A Haptoglobin (HP) Structural Variant Alters the Effect of APOE Alleles on Alzheimer's Disease

Haimeng Bai; Adam Christian Naj; Penelope H. Benchek; Logan C. Dumitrescu; Timothy J. Hohman; Kara L. Hamilton‐Nelson; Asha R. Kallianpur; Anthony J. Griswold; Badri Narayan Vardarajan; Eden R. Martin; Gary W. Beecham; Jennifer Elizabeth Below; Gerard D. Schellenberg; Richard P Mayeux; Lindsay A. Farrer; Margaret Ann Pericak‐Vance; Jonathan L. Haines; William S. Bush

doi:10.1002/alz.13050

GeneticsAlzheimer s & DementiaApr 12, 2023

Peer-reviewed journal article

A Haptoglobin (HP) Structural Variant Alters the Effect of APOE Alleles on Alzheimer's Disease

Haimeng Bai iD, Adam Christian Naj iD, Penelope H. Benchek iD, Logan C. Dumitrescu iD, Timothy J. Hohman iD, Kara L. Hamilton‐Nelson iD, Asha R. Kallianpur iD, Anthony J. Griswold iD, Badri Narayan Vardarajan iD, Eden R. Martin iD, Gary W. Beecham iD, Jennifer Elizabeth Below iD, Gerard D. Schellenberg iD, Richard P Mayeux iD, Lindsay A. Farrer iD, Margaret Ann Pericak‐Vance iD, Jonathan L. Haines iD, William S. Bush iD

Abstract

BackgroundHaptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid-{beta} (A{beta}) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. MethodsHP genotypes were imputed in 29 cohorts from the Alzheimers Disease (AD) Genetics Consortium (N=22,651). Associations between the HP polymorphism and AD risk and age of onset through APOE interactions were investigated using regression models. ResultsThe HP polymorphism significantly impacts AD risk and age at onset in European-descent individuals (and in meta-analysis with African Americans) by modifying both the protective effect of APOE{varepsilon}2 and the detrimental effect of APOE{varepsilon}4, especially for APOE{varepsilon}4 carriers. DiscussionThe effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.

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