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. 2016 Nov;80(5):730-740.
doi: 10.1002/ana.24780. Epub 2016 Oct 19.

Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

Christopher D Anderson  1   2   3   4 Guido J Falcone  1   2   3   4   5 Chia-Ling Phuah  1   2   3   4 Farid Radmanesh  1   2   3   4 H Bart Brouwers  1   2   3   4 Thomas W K Battey  1   2   3   4 Alessandro Biffi  1   2   4   6   7 Gina M Peloso  1   4 Dajiang J Liu  8 Alison M Ayres  1   2 Joshua N Goldstein  9 Anand Viswanathan  2 Steven M Greenberg  2 Magdy Selim  10 James F Meschia  11 Devin L Brown  12 Bradford B Worrall  13 Scott L Silliman  14 David L Tirschwell  15 Matthew L Flaherty  16 Peter Kraft  5 Jeremiasz M Jagiella  17 Helena Schmidt  18 Björn M Hansen  19   20 Jordi Jimenez-Conde  21   22 Eva Giralt-Steinhauer  21   22 Roberto Elosua  21   22 Elisa Cuadrado-Godia  21   22 Carolina Soriano  21   22 Koen M van Nieuwenhuizen  23 Catharina J M Klijn  23   24 Kristiina Rannikmae  25 Neshika Samarasekera  25 Rustam Al-Shahi Salman  25 Catherine L Sudlow  25   26 Ian J Deary  27 Andrea Morotti  28 Alessandro Pezzini  28 Joanna Pera  17 Andrzej Urbanik  17 Alexander Pichler  29 Christian Enzinger  29   30 Bo Norrving  19   20 Joan Montaner  31 Israel Fernandez-Cadenas  31   32 Pilar Delgado  31 Jaume Roquer  21   22 Arne Lindgren  19   20 Agnieszka Slowik  17 Reinhold Schmidt  29 Chelsea S Kidwell  33 Steven J Kittner  34 Salina P Waddy  35 Carl D Langefeld  36 Goncalo Abecasis  37 Cristen J Willer  38   39 Sekar Kathiresan  1   4   40 Daniel Woo  16 Jonathan Rosand  1   2   3   4 Global Lipids Genetics Consortium and International Stroke Genetics Consortium
Affiliations
Free PMC article

Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

Christopher D Anderson et al. Ann Neurol. .
Free PMC article

Abstract

Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.

Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.

Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6 ).

Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

Figures

Figure 1
Figure 1
Regional association plot of rs173539 and single nucleotide polymorphisms (SNPs) exhibiting r 2 > 0.5 in association with intracerebral hemorrhage. SNPs available for replication are circled. Mean recombination rate across the locus is represented by the continuous line. The rs3764261 variant identified was the leading SNP in prior genome‐wide association studies of high‐density lipoprotein cholesterol. chr = chromosome; cM = centimorgans; Mb = megabase. [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]

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