Abstract MP40: Klotho -vS Heterozygosity is Associated With Lower Risk of Lobar Intracerebral Hemorrhage

Abstract

Introduction: Klotho is a transmembrane protein highly expressed in the kidneys and choroid plexus. Klotho modulates insulin sensitivity and suppresses oxidative stress. 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 attenuates the excess risk of Alzheimer’s Disease conferred by APOE epsilon 4. We tested the hypothesis that KL-VS-Het+ lowers the risk of spontaneous intracerebral hemorrhage (ICH) and the excess in this risk conferred by the APOE epsilon variants. Methods: We conducted a genetic association study that combined publicly available data from 3 case-control studies of ICH in Europeans. We identified the two genetic variants that define KL-VS (rs9536314 and rs9527025) and the two genetic variants that define the APOE epsilon alleles (rs429358 and rs7412). We tested for association between KL-VS-Het+ and ICH risk via study-specific logistic regression followed by fixed-effects, inverse-variance weighted meta-analysis using I 2 to quantify heterogeneity. Given the known biological differences between lobar and non-lobar ICH, we conducted stratified analyses based on location. Additionally, we evaluated the role of KL-VS-Het+ in carriers of APOE epsilon 2 and 4 variants. Results: A total of 1066 ICH cases (464 lobar and 602 non-lobar) and 1073 controls were included in the study (mean age 69 [SD 14], female sex 919 [47%]). KL-VS-Het+, present in 554 (26%) participants, was associated with a lower risk of ICH (OR 0.81, 95%CI 0.67-0.99; p=0.04) without heterogeneity across studies (I 2 =0%). Stratified analyses indicated that KL-VS-Het+ was associated with a lower risk of lobar ICH (OR 0.68, 95%CI 0.52-0.88; p=0.004) but not of non-lobar ICH (OR 0.92, 95%CI 0.73-1.16; p=0.48). In secondary analyses, KL-VS-Het+ was associated with a lower risk of ICH in carriers of APOE epsilon 2 (OR 0.52, 95%CI 0.28-0.96; p=0.037; I 2 =0%) but not epsilon 4 (OR 0.82, 95%CI 0.5-1.33; p=0.42). Conclusion: KL-VS -Het+ is associated with a lower risk of ICH. This protective association was stronger in lobar hemorrhages and in carriers of APOE epsilon 2. Further research should evaluate these associations in non-Europeans and identify the mediating molecular pathways.