Dataset Information

The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE).

ABSTRACT:

Background

Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-?4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-?2 allele on diseases in the elderly and survival remains elusive.

Methods

We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-?2, with survival in the population.

Results

During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-?3 carriers, APOE-?2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-?4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-?2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-?4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-?2 (HR 0.95,0.90-1.01), but attenuated for APOE-?4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ?2 versus ?33: -17.1(-18.1-16.0), and ?4 versus ?33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities.

Conclusion

Compared with APOE-?3, APOE-?2 is associated with prolonged survival, whereas mortality risk is increased for APOE-?4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-?2 in health and disease.

SUBMITTER: Wolters FJ

PROVIDER: S-EPMC6663005 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE).

Wolters Frank J FJ Yang Qiong Q Biggs Mary L ML Jakobsdottir Johanna J Li Shuo S Evans Daniel S DS Bis Joshua C JC Harris Tamara B TB Vasan Ramachandran S RS Zilhao Nuno R NR Ghanbari Mohsen M Ikram M Arfan MA Launer Lenore L Psaty Bruce M BM Tranah Gregory J GJ Kulminski Alexander M AM Gudnason Vilmundur V Seshadri Sudha S

PloS one 20190729 7

<h4>Background</h4>Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive.<h4>Methods</h4>We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam ...[more]

PMID: 31356640

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Project description:ImportanceApolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields.ObjectiveTo assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry.Design, setting, participantsThis genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies.Main outcomes and measuresThe main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses.ResultsAmong 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94).Conclusion and relevanceThrough recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

Dataset Information

The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE).

Background

Methods

Results

Conclusion

Publications

The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE).

Similar Datasets

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