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Variants at APOE Influence Risk of Deep and Lobar Intracerebral Hemorrhage

Biffi, Alessandro; Sonni, Akshata; Anderson, Christopher D.; Kissela, Brett; Jagiella, Jeremiasz M.; Schmidt, Helena; Jimenez-Conde, Jordi; Hansen, Björn LU ; Fernandez-Cadenas, Israel and Cortellini, Lynelle, et al. (2010) In Annals of Neurology 68(6). p.934-943
Abstract
Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were... (More)
Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943 (Less)
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@article{9808f595-39fc-4cf7-8c38-e10cf06b96da,
  abstract     = {Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943},
  author       = {Biffi, Alessandro and Sonni, Akshata and Anderson, Christopher D. and Kissela, Brett and Jagiella, Jeremiasz M. and Schmidt, Helena and Jimenez-Conde, Jordi and Hansen, Björn and Fernandez-Cadenas, Israel and Cortellini, Lynelle and Ayres, Alison and Schwab, Kristin and Juchniewicz, Karol and Urbanik, Andrzej and Rost, Natalia S. and Viswanathan, Anand and Seifert-Held, Thomas and Stoegerer, Eva-Maria and Tomas, Marta and Rabionet, Raquel and Estivill, Xavier and Brown, Devin L. and Silliman, Scott L. and Selim, Magdy and Worrall, Bradford B. and Meschia, James F. and Montaner, Joan and Lindgren, Arne and Roquer, Jaume and Schmidt, Reinhold and Greenberg, Steven M. and Slowik, Agnieszka and Broderick, Joseph P. and Woo, Daniel and Rosand, Jonathan},
  issn         = {1531-8249},
  language     = {eng},
  number       = {6},
  pages        = {934--943},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Variants at APOE Influence Risk of Deep and Lobar Intracerebral Hemorrhage},
  url          = {http://dx.doi.org/10.1002/ana.22134},
  volume       = {68},
  year         = {2010},
}