The prevalence of peripheral arterial disease (PAD) is on the rise globally, leading to adverse clinical outcomes. Our aim was to investigate the causal relationship between apolipoprotein and PAD, as well as the potential mediating role of smoking, diabetes, hypertension, myocardial infarction, and ischemic stroke.
Methods
We employed two-sample Mendelian randomization (TSMR) to assess the causal effect of apoB/A1 on the risk of PAD and potential mediators (smoking, diabetes mellitus, hypertension, myocardial infarction, and ischemic stroke), as well as the causal effect of those mediators on PAD. The use of multivariate MR (MVMR) allowed us to explore and quantify the mediating role of these factors in the causal association between apoB/A1 and the risk of PAD.
Results
Our MR analysis showed that each standard deviation increase in apoB/A1 increased the risk of PAD by 46% (OR = 1.460, 95% CI: 1.255–1.697, P = 8.74E-07). Hypertension, myocardial infarction, and ischemic stroke were ultimately recognized as the mediators of the causal relationship between apoB/A1 and PAD, explaining 7.5%, 19.7%, and 62.5% of the causal effect, respectively, and the proportion combined of the three together was 81%.
Conclusions
These studies demonstrated that elevated apoB/A1 increases the risk of developing PAD and that this association may be mediated by hypertension, myocardial infarction, and ischemic stroke.
FowkesFGAboyansVFowkesFJ, et al.Peripheral artery disease: epidemiology and global perspectives. Nat Rev Cardiol2017; 14(3): 156–170.
2.
CriquiMHAboyansV. Epidemiology of peripheral artery disease. Circ Res2015; 116(9): 1509–1526.
3.
KhanNKhanJLyytikainenLP, et al.Serum apolipoprotein A-I concentration differs in coronary and peripheral artery disease. Scand J Clin Lab Invest2020; 80(5): 370–374.
4.
AboyansVRiccoJBBartelinkMLEL, et al.Editor’s choice - 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS). Eur J Vasc Endovasc Surg2018; 55(3): 305–368.
5.
Tunstall-PedoeHPetersSAEWoodwardM, et al.Twenty-year predictors of peripheral arterial disease compared with coronary heart disease in the scottish heart health extended cohort (SHHEC). J Am Heart Assoc2017; 6(9).
6.
HoekAGVan OortSEldersPJM, et al.Causal association of cardiovascular risk factors and lifestyle behaviors with peripheral artery disease: a mendelian randomization approach. J Am Heart Assoc2022; 11(16): e025644.
7.
OksalaNSeppäläIHernesniemiJ, et al.Complementary prediction of cardiovascular events by estimated apo- and lipoprotein concentrations in the working age population. The Health 2000 Study. Ann Med2013; 45(2): 141–148.
8.
TikkanenEJägerroosVHolmesMV, et al.Metabolic biomarker discovery for risk of peripheral artery disease compared with coronary artery disease: lipoprotein and metabolite profiling of 31 657 individuals from 5 prospective cohorts. J Am Heart Assoc2021; 10(23): e021995.
9.
PanayiotouAGriffinMGeorgiouN, et al.ApoB/ApoA1 ratio and subclinical atherosclerosis. Int Angiol2008; 27(1): 74–80.
10.
LevinMGZuberVWalkerVM, et al.Prioritizing the role of major lipoproteins and subfractions as risk factors for peripheral artery disease. Circulation2021; 144(5): 353–364.
11.
SnidermanADRobinsonJG. ApoB in clinical care: pro and con. Atherosclerosis2019; 282: 169–175.
12.
AdayAWLawlerPRCookNR, et al.Lipoprotein particle profiles, standard lipids, and peripheral artery disease incidence. Circulation2018; 138(21): 2330–2341.
13.
ConteMSBradburyAWKolhP, et al.Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg2019; 69(6s): 3S–125S.
14.
AboyansVRiccoJBBartelinkMLEL, et al.2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries endorsed by: the European stroke organization (ESO)the task force for the diagnosis and treatment of peripheral arterial diseases of the European society of cardiology (ESC) and of the European society for vascular surgery (ESVS). Eur Heart J2018; 39(9): 763–816.
15.
CriquiMHMatsushitaKAboyansV, et al.Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the American heart association. Circulation2021; 144(9): e171–e191.
16.
WalldiusGJungnerI. The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy--a review of the evidence. J Intern Med2006; 259(5): 493–519.
17.
Koren-MoragNGoldbourtUGraffE, et al.Apolipoproteins B and AI and the risk of ischemic cerebrovascular events in patients with pre-existing atherothrombotic disease. J Neurol Sci2008; 270(1–2): 82–87.
18.
Azizzadeh-RoodpishSGarzonMHMainaliS. Classifying single nucleotide polymorphisms in humans. Mol Genet Genom2021; 296(5): 1161–1173.
19.
UffelmannEHuangQQMunungNS, et al.Genome-wide association studies. Nat Rev Methods Primers2021; 1(1): 59.
20.
HemaniGTillingKDavey SmithG. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet2017; 13(11): e1007081.
21.
