Genetic determinants of intracranial large artery stenosis in the northern Manhattan study

Minghua Liu; Sanjeev Sariya; Farid Khasiyev; Giuseppe Tosto; Nicole D Dueker; Ying Kuen Cheung; Clinton B Wright; Ralph L Sacco; Tatjana Rundek; Mitchell S V Elkind; Jose Gutierrez

doi:10.1016/j.jns.2022.120218

Genetic determinants of intracranial large artery stenosis in the northern Manhattan study

J Neurol Sci. 2022 May 15:436:120218. doi: 10.1016/j.jns.2022.120218. Epub 2022 Mar 3.

Authors

Affiliations

¹ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
² Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
³ Department of Neurology, Saint Louis University, Saint Louis, MO, USA.
⁴ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁵ John P. Hussman Institute for Human Genomics, University of Miami, FL, USA.
⁶ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁷ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁸ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, FL, USA.
⁹ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁰ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹¹ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: jg3233@cumc.columbia.edu.

Abstract

Background: Intracranial stenosis is one of the most common causes of stroke worldwide. Several single nucleotide polymorphisms have been associated with intracranial atherosclerosis, which is inferred to be the most common underlying cause of intracranial large artery stenosis (ILAS). We previously reviewed known genetic variants related to ILAS in predominantly Asian cohorts, but their prevalence and role in ILAS among western multiethnic populations are uncertain.

Methods: We leveraged existing imaging and genetic data from the Northern Manhattan Study, a multiethnic prospective cohort study. Based on literature review, we selected adiponectin Q (ADIPOQ) rs2241767 and rs182052, ring finger protein 213 (RNF213) rs112735431, apolipoprotein E (APOE) rs429358, phosphodiesterase 4D (PDE4D) rs2910829, lipoprotein lipase (LPL) rs320, and aldosterone synthase (CYP11B2) rs1799998 variants as candidates to explore. We defined ILAS as luminal stenosis >50% in any intracranial large artery using time-of-flight magnetic resonance angiography (MRA).

Results: We included 1109 participants (mean age 70 ± 9 years, 70% Hispanic, 60% women) in this study. ILAS was identified in 81 (7%) NOMAS participants. Logistic regression analyses adjusted for age, sex, principal components, and vascular risk factors showed ILAS prevalence associated with CYP11B2 rs1799998 under the dominant model (OR = 0.56, 95%CI: 0.35-0.89) and LPL rs320 heterozygote genotype (OR = 1.68, 95%CI: 1.05-2.71). The genotype distributions of ADIPOQ rs2241767 and rs182052, APOE rs429358 and CYP11B2 rs1799998 variants were significantly different among non-Hispanic white and Black, and Hispanic groups. When participants were further stratified by race/ethnicity, the estimates were consistent for CYP11B2 rs1799998 across race/ethnic groups but not for LPL rs320.

Conclusion: The CYP11B2 rs1799998 variant may be a protective genetic factor for ILAS across race/ethnic groups, but the risk of ILAS associated with LPL rs320 varies by race/ethnic group. Further functional studies may help elucidate the role that these variants play in the pathophysiology of ILAS.

Keywords: Aldosterone synthase; Epidemiologic studies; Genetic predisposition to disease; Intracranial large artery stenosis; Lipoprotein lipase.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adenosine Triphosphatases / genetics
Aged
Apolipoproteins E / genetics
Arteries*
Constriction, Pathologic
Cytochrome P-450 CYP11B2* / genetics
Female
Genetic Predisposition to Disease / genetics
Humans
Male
Middle Aged
Prospective Studies
Risk Factors
Ubiquitin-Protein Ligases / genetics

Substances

Apolipoproteins E
Cytochrome P-450 CYP11B2
RNF213 protein, human
Ubiquitin-Protein Ligases
Adenosine Triphosphatases

Abstract

Publication types

MeSH terms

Substances

Grants and funding