Abstract P412: Klotho -vS Heterozygosity is Associated With Lower Risk of Non-Traumatic Subarachnoid Hemorrhage

Abstract

Introduction: Klotho is a transmembrane protein that modulates insulin sensitivity and suppresses oxidative stress and inflammation. Two missense variants in the Klotho gene ( KL ) form the functional haplotype KL-VS . Heterozygosity for KL-VS ( KL-VS-Het+ ) increases serum levels of Klotho and is associated with healthy aging and decreased risk of stroke. We tested the hypothesis that KL-VS-Het+ lowers the risk of Non-traumatic Subarachnoid Hemorrhage (SAH). Methods: We conducted a genetic association study that used publicly available individual-level data from the UK Biobank, a large cohort study that enrolled ~500,000 participants across the UK. We included participants from European ancestry. We ascertained the two missense genetic variants that define KL-VS (rs9536314 and rs9527025) using the UK Biobank Axiom Array. We tested for association between KL-VS-Het+ and SAH risk using univariable and multivariable logistic regression models. We conducted stratified analyses using the known effect modifiers of SAH risk sex, hypertension, and smoking. Results: A total of 385,709 participants were included (1,083 SAH cases and 384,626 controls). The mean age at recruitment was 56.8 (SD 8) and 208,042 (54%) were female. KL-VS-Het+ was present in 27% of the population. KL-VS-Het+ was associated with a lower risk of SAH in univariable (OR 0.85, 95%CI 0.74-0.98; p=0.02) and multivariable (OR 0.85, 95%CI 0.74-0.98; p=0.02) models adjusting by age, sex, hypertension, smoking and genetic principal components, This effect was stronger in men (0.80, 95%CI 0.63-1.00; p=0.05) versus women (OR 0.88, 95%CI 0.74-1.05; p=0.15), hypertensives (OR 0.77, 95%CI 0.61-0.97; p=0.03) versus non-hypertensives (OR 0.90, 95%CI 0.75-1.07; p=0.23) and ever-smokers (OR 0.82, 95%CI 0.68-0.99; p=0.04) versus never-smokers (OR 0.89, 95%CI 0.71-1.10; p=0.27). Conclusion: KL-VS -Het+ is associated with a lower risk of SAH. This protective association was stronger in men, hypertensives, and ever-smokers. Further research should validate these associations in non-Caucasian populations and identify possible biological underpinnings behind these relationships.