A variant in the fibronectin (FN1) gene, rs1250229-T, is associated with decreased risk of coronary artery disease in familial hypercholesterolaemia

Michael M Page; Katrina L Ellis; Dick C Chan; Jing Pang; Amanda J Hooper; Damon A Bell; John R Burnett; Eric K Moses; Gerald F Watts

doi:10.1016/j.jacl.2022.05.065

A variant in the fibronectin (FN1) gene, rs1250229-T, is associated with decreased risk of coronary artery disease in familial hypercholesterolaemia

J Clin Lipidol. 2022 Jul-Aug;16(4):525-529. doi: 10.1016/j.jacl.2022.05.065. Epub 2022 May 20.

Authors

Michael M Page¹, Katrina L Ellis², Dick C Chan³, Jing Pang³, Amanda J Hooper⁴, Damon A Bell⁵, John R Burnett⁶, Eric K Moses⁷, Gerald F Watts⁸

Affiliations

¹ School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts); Department of Clinical Biochemistry, Western Diagnostic Pathology, Perth, Australia (Dr Page).
² School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts); School of Population and Global Health, The University of Western Australia, Perth, Australia (Dr Ellis).
³ School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts).
⁴ School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts); Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital, Perth, Australia (Drs Hooper, Bell, and Burnett).
⁵ School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts); Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia (Drs Bell, Burnett, and Watts); Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital, Perth, Australia (Drs Hooper, Bell, and Burnett); Department of Clinical Biochemistry, Clinipath Pathology, Perth, Australia (Dr Bell).
⁶ School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts); Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia (Drs Bell, Burnett, and Watts); Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital, Perth, Australia (Drs Hooper, Bell, and Burnett).
⁷ Menzies Institute for Medical Research, The University of Tasmania, Hobart, Australia (Dr Moses).
⁸ School of Medicine, Faculty of Medicine and Health Sciences, The University of Western Australia, Perth, Australia (Drs Page, Ellis, Chan, Pang, Hooper, Bell, Burnett, and Watts); Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia (Drs Bell, Burnett, and Watts). Electronic address: gerald.watts@uwa.edu.au.

PMID: 35739058
DOI: 10.1016/j.jacl.2022.05.065

Abstract

Background: Increased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion.

Objective: We investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH.

Methods: We collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses.

Results: In patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353; 95% confidence interval [CI] 0.193 - 0.647; P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200; 95% CI 0.091 - 0.441; P < 0.001).

Conclusion: The FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH.

Keywords: Cardiovascular risk prediction; Coronary artery disease; Familial hypercholesterolaemia; Fibronectin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Coronary Artery Disease* / complications
Fibronectins / genetics*
Genome-Wide Association Study
Humans
Hyperlipoproteinemia Type II* / complications
Hyperlipoproteinemia Type II* / genetics
Lipoprotein(a) / genetics
Risk Factors

Substances

FN1 protein, human
Fibronectins
Lipoprotein(a)