Journal of Shandong University (Health Sciences) ›› 2024, Vol. 62 ›› Issue (5): 54-63.doi: 10.6040/j.issn.1671-7554.0.2024.0159

• Precision medicine in chronic airway diseases—Clinical Research • Previous Articles    

Genetic association of lipids and lipid-lowering drugs with chronic obstructive pulmonary disease based on Mendelian randomization

WU Tong, YANG Jingyu, LIN Dang, XU Wanru, ZENG Yujun   

  1. Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215000, Jiangsu, China
  • Published:2024-05-29

PDF (PC)

64

Abstract: Objective To explore the causal role of lipid traits in chronic obstructive pulmonary disease(COPD)from a genetic perspective and to evaluate the potential impact of lipid-lowering medication targets on COPD by using Mendelian randomization(MR)analysis. Methods Genetic variants associated with lipid traits and genetic variants coding for lipid-lowering drug targets were extracted from The Global Lipids Genetics Consortium(GLGC)and the Expressed Quantitative Trait Loci Genome Consortium(eQTLGen Consortium). Lipid traits and lipid-lowering drug targets were extracted from GLGC and eQTLGen Consortium as exposure variables, and COPD was derived from the FinnGen database(https://www.finngen.fi/en)as the outcome variable. Single nucleotide polymorphism(SNP)strongly associated with the exposure variables were used as instrumental variables, and the inverse variance weighted(IVW)was used as the main method to explore the the causal role of lipid traits in COPD and the potential effects of lipid-lowering drug targets on COPD, MR-Egger regression and the weighted median was used as complementary evidence to the IVW results. A Leave-one-out sensitivity analysis was used to explore the effect of individual SNP on the results of IVW analysis, while the intercept of MR-Egger method and Cochrans Q test for horizontal multiplicity and heterogeneity were used to ensure the stability of the results, and funnel plots were used to analyze the potential biases of the study results. For the drug target CETP that reached COPD risk significance, co-localization analysis was used to test the exclusion restriction hypothesis. Results IVW analysis results indicated that increased genetic levels of LDL-C(OR=1.077, 95%CI: 1.001-1.159, P=0.046)and TC(OR=1.088, 95%CI: 1.002-1.181, P=0.044)were associated with an increased risk of COPD. Increased genetic levels of CETP were associated with an increased risk of COPD(OR=1.179, 95%CI: 1.052-1.321, P=0.004). MR-Egger regression, Cochrans Q test, and leave-one-out analysis suggested that the findings were reliable and robust. Conclusion Dyslipidemia is a causative factor in COPD. Increased levels of LDL-C and TC are associated with the pathogenesis of COPD. Among the three lipid-lowering drug targets, CETP is a promising candidate drug target for COPD.

Key words: Mendelian randomization, Statin drugs, Total cholesterol, Triglycerides, Low-density lipoprotein, High-density lipoprotein

CLC Number: 

