Association of HMGCR polymorphism with late-onset Alzheimer's disease in Han Chinese

Abstract

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) acts as a potential genetic modifier for Alzheimer's disease (AD). Previous reports identified that HMGCR rs3846662 polymorphism is associated with biosynthesis of cholesterol in AD pathology. In order to assess the involvement of the HMGCR polymorphism in the risk of late-onset AD (LOAD) in northern Han Chinese, we performed a case–control study of 2334 unrelated subjects (984 cases and 1350 age- and gender-matched controls) to evaluate the genotype and allele distributions of the HMGCR rs3846662 with LOAD. The genotype distribution (GG, AG, AA) of rs3846662 was significantly different between LOAD patients and controls (P = 0.003), but the allele distribution did not reach a significant difference (P = 0.614). After adjusting for age, gender and the APOE ε4 status, the minor A allele of rs3846662 was validated as a protective factor for LOAD in dominant model (OR = 0.796, P = 0.02, 95% CI = 0.657–0.965). Interestingly, we observed rs3846662 polymorphism was only significantly associated with LOAD in APOE ε4 non-carriers (OR = 0.735, P = 0.005, 95% CI = [0.593, 0.912]). In conclusion, our study demonstrates A allele of HMGCR rs3846662 acts as a protective factor for LOAD in northern Han Chinese.

<p>Therapeutic targets of hypercholesterolemia: HMGCR and LDLR</p>

“…Conversely, the rs3761740 variant of HMGCR was not associated with AD in a Swedish case-control study 68. Another HMGCR polymorphism (rs3846662) may increase the mRNA and protein levels of HMGCR by affecting alternative splicing, and thereby contribute to the onset and progression of AD 69–72. Additionally, gene polymorphisms affect the cholesterol-lowering response to statin treatment 73–75…”

Role of ADH1B rs1229984 and ALDH2 rs671 gene polymorphisms in the development of Alzheimer's disease

“…A study conducted in 11,884 twins has shown that genetic predisposition accounts for 58-79% of Alzheimer's disease cases (Gatz et al, 2006). Previous studies have indicated that genetic polymorphisms in protein tyrosine kinase 2b, presenilin 2, apolipoprotein E, cytochrome 46A1, disrupted-in-schizophrenia-1, 3-hydroxy-3-methylglutaryl-CoA reductase, and sortilin receptor 1 all play essential roles in the development of this disease (Chang et al, 2016;Huang et al, 2016;Jia et al, 2016;Li et al, 2016;Suzuki et al, 2016;Zhang et al, 2016;Zheng et al, 2016). Previous studies have reported that alcohol consumption is associated with risk of Alzheimer's disease (Piazza-Gardner et al, 2013;Berntsen et al, 2015;Ilomaki et al, 2015).…”

Proteasome modulator 9 (PSMD9) gene rs14259 polymorphism in Alzheimer’s disease

“…Alzheimer's disease (AD) is a multifactorial neurodegenerative disease including many genetic and environmental factors (Chang et al, 2016, Li et al, 2008. The brain of the patients with AD is essentially characterized by neuronal and synaptic loss, extracellular plaques composed of amyloid-β peptides, and intraneuronal neurofi bril lary tangles consisting of hyperphosphorylated tau proteins (Saraswati et al, 2018, Yang et al, 2015.…”