Mendelian Randomization Study On Causal Effect Of Body Fat Distribution On Venous Thromboembolism

Venous thromboembolism(VTE)is a thrombosis in the vein,which can cause obstructive block to the recirculation of blood and result in changes in pathology and physiology.VTE is the third cause of cardiovascular death.Some patients with VTE have no obvious clinical symptoms.For example,when thromboembolism happens in the distal of the deep vein,pain and edema might not be easily observed.At the end stage of VTE,patients often experience physical and psychological torture,and fatal pulmonary edema might be developed,The incidence and mortality of VTE are often underestimated due to misdiagnosis and difficulty in detecting VTE.VTE has two clinical manifestations:deep vein thrombosis(DVT)and pulmonary embolism(PTE).DVT can progress to PTE.PTE is the major cause of death.VTE is a chronic disease that can cause serious economic and living burden,Therefore,early screening,monitoring,and prevention of VTE are particularly important.Obesity is one of the risk factors for VTE.The associations of anthropometric indicators,such as weight,body mass index(BMI),waist circumference,hip circumference,and waist-to-hip ratio with VTE have been extensively investigated in previous epidemiological studies.Among these indicators,weight and BMI represent the overall degree of obesity;waist circumference,hip circumference and waist-to-hip ratio represent the abdominal obesity.Some researchers suggest that we should pay more attention to the direct,standard indicators of obesity,rather than the alternative ones.However,most of the studies to date have focused on the substitute indicators of fat,and have not examined the sensitivity of the direct indicators of fat to VTE.The fat distributed in different parts of the body can play different roles;therefore,it is important to study the distribution of body fat in the development of VTE.Understanding the relationship between fat distribution and VTE and selecting more sensitive screening indicators for VTE may help the prevention and early detection of VTE.Obesity is one of the easiest factors that can be modified to reduce the risk of VTE.This study explored different obesity indicators:weight and BMI which reflect the overall obesity;waist circumference,hip circumference and waist-to-hip ratio which represent the abdominal obesity;and the proportion of fat mass in different parts.The effects of various obesity indicators on VTE were examined using survival analysis and Mendelian randomization.Using the cohort data of UK Biobank(UKB),Cox proportional hazard model was used to analyze the effect of various obesity indicators(standardization)on VTE;principal component regression analysis was used to study the relationship between the proportion of fat in each part(standardization)and VTE.Using genetic data from Neal Lab,GIANT and Finn Gen,two-sample Mendelian Randomization(MR)was used to analyze the causal relationship between each obesity indicator and VTE.Inverse variance weighting was used as the main analysis method.The weighted median and MR-Egger were used as the secondary analysis method,and the leave-one method,MR-PRESSO(MR Pleiotropy RESidual Sum and Outlier)and MR-RAPS(MR Robust adjusted profile score)was used as the sensitivity analysis methods.Besides,reverse MR to analysis the casual effect of VTE on obesity index.The relationship between each obesity indicator with VTE was compared by the effect value to select a more sensitive indicator.Research results:1.A total of 346,689 subjects were enrolled in this study.The subjects were mostly middle-aged and elderly,female(54.39%),and all of them were European White.The average follow-up time was 8.79 years.During the follow-up period,4206 people developed VTE.The cumulative incidence of VTE was 1.21%.2.The trend chi-square tests indicated that the increased levels of weight,BMI,waist circumference,hip circumference,waist-to-hip ratio,the body fat proportion,the trunk fat mass proportion,and the leg and arm fat proportion were statistically significantly associated with increased incidence rate of VTE.3.The results of multivariate Cox regression analysis showed that female,older age,and lower socioeconomic status were risk factors for VTE.Increased levels of weight(HR=1.33,P<0.001),BMI(HR=1.20,P<0.001),waist circumference(HR=1.26,P<0.001),hip circumference(HR=1.25,P<0.001),waist-to-hip ratioO(HP=1.22,P<0.001),and large proportion fat in parts(the proportion of whole body fat:HR=1.32;the proportion of trunk fat:HR=1.21;the proportion of leg fat:HRS=1.08,1.10;the proportion of arm fat:HRs=l.27,1.28;P<0.001)were also risk factors.The strongest risk factor was the proportion of body fat with a HR of 1.32,P<0.001;followed by the proportion of arm fat,waist circumference and hip circumference,with HRs of 1.28,1.26 and 1.25,respectively.Smoking and alcohol use were not associated with VTE.All obesity indicators were risk factors for DVT and PTE,and the proportion of body fat showed the greatest effect on DVT and PTE(HR=1.29,P<0.001 for DVT;HR=1.35,P<0.001 for PTE).4.The first principal component of the proportion of trunk and limbs fat was mainly the proportion of total body fat,and the second principal component was mainly the proportion of upper and lower body fat.The cumulative variance contribution rate of the former two was 96.87%.The Cox regression model showed that the HRs of the first and second principal component scores were 1.18 and 1.24,respectively,suggesting that people have a higher risk of VTE with a high proportion of body fat and more obese upper body.5.Mendelian randomization analysis results showed the negative causal effects of various obesity indicators on VTE.The HRs for weight,BMI,waist circumference,hip circumference,waist-to-hip ratio,the proportion of body fat,the proportion of trunk fat and limb fat were 1.47,1.38,1.79,1.80,1.16,1.78,1.37,1.54,1.74,1.57 and 1.48.The proportion of body fat,waist and hip circumferences were more sensitive than others.The instrumental variables were not weak instrumental variables,and there is no pleiotropy.Leave-one-out,MR-PRESSO and MR-RAPS showed that the results are robust.Reverse MR result showed VTE had no casual effect on obesity index.Research conclusion:1.Obesity was a risk factor for VTE;2.Among the obesity indicators,the proportion of body fat,waist circumference and hip circumference showed a more sensitive risk effect on VTE;3.Among the VTE subtypes,obesity had a greater risk of PTE.