Ramp Sequence May Explain Synonymous Variant Association with Alzheimer’s Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

<b>Background:</b> The synonymous variant <i>NC_000007.14:g.100373690T>C</i> (<i>rs2405442:T>C</i>) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (<i>PILRA</i>) gene was previously associated with decreased risk for Alzheimer's disease (AD) in genome-wide association studies, but its biological impact is largely unknown. <b>Objective:</b> We hypothesized that <i>rs2405442:T>C</i> decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5' end of <i>PILRA</i>. <b>Methods:</b> We assessed <i>rs2405442:T>C</i> predicted effects on <i>PILRA</i> through quantitative polymerase chain reactions (qPCRs) and enzyme-linked immunosorbent assays (ELISAs) using Chinese hamster ovary (CHO) cells. RESULTS: Both mRNA (<i>p</i> = 1.9184 × 10^-13) and protein (<i>p</i> = 0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on the destruction of a ramp sequence. <b>Conclusions:</b> We show that <i>rs2405442:T>C</i> alone directly impacts <i>PILRA</i> mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.