Angiotensin-converting enzyme insertion/deletion gene polymorphism and the progression of cerebral microbleeds

Cindy W Yoon; Jonguk Kim; Young Ju Suh; Byeong C Kim; Young Chul Youn; Jee Hyang Jeong; Hyun Jeong Han; Seong Hye Choi

doi:10.3389/fneur.2023.1230141

Angiotensin-converting enzyme insertion/deletion gene polymorphism and the progression of cerebral microbleeds

Front Neurol. 2023 Oct 12:14:1230141. doi: 10.3389/fneur.2023.1230141. eCollection 2023.

Authors

Cindy W Yoon¹, Jonguk Kim¹, Young Ju Suh², Byeong C Kim³, Young Chul Youn⁴, Jee Hyang Jeong⁵, Hyun Jeong Han⁶, Seong Hye Choi¹

Affiliations

¹ Department of Neurology, Inha University School of Medicine, Incheon, Republic of Korea.
² Department of Biomedical Sciences, Inha University School of Medicine, Incheon, Republic of Korea.
³ Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
⁴ Department of Neurology, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
⁵ Department of Neurology, Ewha Womans University School of Medicine, Seoul, Republic of Korea.
⁶ Department of Neurology, Myongji Hospital, Hanyang University College of Medicine, Goyang, Republic of Korea.

Abstract

Background and purpose: The angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been studied as a genetic candidate for cerebral small vessel disease (CSVD). However, no previous study has evaluated the relationship between the ACE I/D polymorphism and cerebral microbleed (CMB), an important CSVD marker. We evaluated the association between ACE I/D polymorphisms and 2-year changes in CMBs.

Methods: The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Of 256 subjects, 186 participants who underwent a 2-year follow-up brain scan and ACE genotyping were included. Our analysis was conducted by dividing the ACE genotype into two groups (DD vs. ID/II) under the assumption of the recessive effects of the D allele. A linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between the DD and combined ID/II genotypes.

Results: Among 186 patients included in this study, 24 (12.9%) had the DD genotype, 91 (48.9%) had the ID genotype, and 71 (38.2%) had the II genotype. Baseline clinical characteristics and cerebral small vessel disease markers were not different between the two groups (DD vs. ID/II) except for the prevalence of hypertension (DD 66.7% vs. ID/II 84.6%; p = 0.04). A multivariate linear mixed-effects model showed that the DD carriers had a greater increase in total CMB counts than the ID/II carriers after adjusting for the baseline number of CMBs, age, sex, and hypertension (estimated mean of difference [standard error (SE)] = 1.33 [0.61]; p = 0.03). When we performed an analysis of cases divided into deep and lobar CMBs, only lobar CMBs were significantly different between the two groups (estimated mean of difference [SE] = 0.94 [0.42]; p = 0.02).

Conclusion: The progression of CMBs over 2 years was greater in the ACE DD carriers compared with the combined II/ID carriers. The results of our study indicate a possible association between the ACE I/D polymorphism and CMB. A study with a larger sample size is needed to confirm this association.

Keywords: angiotensin-converting enzyme; cerebral microbleeds (CMB); cerebral small vessel disease (CSVD); insertion/deletion polymorphism; polymorphism.

Grants and funding

This study was supported by grants from the National Research Council of Science and Technology (NST) Aging Convergence Research Center (CRC22011-600), the Institute of Information and Communications Technology Planning and Evaluation (IITP) (2022-0-00448), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRF-2020M3E5D2A01084721) funded by the Ministry of Science and ICT, Republic of Korea, from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and Korea Dementia Research Center (KDRC) funded by the Ministry of Health and Welfare and Ministry of Science and ICT, Republic of Korea (HU21C0016), and from Inha University and the Korea Otsuka Pharmaceutical Company. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.