Abstract Details

Title Klotho-VS Heterozygosity is Associated with Lower Risk of Non-traumatic Subarachnoid Hemorrhage

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) Cerebrovascular Disease and Interventional Neurology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 096

Objective To test the hypothesis that heterozygosity for KL-VS (KL-VS-Het+) lowers the risk of Non-traumatic Subarachnoid Hemorrhage (SAH).

Background 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. KL-VS-Het+ increases serum levels of Klotho and is associated with healthy aging and decreased risk of stroke.

Design/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).

Conclusions 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.

Authors/Disclosures
PRESENTER	No disclosure on file
Natalia Szejko, MD, PhD	Dr. Szejko has nothing to disclose.
Victor M. Torres-Lopez, MA (Yale University)	Mr. Torres-Lopez has nothing to disclose.
	No disclosure on file
Lauren H. Sansing, MD	Dr. Sansing has nothing to disclose.
Kevin N. Sheth, MD, F�鶹��ýӳ�� (Yale UniversityDivision of Neuro and Critical Care)	Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care.
Charles Matouk	Charles Matouk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Silk Road Medical. Charles Matouk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Microvention. Charles Matouk has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Navigantis.
Guido J. Falcone, MD (Yale School of Medicine)	The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.

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