A Haptoglobin (HP) Exon Deletion Polymorphism Alters the Effect of APOE Alleles on Alzheimer’s Disease in European‐Descent People with APOEε4

• DOI: 10.1002/alz.067725
• Publication Date: 2022-12-20T15:19:34Z
• Authors: Haimeng Bai; Adam C. Naj; Yuk Yee Leung; Li‐San Wang; Gerard D. Schelle...; Richard Mayeux; Margaret A. Peric...; Lindsay A. Farrer; Logan Dumitrescu; Timothy J. Hohman; Brian W. Kunkle; Eden R. Martin; Jonathan L. Haines; William S. Bush
• Keywords: Haptoglobin; Apolipoprotein E

Abstract Background Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE) – the strongest risk gene for sporadic Alzheimer’s disease (AD). The HP has two functional alleles, HP2 and HP1 , which contains a two‐exon deletion that changes its protein structure conformation. We hypothesize this structural variation associated with AD. Method To investigate this, we imputed genotypes 12,403 cases 11,699 normal controls from Disease Genetics Consortium (ADGC), respectively within each cohort 18 European‐descent cohorts, using custom reference panel. then evaluated association between genotype AD status logistic regression, adjusting sex, age, first 3 principal components. Result frequency 0.376. found influences given APOEε4 genetic context. In individuals ≥1 allele (n=10,054), homozygotes attenuate effect second APOE allele; both protective ε2 ε4 are dramatically reduced (odds ratio, OR=0.92, p=0.415 versus ε3 OR=1.09, ). However, accentuates allele, (OR=0.80, p= 0.003 OR=1.25, p=0.003 This even stronger in (OR=0.64, OR=1.55, addition, analyzed time to diagnosis cox proportional hazard regression model more consistently examined National Alzheimer's Coordinating Center (NACC) cohorts (n=7,448). A shows alleles additively decrease (hazard ratio=0.94, p=6.85e‐3). Conclusion impacts people . Furthermore, different APOEε24 APOEε34 APOEε44 genotypes. Though mechanism still awaits investigation, based on current knowledge function our results suggest possible differential anti‐oxidative ability proteins distinct proteins. As such, may be imminently translatable therapeutic target carriers.