RichmondRCHemaniGTillingK, et al.Challenges and novel approaches for investigating molecular mediation. Hum Mol Genet2016; 25(R2): R149–R156.
22.
BurgessSThompsonSG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol2015; 181(4): 251–260.
23.
DongHChenWWangX, et al.Apolipoprotein A1, B levels, and their ratio and the risk of a first stroke: a meta-analysis and case-control study. Metab Brain Dis2015; 30(6): 1319–1330.
24.
ForteFCalcaterraILupoliR, et al.Association of apolipoprotein levels with peripheral arterial disease: a meta-analysis of literature studies. Eur J Prev Cardiol2022; 28(18): 1980–1990.
25.
HuangX-WPangS-WZhangT, et al.Assessment of causal associations between obesity and peripheral artery disease: a bidirectional Mendelian randomization study. Front Cardiovasc Med2024; 11: 1332530.
26.
LanGXieMLanJ, et al.Association and mediation between educational attainment and respiratory diseases: a Mendelian randomization study. Respir Res2024; 25(1): 115.
27.
LyonMSAndrewsSJElsworthB, et al.The variant call format provides efficient and robust storage of GWAS summary statistics. Genome Biol2021; 22(1): 32.
28.
SakaueSKanaiMTanigawaY, et al.A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet2021; 53(10): 1415–1424.
29.
DönertaşHMFabianDKValenzuelaMF, et al.Common genetic associations between age-related diseases. Nat Aging2021; 1(4): 400–412.
30.
MalikRChauhanGTraylorM, et al.Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet2018; 50(4): 524–537.
31.
ChoYKwonJ-MKimK-H, et al.Artificial intelligence algorithm for detecting myocardial infarction using six-lead electrocardiography. Sci Rep2020; 10(1): 20495.
32.
EmdinCAKheraAVNatarajanP, et al.Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease. JAMA2017; 317(6): 626–634.
33.
BurgessSSmallDSThompsonSG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res2017; 26(5): 2333–2355.
34.
ShimHChasmanDISmithJD, et al.A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians. Plos One2015; 10(4): e0120758.
35.
BurgessSBowdenJFallT, et al.Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology2017; 28(1): 30–42.
36.
CarterARSandersonEHammertonG, et al.Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol2021; 36(5): 465–478.
37.
BowdenJDavey SmithGBurgessS. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol2015; 44(2): 512–525.
38.
BurgessSThompsonSG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol2017; 32(5): 377–389.
39.
VerbanckMChenCYNealeB, et al.Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet2018; 50(5): 693–698.
40.
Gerhard-HermanMDGornikHLBarrettC, et al.2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. Circulation2017; 135(12): e726–e779.
41.
SelvinEErlingerTP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000. Circulation2004; 110(6): 738–743.
42.
McdermottMMLiuKCriquiMH, et al.Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis. Am J Epidemiol2005; 162(1): 33–41.
43.
AllisonMACushmanMSolomonC, et al.Ethnicity and risk factors for change in the ankle-brachial index: the Multi-Ethnic Study of Atherosclerosis. J Vasc Surg2009; 50(5): 1049–1056.
44.
LevinMGKlarinDAssimesTL, et al.Genetics of smoking and risk of atherosclerotic cardiovascular diseases: a mendelian randomization study. JAMA Netw Open2021; 4(1): e2034461.
45.
LiuLShiZJiX, et al.Adipokines, adiposity, and atherosclerosis. Cell Mol Life Sci2022; 79(5): 272.
46.
HuxleyRRYatsuyaHLutseyPL, et al.Impact of age at smoking initiation, dosage, and time since quitting on cardiovascular disease in african americans and whites: the atherosclerosis risk in communities study. Am J Epidemiol2012; 175(8): 816–826.
47.
DikilitasOSatterfieldBAKulloIJ. Risk factors for polyvascular involvement in patients with peripheral artery disease: a mendelian randomization study. J Am Heart Assoc2020; 9(24): e017740.
48.
TranATSpertusJAMena-HurtadoCI, et al.Association of disease-specific health status with long-term survival in peripheral artery disease. J Am Heart Assoc2022; 11(4): e022232.
49.
JangSYJuEYChoSI, et al.Comparison of cardiovascular risk factors for peripheral artery disease and coronary artery disease in the Korean population. Korean Circ J2013; 43(5): 316–328.
50.
LangloisMRChapmanMJCobbaertC, et al.Quantifying atherogenic lipoproteins: current and future challenges in the era of personalized medicine and very low concentrations of LDL cholesterol. A consensus statement from EAS and EFLM. Clin Chem2018; 64(7): 1006–1033.
51.
PolTHeldCWesterberghJ, et al.Dyslipidemia and risk of cardiovascular events in patients with atrial fibrillation treated with oral anticoagulation therapy: insights from the ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) trial. J Am Heart Assoc2018; 7(3).
52.
AhnströmJGottsäterALindbladB, et al.Plasma concentrations of apolipoproteins A-I, B, and M in patients with critical limb ischemia. Clin Biochem2010; 43(6): 599–603.
53.
WalldiusGJungnerI. Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy. J Intern Med2004; 255(2): 188–205.
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