Association of genetic polymorphisms of claudin‐1 with small vessel vascular dementia

Abstract

The most recent hypothesis of the development of small vessel vascular dementia (VaD) emphasises the role of blood-brain barrier (BBB) dysfunction. It is hypothesised that certain genetic polymorphisms of the BBB tight junction claudin-1 protein, in combination with adverse environmental risk factors, increase the risk of BBB dysfunction and small vessel VaD. In this case-control study, 97 control participants, with a mean Mini Mental State Exam (MMSE) score of 29.1, and 38 VaD participants were recruited and completed a questionnaire on their medical history and lifestyle factors. Blood was also collected and two single nucleotide polymorphisms (SNPs), rs17501010 and rs893051 of claudin-1 genotyping, were analysed by real-time polymerase chain reaction (PCR) assay. A significantly higher frequency of all rs893051 SNP genotypes (GC and CC) was found in the VaD population (OR=4.8, P=0.006 and OR=6, P<0.001 respectively). Patients with TT genotype of rs17501010 were also more likely to have VaD (OR=3.25, P=0.022). Stratification analysis revealed that having combined haplotype GC+CC of rs893051 and lipid disorders was associated with higher risk of VaD (OR=9.9, P<0.001). For patients with type 2 diabetes the odds ratio of VaD increased significantly in GC+CC genotypes of rs893051 (OR=12.57, P<0.0001) and GT+TT of rs17501010 (OR=5.33, P=0.01).

Emerging molecular mechanisms of vascular dementia

“…Claudins play an important role in organizing tight junctions between endothelial cells. Polymorphisms of CLDN1 (claudin1) were recently associated with small vessel vascular dementia [18]. Further supporting a previous study indicating that claudin expression profile alone was able to segregate Alzheimer's disease cases from normal aging and from vascular dementia patients [19].…”

Polymorphisms inCLDN1are associated with age and differentiation of triple-negative breast cancer patients

“…CLDN1 is a 17 kb gene that codes for a 3.4 kb transcript which translates to an important protein CLDN1 [25]. It has been reported that polymorphisms in CLDN1 are associated with the risk of cancer [14], small vessel vascular dementia [26], leukoaraiosis [27], and hepatitis C virus infection [28,29]. In Hahn-Strömberg V’s study, they found that CLDN1 rs9869263 genotype was related to risk of colon cancer and polymorphisms in CLDN7 were associated with differentiation and age of colon cancer [14].…”

Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

“…This suggests that claudin-1 overexpression compensated for BBB dysfunction only in the acute phase of injury. In addition to this, genetic polymorphisms in claudin-1 have been shown to contribute to small vessel vascular dementia (Srinivasan et al, 2017). Claudin-3 is involved in BBB induction and maintenance through signaling via the Wnt/β-catenin pathway (Polakis, 2008), while claudin-5 restricts the entrance of molecules up to 800 Da (Morita et al, 1999).…”