  • R563
[1] Christenson SA, Smith BM, Bafadhel M, et al. Chronic obstructive pulmonary disease[J]. Lancet, 2022, 399(10342): 2227-2242.
[2] Shen YC, Yang T, Guo SJ, et al. Increased serum ox-LDL levels correlated with lung function, inflammation, and oxidative stress in COPD[J]. Mediators Inflamm, 2013, 2013: 972347. doi:10.1155/2013/972347.
[3] Xue XM, Cai HY, Chai Z, et al. Efficacy of statin therapy in chronic obstructive pulmonary disease: a systematic review and meta-analysis from 2008-2019[J]. Panminerva Med, 2023, 65(3): 376-384.
[4] Walker VM, Davey Smith G, Davies NM, et al. Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities[J]. Int J Epidemiol, 2017, 46(6): 2078-2089.
[5] Schmidt AF, Finan C, Gordillo-Marañón M, et al. Genetic drug target validation using Mendelian randomisation[J]. Nat Commun, 2020, 11(1): 3255. doi:10.1038/s41467-020-16969-0.
[6] Williams DM, Finan C, Schmidt AF, et al. Lipid lowering and Alzheimer disease risk: a Mendelian randomization study[J]. Ann Neurol, 2020, 87(1): 30-39.
[7] Yarmolinsky J, Bull CJ, Vincent EE, et al. Association between genetically proxied inhibition of HMG-CoA reductase and epithelial ovarian cancer[J]. JAMA, 2020, 323(7): 646-655.
[8] Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and refinement of loci associated with lipid levels[J]. Nat Genet, 2013, 45(11): 1274-1283.
[9] Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508-518.
[10] Võsa U, Claringbould A, Westra HJ, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression[J]. Nat Genet, 2021, 53(9): 1300-1310.
[11] Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology[J]. Stat Med, 2008, 27(8): 1133-1163.
[12] Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement[J]. JAMA, 2021, 326(16): 1614-1621.
[13] Berberich AJ, Hegele RA. A modern approach to dyslipidemia[J]. Endocr Rev, 2022, 43(4): 611-653.
[14] Arvanitis M, Lowenstein CJ. Dyslipidemia[J]. Ann Intern Med, 2023, 176(6): ITC81-ITC96.
[15] 王晶,张国燕,程杉.孟德尔随机化的良好实践—孟德尔随机化分析的常见设计、关键挑战及优化[J]. 首都医科大学学报, 2023, 44(6): 1087-1094. WANG Jing, ZHANG Guoyan, CHENG Shan. Good practices in Mendelian randomization: common designs, key challenges, and optimization in Mendelian randomization analysis [J]. Journal of Capital Medical University, 2023, 44(6): 1087-1094.
[16] Yin KJ, Huang JX, Wang P, et al. No genetic causal association between periodontitis and arthritis: a bidirectional two-sample Mendelian randomization analysis[J]. Front Immunol, 2022, 13: 808832. doi:10.3389/fimmu.2022.808832.
[17] Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method[J]. Eur J Epidemiol, 2017, 32(5): 377-389.
[18] Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics[J]. PLoS Genet, 2014, 10(5): e1004383. doi:10.1371/journal.pgen.1004383.
[19] Zuber V, Grinberg NF, Gill D, et al. Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches[J]. Am J Hum Genet, 2022, 109(5): 767-782.
[20] Butler LM, Perone Y, Dehairs J, et al. Lipids and cancer: emerging roles in pathogenesis, diagnosis and therapeutic intervention[J]. Adv Drug Deliv Rev, 2020, 159: 245-293. doi:10.1016/j.addr.2020.07.013.
[21] Li HC, Feng ZY, He ML. Lipid metabolism alteration contributes to and maintains the properties of cancer stem cells[J]. Theranostics, 2020, 10(16): 7053-7069.
[22] Agudelo CW, Samaha G, Garcia-Arcos I. Alveolar lipids in pulmonary disease. A review[J]. Lipids Health Dis, 2020, 19(1): 122. doi:10.1186/s12944-020-01278-8.
[23] Suryadevara V, Ramchandran R, Kamp DW, et al. Lipid mediators regulate pulmonary fibrosis: potential mechanisms and signaling pathways[J]. Int J Mol Sci, 2020, 21(12): 4257. doi:10.3390/ijms21124257.
[24] Kotlyarov S, Kotlyarova A. Anti-inflammatory function of fatty acids and involvement of their metabolites in the resolution of inflammation in chronic obstructive pulmonary disease[J]. Int J Mol Sci, 2021, 22(23): 12803. doi:10.3390/ijms222312803.
[25] Wang YX, Xia SY. Relationship between ACSL4-mediated ferroptosis and chronic obstructive pulmonary disease[J]. Int J Chron Obstruct Pulmon Dis, 2023, 18: 99-111. doi:10.2147/COPD.S391129.
[26] Can U, Yerlikaya FH, Yosunkaya S. Role of oxidative stress and serum lipid levels in stable chronic obstructive pulmonary disease[J]. J Chin Med Assoc, 2015, 78(12): 702-708.
[27] Reed RM, Iacono A, DeFilippis A, et al. Advanced chronic obstructive pulmonary disease is associated with high levels of high-density lipoprotein cholesterol[J]. J Heart Lung Transplant, 2011, 30(6): 674-678.
[28] Markeli c I, Hlap ci c I, Rogi c D, et al. Lipid profile and atherogenic indices in patients with stable chronic obstructive pulmonary disease[J]. Nutr Metab Cardiovasc Dis, 2021, 31(1): 153-161.
[29] Huang YB, Ding KK, Dai ZC, et al. The relationship of low-density-lipoprotein to lymphocyte ratio with chronic obstructive pulmonary disease[J]. Int J Chron Obstruct Pulmon Dis, 2022, 17: 2175-2185. doi:10.2147/COPD.S369161.
[30] McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease[J]. N Engl J Med, 2011, 365(17): 1567-1575.
