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

Justin B. Miller; J. Anthony Brandon; Lauren M. Harmon; Hady W. Sabra; Chloe C. Lucido; Josue D.Gonzalez Murcia; Kayla A. Nations; Samuel H. Payne; Mark T.W. Ebbert; John S.K. Kauwe; Perry G. Ridge

doi:10.3390/biomedicines13030739

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

Justin B. Miller, J. Anthony Brandon, Lauren M. Harmon, Hady W. Sabra, Chloe C. Lucido, Josue D.Gonzalez Murcia, Kayla A. Nations, Samuel H. Payne, Mark T.W. Ebbert, John S.K. Kauwe, Perry G. Ridge

Research output: Contribution to journal › Article › peer-review

Abstract

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

Original language	English
Article number	739
Journal	Biomedicines
Volume	13
Issue number	3
DOIs	https://doi.org/10.3390/biomedicines13030739
State	Published - Mar 2025

Bibliographical note

Publisher Copyright:
© 2025 by the authors.

Funding

This work was supported by the BrightFocus Foundation and its donors [A2020118F to Miller; A2020161S to Ebbert], the National Institutes of Health [1P30AG072946-01 to the University of Kentucky Alzheimer\u2019s Disease Research Center; AG068331 to Ebbert; GM138636 to Ebbert], and the Alzheimer\u2019s Association [2019-AARG-644082 to Ebbert].

Funders	Funder number
National Institutes of Health (NIH)	1P30AG072946-01
National Institutes of Health (NIH)
University of Kentucky Alzheimer’s Disease Research Center	GM138636, AG068331
Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment	2019-AARG-644082
Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment
BrightFocus Foundation	A2020161S, A2020118F
BrightFocus Foundation

Keywords

Alzheimer’s disease
codon usage bias
disease association
genetic association
ramp sequence

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology

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10.3390/biomedicines13030739

Cite this

Miller, J. B., Brandon, J. A., Harmon, L. M., Sabra, H. W., Lucido, C. C., Murcia, J. D. G., Nations, K. A., Payne, S. H., Ebbert, M. T. W., Kauwe, J. S. K., & Ridge, P. G. (2025). Ramp Sequence May Explain Synonymous Variant Association with Alzheimer’s Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA). Biomedicines, 13(3), Article 739. https://doi.org/10.3390/biomedicines13030739

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title = "Ramp Sequence May Explain Synonymous Variant Association with Alzheimer{\textquoteright}s Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)",

abstract = "Background: The synonymous variant NC\_000007.14:g.100373690T>C (rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimer{\textquoteright}s disease (AD) in genome-wide association studies, but its biological impact is largely unknown. Objective: We hypothesized that rs2405442:T>C decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5′ end of PILRA. Methods: We assessed rs2405442:T>C predicted effects on PILRA through quantitative polymerase chain reactions (qPCRs) and enzyme-linked immunosorbent assays (ELISAs) using Chinese hamster ovary (CHO) cells. RESULTS: Both mRNA (p = 1.9184 × 10−13) and protein (p = 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. Conclusions: We show that rs2405442:T>C alone directly impacts PILRA mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.",

keywords = "Alzheimer{\textquoteright}s disease, codon usage bias, disease association, genetic association, ramp sequence",

author = "Miller, \{Justin B.\} and Brandon, \{J. Anthony\} and Harmon, \{Lauren M.\} and Sabra, \{Hady W.\} and Lucido, \{Chloe C.\} and Murcia, \{Josue D.Gonzalez\} and Nations, \{Kayla A.\} and Payne, \{Samuel H.\} and Ebbert, \{Mark T.W.\} and Kauwe, \{John S.K.\} and Ridge, \{Perry G.\}",

note = "Publisher Copyright: {\textcopyright} 2025 by the authors.",

year = "2025",

month = mar,

doi = "10.3390/biomedicines13030739",

language = "English",

volume = "13",

number = "3",

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AU - Miller, Justin B.

AU - Brandon, J. Anthony

AU - Harmon, Lauren M.

AU - Sabra, Hady W.

AU - Lucido, Chloe C.

AU - Murcia, Josue D.Gonzalez

AU - Nations, Kayla A.

AU - Payne, Samuel H.

AU - Ebbert, Mark T.W.

AU - Kauwe, John S.K.

AU - Ridge, Perry G.

PY - 2025/3

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N2 - Background: The synonymous variant NC_000007.14:g.100373690T>C (rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown. Objective: We hypothesized that rs2405442:T>C decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5′ end of PILRA. Methods: We assessed rs2405442:T>C predicted effects on PILRA through quantitative polymerase chain reactions (qPCRs) and enzyme-linked immunosorbent assays (ELISAs) using Chinese hamster ovary (CHO) cells. RESULTS: Both mRNA (p = 1.9184 × 10−13) and protein (p = 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. Conclusions: We show that rs2405442:T>C alone directly impacts PILRA mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.

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

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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