Longyi Zheng,1,* Chengjing Zhang,2,* Shichang Bu,1,* Wencheng Guo,3,* Tongtong Li,4 Ying Xu,5 Yunan Liu,4 Caimei Yuan,4 Chengwu Feng,4 Geng Zong,4 Jingwen Zhu,4 Maoying Xing,5 Xin Geng5 

1Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Nutrition, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 3Department of General Surgery and Vascular Surgery, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China; 5National Center for Liver Cancer, Naval Medical University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Maoying Xing; Xin Geng, Email xmyxing@sina.com; gxouc@hotmail.com

Background: Neuregulin 4 (NRG4) was known to be associated with serum lipid levels and atherosclerosis. However, it is unknown whether the role of NRG4 in lipid homeostasis is causal to atherosclerosis and whether the effect is beneficial across different atherosclerosis subtypes.
Methods: We investigated the causal role of the levels of serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides regulated by NRG4 in subtypes of atherosclerosis through two sample Mendelian randomization. Aggregated genome-wide association study (GWAS) summary data for serum lipid level of 1.32 million individuals with European ancestry were obtained from the Global Lipids Genetics Consortium. GWAS summary data for four atherosclerosis subtypes (peripheral, coronary, cerebral and the other atherosclerosis) were obtained from FinnGen Consortium. Generalized inverse-variance–weighted Mendelian randomization and several sensitivity analyses were used to obtain the causal estimates.
Results: A 1-SD genetically elevated LDL-C level mediated by NRG4 was validated to be nominally associated with the risk of peripheral atherosclerosis (log (odds ratio)= 4.14, 95% confidence interval 0.11 to 8.17, P = 0.04), and the other associations were not significant or could not be validated by sensitivity analyses.
Conclusion: LDL-C lowering mediated by NRG4 is likely to prevent peripheral atherosclerosis.

Keywords: Mendelian randomization analysis, NRG4, atherosclerosis, lipid