Abstract
Cystatin C (CST3) is a cysteine protease inhibitor abundant in the central nervous system, and demonstrated to have roles in several pathophysiological processes including vascular remodeling and inflammation. Previously, we showed a relation of CST3 gene polymorphisms with deep and subcortical white matter hyperintensity (DSWMH) in a small case-control study. In this study, we aimed to investigate the relation in a larger cross-sectional study. Participants of a brain health examination program were recruited (n = 1795) in the study, who underwent routine blood tests and cognitive function tests. Cerebral white matter changes were analyzed by MRI. Additionally, 7 single nucleotide polymorphisms (SNPs) (−82G/C, −78T/G, −5G/A, +4A/C, +87C/T, +148G/A and +213G/A) in the promoter and coding regions of CST3 gene were examined. Among them, carriers of the minor allele haplotype −82C/+4C/+148A were significantly associated with decreased CST3 concentration in the plasma. Unadjusted analysis did not show significant relation between carriers of the minor allele haplotype and periventricular hyperintensity (PVH), but DSWMH was marginally (p < 0.054) increased in this group. After adjusting the effects of other variables like age and kidney function, logistic regression analysis revealed that carriers of the minor allele haplotype were at a significantly increased risk of developing both PVH and DSWMH. Thus, our results suggest that carriers of the minor allele haplotype −82C/+4C/+148A of CST3 gene could be at an increased risk to develop cerebral white matter disturbance.
Highlights
Cystatin C (CST3) is a 13-kDa protein consisting of 120 amino acids, encoded by a 7.3-kb gene located in chromosome 201
In non-hereditary cerebral amyloid angiopathy (CAA), especially in Alzheimer’s disease (AD), CST3 is usually co-deposited with amyloid β (Aβ) peptide indicating its important role in the disease pathology[21]
The analysis revealed that in the study population, there was no polymorphism at −5, +87 and +213 positions in the gene
Summary
Cystatin C (CST3) is a 13-kDa protein consisting of 120 amino acids, encoded by a 7.3-kb gene located in chromosome 201 It is expressed in all types of cells[2], where it is located in the lysosome, Golgi apparatus and endoplasmic reticulum[3,4,5,6,7]. CST3 concentration is high in cerebrospinal fluid (CSF), signifying its high expression and important function in central nervous system (CNS)[8,9] It can inhibit the activity of cysteine proteases including cathepsin B, L and H, and is considered to be the main endogenous inhibitor of those enzymes[8]. On the other hand, increased serum CST3 concentration positively correlates with the plaque area and plaque burden in patients with unstable angina[16] These findings suggest that a precise balance of proteases and CST3 is important for the vascular physiological processes. Such information would be valuable to understand the role of protease systems in pathophysiology of cerebral white matter diseases
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