 3.05), respectively. There was a significant interaction between rs3025039 (T) allele carrier status and the association between EBV EA-IgG titer and atherosclerosis (adjusted p = 0.0497).

EBV EA-IgG titer was significantly positively associated with atherosclerosis only among participants who are genetically less likely to have progressive angiogenesis. An angiogenesis-related genetic factor was revealed as a determinant of the association between EBV EA-IgG titer and atherosclerosis. These findings introduce a novel concept that could explain the association between viral infection and atherosclerosis.