Two polymorphisms of RCAN1 gene associated with Alzheimer's disease in the Chinese Han population.

Abstract Objective: Regulator of calcineurin 1 (RCAN1) gene is a regulator on the activity of calcineurin and was reported to be overexpressed in Alzheimer's disease. The aim of this study was to evaluate several polymorphisms of RCAN1, located in the probable promoter region of RCAN1-4 and around the exonic splicing enhancer motifs of RCAN1, in a cohort of Chinese late-onset Alzheimer's disease. Methods: A pilot case-control study was conducted in 142 Alzheimer's disease patients and 99 nondemented controls from Chinese Han population. Fragments of the RCAN1 including 5 polymorphisms (rs71324311, rs3831376, rs10550296, rs8135540, rs78899361) were amplified and sequenced. Results: In our sample, 2 polymorphisms (rs71324311 and rs10550296) were associated with Alzheimer's disease. Of these 2 polymorphisms, the heterozygous deletion genotype of rs71324311 was more prevalent in non-demented controls than in those with Alzheimer's disease (4% vs. 0%), indicating a slight protective role (Fisher's exact test, p = 0.03; crude odds ratio = 0.96, 95% confidence interval = 0.92-0.99). There was only a trend towards a significant difference in the distributions of genotypes of rs10550296 between 2 groups (x^sup 2^ = 1.93; p = 0.17; crude odds ratio = 1.44, 95% confidence interval = 0.85-2.41). However, logistic regression analysis showed that the age-, gender- and apolipoprotein E e4- adjusted odds ratio of Alzheimer's disease with rs10550296 heterozygous deletion genotype was 2.11 (x^sup 2^ = 4.42; p = 0.04; 95% confidence interval = 1.05-4.20). Conclusions: Regarding Alzheimer's disease susceptibility in Chinese Han population, our data suggested a protective role for the rs71324311 heterozygous deletion genotype and a risk role from the rs10550296 heterozygous deletion genotype. Key words: Alzheimer disease; Association; Calcineurin; Polymorphism, genetic ... (ProQuest: ... denotes non-US-ASCII text omitted.) Introduction Late-onset Alzheimer's disease (LOAD) is a genetically complex and heterogeneous disorder. A hereditary basis for Alzheimer's disease (AD) was estimated to about 60% to 80%.1 Nearly all subsequent studies confirmed that e4 allele of apolipoprotein E (ApoE) as a genetic susceptibility factor for LOAD, since it was first found by means of genetic linkage analysis in 1991.2 The ApoE e4 allele has been estimated to account for only 20% of the genetic risk in LOAD, and recent studies including both the candidate gene and genome-wide approaches have found several risk genes for LOAD3 (http://www. alzgene.org). Although highly estimated, all the candidate genes reported might not explain over 50% of all LOAD inheritance, which is in contrast to what is known about the genetics of other complex diseases such as age-related macular degeneration.4 In other words, there is a substantial proportion of unaccounted genetic risk for LOAD, even after genome-wide association studies.5 The human regulator of calcineurin 1 gene (RCAN1, also called DSCR1, Adapt78, MCIPI, or calcipressin 1) is located on chromosome 21q22.12.6 RCAN1 is a regulator on the activity of calcineurin and observed to be overexpressed both in the brains of Down's syndrome patients and AD patients.7,8 Overexpression of RCAN1 contributed to hyperphosphorylated tau,9,10 reduced synaptic vesicles,11 and abnormal synaptic morphology.12 However, lack of RCAN1 displayed severe learning deficits in drosophila,13 memory defects, and impaired late-phase long-term potentiation in mice.14 Furthermore, Porta et al15 found that RCAN1 modulated neuronal cell survival and death pathways depending on the RCAN1 dosage. The RCAN1 gene consists of 7 exons, which can be alternatively spliced to produce different mRNA isoforms, of which RCAN1-1 and RCAN1-4 are the 2 major observed forms.16 Yang et al17 found that the upstream of exon 4 contained a cluster of nuclear factor of activated T-cells (NFAT)-binding motifs that contributed to the alternative promoter usage. …