| BACKGROUND AND OBJECTION Obesity,type 2 diabetes(T2D)and cardiovascular diseases are complex polygenic diseases,which are influenced by both environmental and genetic factors.In recent years,the ‘‘Mendelian Randomization’’(MR)analysis using genetic variants as the instrumental variable(IV)has been widely used for assessing causality in the cardiovascular epidemiological studies.Genetic alleles are allocated randomly during gamete formation;and the common variants are inherited independent of potential confounding factors.Therefore,the IV using an independent genetic factor is regarded as independent of confounders in affecting the intermediate phenotype(BMI and T2 D in the present analysis for instance)–outcome relationship.Previously MR studies provided significant evidence to support causal links between increased BMI and heart failure,hypertension and T2 D.In addition,there are also studies reported the causal associations of T2 D and coronary heart disease and subclinical atherosclerosis using the MR approach.This study aims to investigate the causal associations of genetic susceptibility to metabolism disease(obesity and T2D)with subclinical cardiovascular disease(peripheral arterial disease and increased arterial stiffness)using the MR approach.SUBJECTS AND METHODSThe participants in the present study were recruited from two nearby communities at Baoshan district in the city of Shanghai during 2011 and 2013.A questionnaire was used to collect the social demographic information,the history of chronic diseases,use of medications and lifestyle factors,such as tobacco smoking and alcoholic drinking habits.We performed anthropometric measurements,including body height,weight,waist circumference,and blood pressure taken in seated position.75-g oral glucose tolerances test(OGTT)was performed for all subjects.Fasting venous blood samplings were taken for biochemical analysis which included plasma glucose,lipid,and insulin levels,and liver and kidney function.A fully automatic arteriosclerosis diagnosis device(Colin VP-1000,Model BP203 RPE II,form PWV/ABI)was used to measure the ankle-to-brachial index(ABI)and brachial-ankle pulse wave velocity(ba PWV)with the participants in the supine position after resting for 10–15 min.Participants who had an ABI < 0.9 or >1.4 at either side were diagnosed as having PAD.The forth quartile of ba PWV(1902 cm/s)in the present study was defined as increased arterial stiffness.RESULTS1.The association of genetic susceptibility to obesity with subclinical cardiovascular diseaseAmong the 11477 participants in this study,the number(proportion)of patients with PAD and increased arterial stiffness were 701(6.1%)and 1056(26.1%),respectively.The mean value of weighted BMI_GRS was 10.15(range from 1.30 to 19.66)with a SD of 2.76.Each SD(2.76 points)increase in BMI-GRS was associated with 17% increased risk of PAD after adjusted for age,sex,smoking and drinking status,blood pressure,plasma glucose,and serum lipids(OR = 1.17,95% CI: 1.07-1.27,P = 0.0004).The observational analysis showed that each unit increase in BMI(kg/m2)associated with 1.06-folds risk for PAD(95% CI: 1.03-1.08,P < 0.0001)in multivariable adjusted model.For comparison,in the IV analysis,the causal OR of one kg/m2 increase in genetically determined BMI for PAD was 1.44(95% CI: 1.18-1.75,P = 0.0003).The association between BMI_GRS and increased arterial stiffness was not statistically significant,with an OR of 0.97 and P value of 0.40.Genetically determined obesity may be not the causal factor for increased arterial stiffness.2.The association of genetic susceptibility to type 2 diabetes with subclinical cardiovascular diseaseAmong the 11502 participants of this study,the number(proportion)of patients with increased arterial stiffness and PAD were 2853(25.1%)and 694(6.1%),respectively.The mean value of weighted T2D_GRS was 35.52 with a SD of 3.89.Per SD(3.89 points)increase in T2D_GRS was associated with 6% increased risk of increased arterial stiffness after adjustment for age,sex,BMI,smoking,drinking status,physical activity,hypertension and serum lipids(95% CI: 1.01-1.11,P = 0.01).In multivariable adjusted model,present T2 D was associated with a 1.78-folds(95% CI: 1.59-2.00)increased risk of arterial stiffening risk.In the IV analysis,the causal OR of genetically determined T2 D for increased arterial stiffness was 1.24(95% CI: 1.06-1.47,P = 0.008).The association between T2D_GRS and PAD was not statistically significant,with an OR of 1.05 and P value of 0.28.Genetically determined T2 D may be not the causal factor for PAD.CONCLUSIONS:This study suggested that genetically determined obesity may be causally associated with PAD.In addition,this study maybe also provided a causal association between genetically determined T2 D and increased arterial stiffness. |
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