[31] 中国胆固醇教育计划(CCEP)工作委员会,中国医疗保健国际交流促进会动脉粥样硬化血栓疾病防治分会,中国老年学和老年医学学会心血管病分会,等.中国胆固醇教育计划调脂治疗降低心血管事件专家建议[J]. 中华内科杂志, 2020, 59(1): 18-22. China Cholesterol Education Program(CCEP)Working Committee, Atherosclerosis Thrombosis Prevention and Control Subcommittee of Chinese International Exchange and Promotion Association for Medical and Healthcare, Cardiovascular Disease Subcommittee of China Association of Gerontology and Geriatrics, et al. China cholesterol education program(CCEP)expert advice for the management of dyslipidaemias to reduce cardiovascular risk(2019)[J]. Chinese Journal of Internal Medicine, 2020, 59(1): 18-22.
[32] Liu DJ, Peloso GM, Yu HJ, et al. Exome-wide association study of plasma lipids in >300, 000 individuals[J]. Nat Genet, 2017, 49(12): 1758-1766.
[33] Hukku A, Pividori M, Luca F, et al. Probabilistic colocalization of genetic variants from complex and molecular traits: promise and limitations[J]. Am J Hum Genet, 2021, 108(1): 25-35.
[34] Li ZA, Zhang B, Liu QR, et al. Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease[J]. EBioMedicine, 2023, 90: 104543. doi:10.1016/j.ebiom.2023.104543.
[35] Holmes MV, Richardson TG, Ference BA, et al. Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development[J]. Nat Rev Cardiol, 2021, 18(6): 435-453.
[1] ZHANG Nana, ZHAO Yiming, LIU Xinmin. Causal relationship between uterine leiomyomas and breast cancer: a two-sample Mendelian randomization study [J]. Journal of Shandong University (Health Sciences), 2023, 61(8): 86-93.
[2] ZHANG Tianxin, ZHANG Ting, HUANG Xin, HAN Jiayi, WANG Shukang. A mendelian randomization analysis on the causal associations between amino acids and type 2 diabetes [J]. Journal of Shandong University (Health Sciences), 2023, 61(5): 102-107.
[3] CHANG Xin, LIU Shijia, HAN Lu. A Mendelian randomization study of aspirin use and the risk of endometrial cancer [J]. Journal of Shandong University (Health Sciences), 2023, 61(10): 58-62.
[4] WU Hong, ZHANG Zhengduo, TANG Yanjin, QI Shaojun, GAO Xibao. Potential intervention effects of 5-methyltetrahydrofolate on atherosclerosis in rats [J]. Journal of Shandong University (Health Sciences), 2022, 60(8): 6-13.
[5] ZHANG Kai, SI Shucheng, LI Jiqing, LIU Xiaowen, ZHAO Yingqi, XUE Fuzhong. Mendelian randomization study of sleep phenotypes and irritable bowel syndrome [J]. Journal of Shandong University (Health Sciences), 2022, 60(8): 109-114.
[6] ZHAO Meiru, ZHU Di, LIU Lin, GUAN Qingbo, ZHANG Xu. Association of 4 simple insulin resistance indicators with the risk of hyperuricemia in 698 patients with type 2 diabetes mellitus [J]. Journal of Shandong University (Health Sciences), 2022, 60(12): 44-51.
[7] YANG Xuan, LI Yanzhi, MA Wei, JIA Chongqi. Causal influence of lung function on risk of fatality of COVID-19: a two-sample Mendelian randomization study [J]. Journal of Shandong University (Health Sciences), 2021, 59(7): 104-111.
[8] FU Jieqi, ZHANG Man, ZHANG Xiaolu, LI Hui, CHEN Hong. Molecular mechanism of Toll-like receptor 4 in the aggravation of blood lipid accumulation by inhibiting the peroxisome proliferator-activate receptor γ [J]. Journal of Shandong University (Health Sciences), 2020, 1(7): 24-31.
[9] XU Yuxiang, LIU Yudong, ZHANG Peng, DUAN Ruisheng. A retrospective analysis of risk factors of cerebral microbleeds in 101 patients with cerebral small vessel disease [J]. Journal of Shandong University (Health Sciences), 2020, 1(7): 67-71.
[10] LI Yunxia, LI Hongkai, MA Yuntao, YU Yuanyuan, SUN Xiaoru, LIU Xinhui, SI Shucheng, HOU Lei, YUAN Tonghui, LIU Lu, LI Wenchao, XUE Fuzhong, LIU Yanxun. Causal association between height and risk of coronary heart disease: a two-sample Mendelian randomization analysis [J]. Journal of Shandong University (Health Sciences), 2020, 58(5): 107-114.
[11] TANG Bo, SHAO Jing, CUI Jing, SUN Jianping. A mechanism study on the association of type 2 diabetes and high-density lipoprotein [J]. Journal of Shandong University (Health Sciences), 2020, 58(3): 99-106.
[12] LI Mingzhuo, SUN Xiubin, WANG Chunxia, YANG Yang, LIU Xinhui, LIU Yanxun, XUE Fuzhong, YUAN Zhongshang. Association between longitudinal changes of HDL-C and coronary heart disease in a population with normal serum lipids: a retrospective cohort study [J]. Journal of Shandong University (Health Sciences), 2019, 57(8): 110-116.
[13] LIU Xinhui, LI Hongkai, LI Mingzhuo, YU Yuanyuan, SI Shucheng, HOU Lei, LIU Lu, LI Wenchao, YUAN Tonghui, LI Yunxia, ZHOU Yuchang, XUE Fuzhong. A Mendelian randomization study on the causal relationship between waist circumference and incidence of coronary heart disease [J]. Journal of Shandong University (Health Sciences), 2019, 57(11): 103-109.
[14] WANG Xue, LI Qian, WANG Li, SUN Shuzhen, MA Aihua. CXCL16 gene silencing alleviates injury of mouse podocytes treated with the oxidized low-density lipoprotein [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(6): 16-21.
[15] WANG Chuan1, HOU Xinguo1, LIANG Kai1, YAN Fei1, YANG Junpeng1, WANG Lingshu1, TIAN Meng1, LI Chengqiao2, ZHANG Xiuping3, YANG Weifang4, MA Zeqiang5, CHEN Li1. HDL-C and TG/HDL-C ratio to identify insulin resistance in middle-aged and older Hui ethnic population in Shandong Province [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2014, 52(5): 73-76.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd