Racial/ethnic variation of
            <i>APOE</i>
            alleles for lobar intracerebral hemorrhage

Sawyer, Russell P.; Sekar, Padmini; Osborne, Jennifer; Kittner, Steven J.; Moomaw, Charles J.; Flaherty, Matthew L.; Langefeld, Carl D.; Anderson, Chris; Rosand, Jonathan; Woo, Daniel

doi:10.1212/wnl.0000000000005908

Cited by 21 publications

(21 citation statements)

References 28 publications

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“…This might specifically apply for ICH 30 given the evidence from observational studies for differential associations of BP with lobar ICH depending on ethnicity. 51 Furthermore, there is evidence for differential responses to antihypertensive drug classes by ethnicity, which could not be examined in the current study. 52 The availability of large-scale GWAS data from more diverse populations with higher representation of non-European ethnicities will enable future Mendelian randomization studies to explore potential ethnic disparities in more detail.…”

Section: Figure 3 Mendelian Randomization Associations Between Genetimentioning

confidence: 78%

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Georgakis¹,

Gill²,

Webb

et al. 2020

Neurology

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ObjectiveWe employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.MethodsWe selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).ResultsGenetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.ConclusionsThis study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.

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Section: Figure 3 Mendelian Randomization Associations Between Genetimentioning

confidence: 78%

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Georgakis¹,

Gill²,

Webb

et al. 2020

Neurology

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“… 42 , 43 , 44 , 45 , 46 In ICH, APOE ε alleles have already been shown to exert higher risks in East Asian individuals when compared with those of European ancestry. 47 Although recent analyses by Sawyer et al 48 demonstrate the association of hypertension and APOE ε allele status with ICH risk across race/ethnicity specific to the ERICH study, the present analysis has the advantage of a larger sample size via formal transethnic meta-analysis as well as a PS matching approach that helps to illustrate the potential mechanisms underlying the observed variability of APOE ε alleles on lobar ICH risk across populations.…”

Section: Discussionmentioning

confidence: 97%

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity

Marini¹,

Crawford²,

Morotti³

et al. 2019

JAMA Neurol

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Key Points Question Is history of hypertension and apolipoprotein E ( APOE ) associated with intracerebral hemorrhage risk in participants stratified by self-reported race/ethnicity? Findings In this case-control study of 13 124 adults, having a copy of APOE ε4 alleles increased the risk for lobar intracerebral hemorrhage only in white individuals, but after propensity score matching for hypertension burden, Hispanic individuals showed the same risk of APOE ε4. Meaning APOE ε4 appears to be confirmed as a risk factor for lobar intracerebral hemorrhage in nonwhite populations but is masked by differential hypertension burden in Hispanic individuals; further studies are needed to explore the interactions between APOE alleles and environmental exposures.

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“…An early illustration of AD risk differences based on APOE genotype and ethnicity is shown in Figure 5B (Farrer et al, 1997). Similarly, APOE alleles appear to have no effect on lobar hemorrhage in African-Americans (Sawyer et al, 2018) or on CAD in Afro-Carribeans (Larifla et al, 2017). Recent efforts further demonstrate that the continuum of African ancestry in admixed African-Americans impacts the effect of APOE4 on AD and cognitive decline (Deters et al, 2018;Rajabli et al, 2018), such that APOE4 confers greater risk with decreasing percent of African ancestry.…”

Section: Apoe and Ancestral Backgroundmentioning

confidence: 99%

A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

Belloy

Napolioni

Greicius

2019

Neuron

403

354

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Alzheimer's disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi ''monogenic'' role of apolipoprotein E (APOE). The APOE4 allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders. This review, based mostly on data from human studies, ranges across a variety of APOE-related pathologies, touching on evolutionary genetics and risk mitigation by ethnicity and sex. The authors also address one of the most fundamental question pertaining to APOE4 and AD: does APOE4 increase AD risk via a loss or gain of function? The answer will be of the utmost importance in guiding future research in AD. (A) The three main APOE isoforms APOE2, APOE3, and APOE4, respectively, encoded by the Apolipoprotein E2, E3, and E4 alleles, are the result of non-synonymous polymorphisms that cause amino acid changes at position 112 and 158 of the APOE protein (Rall et al., 1982; Weisgraber et al., 1981). APOE3 is the most common variant in the general population. The APOE4 variant is a major genetic risk factor for AD, while APOE2 is protective (Farrer et al., 1997). (B) Structural models of lipid-free APOE are shown for each major isoform, based on X-ray crystallography, structure prediction, and circular dichroism spectroscopy (Zhong and Weisgraber, 2009). The N-terminal domain contains APOE's low-density lipoprotein receptor (LDLR) region at amino acid residues 134-150, while the C-terminal holds the lipid-binding region at residues 244-272. Amino acid substitutions in APOE4 promote a salt bridge between Arg61 and Glu255, which, compared to the APOE2 and APOE3 variants, drives increased domain interaction between the N-and C-terminal domains. In (A), APOE allele frequencies are obtained, with permission, from American

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Racial/ethnic variation of APOE alleles for lobar intracerebral hemorrhage

Cited by 21 publications

References 28 publications

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity

A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

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