Associations of Mitochondrial Variants With Lipidomic Traits in a Chinese Cohort With Coronary Artery Disease

Zixian Wang,Xiaoping Chen,Min Qin,Ying Zhang,Chen Liu,Shilong Zhong,Weihua Lai,Xiaojuan Zhang,Qilin Ma,Hui Chen

doi:10.3389/fgene.2021.630359

Abstract

Plasma lipids have been at the center stage of the prediction and prevention strategies for cardiovascular diseases (CVDs), and novel lipidomic traits have been recognized as reliable biomarkers for CVD risk prediction. The mitochondria serve as energy supply sites for cells and can synthesize a variety of lipids autonomously. Therefore, investigating the relationships between mitochondrial single nucleotide polymorphism (SNPs) and plasma lipidomic traits is meaningful. Here, we enrolled a total of 1,409 Han Chinese patients with coronary artery disease from three centers and performed linear regression analyses on the SNPs of mitochondrial DNA (mtDNA) and lipidomic traits in two independent groups. Sex, age, aspartate aminotransferase, estimated glomerular filtration rate, antihypertensive drugs, hypertension, and diabetes were adjusted. We identified three associations, namely, D-loopm.16089T>C with TG(50:4) NL-16:0, D-loopm.16145G>A with TG(54:5) NL-18:0, and D-loopm.16089T>C with PC(16:0_16:1) at the statistically significant threshold of FDR < 0.05. Then, we explored the relationships between mitochondrial genetic variants and traditional lipids, including triglyceride, total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and high-density lipoprotein cholesterol. Two significant associations were found, namely MT-ND6m.14178T>C with TC and D-loopm.215A>G with LDLC. Furthermore, we performed linear regression analysis to determine on the SNPs of mtDNA and left ventricular ejection fraction (LVEF) and found that the SNP D-loopm.16145G>A was nominally significantly associated with LVEF (P = 0.047). Our findings provide insights into the lipidomic context of mtDNA variations and highlight the importance of studying mitochondrial genetic variants related to lipid species.

Highlights

Coronary artery disease (CAD) is one of the greatest threats to human health (Virani et al, 2020)
We explored the effects of mitochondrial genetic variants on heart function by using linear regression to analyze the variations in mitochondrial DNA (mtDNA) with left ventricular ejection fraction (LVEF)
We performed linear regression to identify the relationships of the single nucleotide polymorphism (SNP) of mtDNA with traditional lipids, and heart function to explore the influence of mitochondrial genetic variants with clinical manifestations

Summary

Introduction

Coronary artery disease (CAD) is one of the greatest threats to human health (Virani et al, 2020). Lipidomic traits can be used independently in predicting long-term CVD risk and adverse clinical outcome. The application of lipidomic traits for risk prediction is more comprehensive than traditional lipids, namely triglycerides (TRIG), total cholesterol (TC), low-density lipoprotein (LDLC), and high-density lipoprotein cholesterol (HDLC) (Razquin et al, 2018; Cadby et al, 2020; Poss et al, 2020). Human mitochondrial DNA (mtDNA) is in a circular double-stranded state and approximately 16.5 kb in length and encodes 37 genes (Sobenin et al, 2012). The sequences outside the D-loop region are all exons and encode genes, and mtDNA mutations are more likely to occur in the coding region than autosomal DNA mutations and directly affect the physiological functions of the genes encoded by them. Identifying the associations between mitochondrial genetic patterns and lipid species can provide a deeper understanding of lipid metabolism and its biological links to clinical features and disease progression

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