Genome sequencing reveals the role of rare genomic variants in Chinese patients with symptomatic intracranial atherosclerotic disease.

Abstract

OBJECTIVES:

The predisposition of intracranial atherosclerotic disease (ICAD) to East Asians over Caucasians infers a genetic basis which, however, remains largely unknown. Higher prevalence of vascular risk factors (VRFs) in Chinese over Caucasian patients who had a stroke, and shared risk factors of ICAD with other stroke subtypes indicate genes related to VRFs and/or other stroke subtypes may also contribute to ICAD.

METHODS:

Unrelated symptomatic patients with ICAD were recruited for genome sequencing (GS, 60-fold). Rare and potentially deleterious single-nucleotide variants (SNVs) and small insertions/deletions (InDels) were detected in genome-wide and correlated to genes related to VRFs and/or other stroke subtypes. Rare aneuploidies, copy number variants (CNVs) and chromosomal structural rearrangements were also investigated. Lastly, candidate genes were used for pathway and gene ontology enrichment analysis.

RESULTS:

Among 92 patients (mean age at stroke onset 61.0±9.3 years), GS identified likely ICAD-associated rare genomic variants in 54.3% (50/92) of patients. Forty-eight patients (52.2%, 48/92) had 59 rare SNVs/InDels reported or predicted to be deleterious in genes related to VRFs and/or other stroke subtypes. None of the 59 rare variants were identified in local subjects without ICAD (n=126). 31 SNVs/InDels were related to conventional VRFs, and 28 were discovered in genes related to other stroke subtypes. Our study also showed that rare CNVs (n=7) and structural rearrangement (a balanced translocation) were potentially related to ICAD in 8.7% (8/92) of patients. Lastly, candidate genes were significantly enriched in pathways related to lipoprotein metabolism and cellular lipid catabolic process.

CONCLUSIONS:

Our GS study suggests a role of rare genomic variants with various variant types contributing to the development of ICAD in Chinese patients.

• Authors: Mengmeng Shi, Xinyi Leng, Ying Li, Zihan Chen, Ye Cao, Tiffany Chung, Bonaventure Ym Ip, Vincent Hl Ip, Yannie Oy Soo, Florence Sy Fan, Sze Ho Ma, Karen Ma, Anne Y Y Chan, Lisa Wc Au, Howan Leung, Alexander Y Lau, Vincent Ct Mok, Kwong Wai Choy, Zirui Dong, Thomas W Leung
• Journal: Stroke and vascular neurology (Stroke Vasc Neurol) Vol. 7 Issue 3 Pg. 182-189 (06 2022) ISSN: 2059-8696 [Electronic] England
• PMID: 34880113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Topics

• Asian People (genetics)
• China (epidemiology)
• Genomics
• Humans
• Intracranial Arteriosclerosis (complications, diagnostic imaging, genetics)
• Stroke (epidemiology)