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A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease. 2023
Haimeng Bai, and
Adam C Naj, and
Penelope Benchek, and
Logan Dumitrescu, and
Timothy Hohman, and
Kara Hamilton-Nelson, and
Asha R Kallianpur, and
Anthony J Griswold, and
Badri Vardarajan, and
Eden R Martin, and
Gary W Beecham, and
Jennifer E Below, and
Gerard Schellenberg, and
Richard Mayeux, and
Lindsay Farrer, and
Margaret A Pericak-Vance, and
Jonathan L Haines, and
William S Bush, and
Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. The 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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