Associations between modifiable risk factors and frailty: a Mendelian randomisation study

Background: Early identification of modifiable risk factors is essential for the prevention of frailty. This study aimed to explore the causal relationships between a spectrum of genetically predicted risk factors and frailty.

Methods: Univariable and multivariable Mendelian randomisation (MR) analyses were performed to explore the relationships between 22 potential risk factors and frailty, using summary genome-wide association statistics. Frailty was accessed by the frailty index.

Results: Genetic liability to coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), ischaemic stroke, atrial fibrillation and regular smoking history, as well as genetically predicted 1-SD increase in body mass index, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, alcohol intake frequency and sleeplessness were significantly associated with increased risk of frailty (all p<0.001). In addition, there was a significant inverse association between genetically predicted college or university degree with risk of frailty (beta −0.474; 95% CI (−0.561 to –0.388); p<0.001), and a suggestive inverse association between high-density lipoprotein cholesterol level with risk of frailty (beta −0.032; 95% CI (−0.055 to –0.010); p=0.004). However, no significant causal associations were observed between coffee consumption, tea consumption, serum level of total testosterone, oestradiol, 25-hydroxyvitamin D, C reactive protein or moderate to vigorous physical activity level with frailty (all p>0.05). Results of the reverse directional MR suggested bidirectional causal associations between T2DM and CAD with frailty.

Conclusions: This study provided genetic evidence for the causal associations between several modifiable risk factors with lifetime frailty risk. A multidimensional approach targeting these factors may hold a promising prospect for prevention frailty.