Basic Science and Pathogenesis

A structural variant (SV) of haptoglobin (HP) was shown to interact with apolipoprotein E (APOE) genotypes to modify Alzheimer's disease (AD) risk effect. The two-tandem exon repeat of HP1 to HP2 affects the structure and antioxidative function of the HP protein. HP protein has been found to bind APOE in the brain tissue of human AD patients, and is able to bind amyloid-beta in vitro. Our previous discovery was conducted in an array-genotyped European-descent cohort, and here we replicate this with whole-genome sequenced non-Hispanic White (NHW) and African-American (AFR) datasets.

HP1/HP2 alleles were imputed from 5155 NHW and 4133 AFR samples in the Alzheimer's Disease Sequencing Project using a published panel. We encoded HP status as the number of HP2 alleles. Each allele of APOE was encoded separately as APOE1 and APOE2, and as a single dosage variable ε2-ε3-ε4, assigning APOE ε2 baseline risk, with linearly additive risk in ε3 and ε4. Logistic regression was used to model AD associations, HP-by-APOE interactions, and a three-way term for HP-APOE1-APOE2. We accounted for deviations from additivity with stratified analysis for APOE carriers of each allele. Age-of-onset, sex, and 3 principal components are used as covariates.

The imputed HP2 SV frequency was 0.38 in NHW and 0.59 in AFR. Although HP did not independently associate with AD, we detected interaction effects between HP2 and APOE on AD risk. Increase in HP2 allele count increased the risk effect of APOE ε4 and protective effect of APOE ε2 (NHW OR=1.43, p = 0.083; AFR OR=1.50, p = 0.029). In analysis stratified by one APOE allele, we find the largest interaction effect between HP and the remaining APOE allele (HP-APOE-alt) in APOE ε2 carriers (NHW OR=1.31, p = 0.121; AFR OR=1.43, p = 0.025). Modeled AD risk is lowest in individuals homozygous for both APOE ε2 and HP2.

We find that a structural variant of HP modifies the risk effect of APOE alleles. Our findings in an independent dataset corroborate elements of our previous discovery of this interaction effect.