Association Of HMGCR Polymorphism With Late-Onset Alzheimer's Disease In Han Chinese

Background: Alzheimer's disease(AD)is a chronic progressive neurodegenerative disease occurring in or pre the geriatric period.AD is also the most common type of dementia which accounts for an estimated 60 percent to 80 percent of cases.As the geriatric population growth,it was estimated that the number of people older than 65 years old will be triple while the number of AD patients could double.Currently,the etiology and pathogenesis is unclear,the existed hypothesis include:The beta amyloid protein theory,the tau protein theory,the cholinergic theory,the inflammatory factor theory,the signal transduction theory,cholesterol theory and the signal transduction of mitogen-activated protein kinase theory.However,the pathogenesis could not be fully explained by these theories.Due to the lack of effective treatment and the failure of clinic trials for related drugs,researches has gradually turned to the prevention or pre-clinic treatment.Cross-sectional studies suggest stain is able to decrease the risk of AD as much as 70%?HMGCR serves as the rate-limiting step in cholesterol synthesis,which is also the binding site of statins.The polymorphism(SNP)rs3846662 regulate of HMGCR exon 13 skipping.The minor A allele in rs3846662 is associated with a increased proportion of ?13 HMGCR m RNA,which known to related with a blunt response of statins in AD treatment.Recently,study suggests that HMGCR intron 13 SNP rs3846662 A allele is associated with a delayed age of onset and the mild cognitive impairment(MCI)conversion to Alzheimer's disease(AD).Objectives: To evaluate the influences of HMGCR gene single-nucleotide polymorphisms(SNPs)on the risk of late-onset Alzheimer's disease(LOAD)in a North Chinese Han population.Methods: 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).Differences of the characteristics between AD patients and control subjects were calculated through the Student t-test or the chi-square test.Differences of genotype and allele frequencies were compared using chi-square test.OR value and the 95% confidence interval(CI)for assessing genotypic and allelic associations with AD were analyzed using logistic regression,adjusting for age of onset(age at examination for control subjects),gender,and APOE ?4 status(presence or absence of an ?4 allele)under various genetic models.We also divided the subjects by APOE ?4 allele status to further evaluate the relation between rs3846662 and the risk of AD,then explore the role of rs3846662 in statin response in treatment of AD.Results: In total sample,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).Multivariate logistic regression analysis adjusting for age,gender and APOE found that the rs3846662 significantly protected LOAD in dominant model(OR = 0.796,P = 0.02,95% CI = [0.657,0.965]).After divided the subjects by APOE ?4 allele status,the protective role of rs3846662 between cases and controls was more remarkable in the APOE?4 non-carriers(OR = 0.735,P = 0.005,95% CI = [0.593,0.912])Conclusions: In conclusion,our study demonstrates A allele of HMGCR rs3846662 acts as a protective factor for LOAD in northern Han Chinese.HMGCR polymorphism may play a decisive role in statin response in AD treatment.For statins to reduce risk,it must be taken during a certain critical period,preferably years before the expected.