Ischemic stroke susceptibility associated with ALPK1 single nucleotide polymorphisms by inhibiting URAT1 in uric acid hemostasis

Luying Qiu; Xiaoqin Lu; Weishuang Xue; Hefei Fu; Shumin Deng; Long Li; Meilin Chen; Yanzhe Wang

doi:10.1016/j.gene.2024.149017

Ischemic stroke susceptibility associated with ALPK1 single nucleotide polymorphisms by inhibiting URAT1 in uric acid hemostasis

Gene. 2025 Jan 20:934:149017. doi: 10.1016/j.gene.2024.149017. Epub 2024 Oct 20.

Authors

Luying Qiu¹, Xiaoqin Lu¹, Weishuang Xue¹, Hefei Fu¹, Shumin Deng¹, Long Li², Meilin Chen³, Yanzhe Wang⁴

Affiliations

¹ Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China.
² Department of Neurosurgery, The First Hospital of China Medical University, China Medical University, Shenyang 110001, China.
³ Department of Neurology, Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100069, China.
⁴ Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China. Electronic address: yanzhewangcmu@126.com.

PMID: 39437898
DOI: 10.1016/j.gene.2024.149017

Abstract

Objectives: Ischemic stroke (IS) prevalence rising annually, the necessity of discovering non-interventional genetic influences is progressing. Single nucleotide polymorphism (SNP) plays a pivotal role in stable inheritance of disease susceptibility. Based on the relationship between Alpha- Kinase 1 (ALPK1) and traditional IS risk factors especially hyperuricemia, our study investigated the association and function of ALPK1 SNPs with IS susceptibility.

Methods: A case-control study of 1539 patients and 933 controls from northeast China was conducted. Genotyping information of ALPK1 rs2074379 and rs2074388 was collected. Four types of plasmids including rs2074379/rs2074388 G/G, A/G, G/A, and A/A were transfected into 293T cells to observe ALPK1 and SLC22A12 expression. Possible ALPK1 structures of different SNPs were predicted online.

Results: Genotype GG (OR = 1.371, CI = 1.029-1.828, P = 0.031) and GA (OR = 1.326, CI = 1.110-1.584, P = 0.002) of rs2074379 and GA of rs2074388 (OR = 1.359, CI = 1.137-1.624, P = 0.001) were found significantly susceptible to IS, with G allele on sites to be a risk allele. Rs2074379 had a multiplicative interaction with hyperuricemia (OR = 1.637, CI = 1.157-2.315, P = 0.005). Uric acid levels differed in genotypes (P < 0.001). The expression of ALPK1 (P < 0.01) and SLC22A12 in membrane urate transporter 1 (URAT1) protein (P < 0.05) functionally changed with G allele on either site. With glycine changing into aspartic acid at rs2074388, the protein secondary structure changed, but the ALPK1 protein subtype remained still.

Conclusions: ALPK1 rs2074379 and rs2074388 SNPs were functionally associated with IS susceptibility. The wild allele progressed IS risk probably by reducing ALPK1 expression and inhibiting URAT1 raising the uric acid level, contributing to further exploration of pathogenetic mechanisms of stroke. Chinese Clinical Trial Registration number: ChiCTR-COC-17013559.

Keywords: ALPK1; Functional analysis; Ischemic stroke; Single nucleotide polymorphism; URAT1; Uric acid level.

MeSH terms

Aged
Case-Control Studies
China
Female
Genetic Predisposition to Disease*
Genotype
HEK293 Cells
Humans
Ischemic Stroke* / genetics
Male
Middle Aged
Organic Anion Transporters* / genetics
Organic Cation Transport Proteins* / genetics
Polymorphism, Single Nucleotide*
Uric Acid* / blood
Uric Acid* / metabolism

Substances

Uric Acid
SLC22A12 protein, human
Organic Cation Transport Proteins
Organic Anion Transporters