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Title: 'An Association Analysis of Candidate Genes in Dementia''
Authors: Chaudhry, Mamoonah
Keywords: Microbiology & Molecular Genetics
Issue Date: 2015
Publisher: University of the Punjab , Lahore
Abstract: Dementia is a major public health problem worldwide. Alzheimer’s disease (AD) is a major form of dementia, and the APOE*4 allele is an established genetic risk factor for AD. Similarly, stressful life events are also associated with dementia. The first objective of this study was to examine the association of APOE*4 and stressful life events with dementia in a Pakistani sample, which has not been reported previously. Combined interaction effect on dementia of stressful life events and APOE*4 status was also tested. A total of 176 subjects (61 cases and 115 controls) were recruited. Dementia patients for this study were recruited from various clinical settings of Lahore (Alzheimer’s Pakistan Day Care Center for Alzheimer’s and Related Dementias; Psychiatry Department of the Services Institute of Medical Sciences; out-patient service of the Punjab Institute of Mental Health) and Rawalpindi (out-patient service of the Armed Force Institute of Mental Health) from February 2011 to September 2012. The majority of cases were obtained from the Punjab Institute of Mental Health (PIMH), Lahore, Pakistan. All cases and healthy controls were interviewed to assess cognition, co-morbidities, history of stressful life events, and demographics. Cases were older than controls (cases, 71.3 ± (9.9) years; controls, 66.3 ± (7.6) years), and there were more female cases than female controls (female cases=50.8%; female controls=30.4%). Cases were similar to controls on marital status and educational background. The majority of the cases (72%) and controls (83%) had less than 8 years of formal education, and only 28% of cases and 17% of controls had more than 8 years of formal education. However, cases and controls differed on income where a greater percent of controls fell into the lower income category. Cases and controls were also different on a number of comorbidities, with cases having higher proportions of heart diseases, hypertension, stroke, diabetes and depression, and controls showing a higher rate of smoking than cases. Blood genotyping for the APOE polymorphism (E2/E3/E4) was performed. APOE*4 and stressful life events were each independently and significantly associated with the risk of dementia (APOE*4: P=0.00697; stressful life events: P=5.29E-09). However, significant interaction between APOE*4 carrier status and stressful life events on risk of dementia (P=0.677) was not observed. Although the sample size of this study was small, the established association of APOE*4 with dementia was confirmed for the first time in a Pakistani sample. Furthermore, stressful life events were also found to be significantly associated with dementia in this population. Genetic studies have identified several susceptibility loci for late-onset Alzheimer’s disease (LOAD) in different populations. These loci are associated with risk and age at onset (AAO) of LOAD. It is important to determine whether the same susceptibility loci are associated with dementia risk in a Pakistani population. In this study, association of 23 loci (known and suggestive) was examined in a Pakistani sample, which has not been published previously. A total of 23 SNPs were genotyped in 61 dementia patients and 115 controls. The genotyping was performed using TaqMan assays. The results were analyzed after sex, age, and APOE*4 adjustment, as well as without APOE*4 adjustment. In this study, the only SNP that showed significant association with risk of dementia without APOE*4 adjustment was rs1466662 (OR= 0.576, CI= 0.331-0.986; P= 0.044), located in DCHS2 on chromosome 4. Another set of SNPs was also genotyped in Pakistani sample (cases, 37; controls, 115) using allele specific PCR. The only SNP that showed significant association with dementia risk (OR=2.79; 95 % CI=1.24-6.25; P= 0.035) was CR1/rs3818361, located in complement component (3b/4b) receptor 1 gene (CR1) on chromosome 1. These findings suggest that LOAD susceptibility loci are shared across different populations. Epigenetic changes including genomic imprinting may also affect risk of late-onset Alzheimer’s disease (LOAD). There are >100 known imprinted genes and most of them are expressed in human brain. In this study, the association of single nucleotide polymorphisms (SNPs) in 93 imprinted genes was also examined with LOAD risk in 1,291 LOAD Caucasian cases and 958 cognitively normal Caucasian controls. Single-site, gene-based, and haplotype analyses were performed. Single site analysis showed 14 significant associations at P<0.01. The most significant SNP (rs11770199; P=0.0003) in single site analysis was located on chromosome 7 in GRB10 gene. Gene-based analyses revealed 4 significant associations at P <0.05. The most significant association seen was with WT1 (P=0.0100). However, this association did not remain significant after correcting for gene-based multiple comparisons. WT1 is expressed in different tissues especially in brain during development. A previous study has identified higher levels of Wilms tumor 1 protein during neuronal apoptosis which is an important suggestive mechanism of Alzheimer’s disease pathogenesis. The other 3 risk genes that showed associations in both single-site and gene-based analyses are ZC3H12C, DLGAP2, and GPR1, The haplotype analysis also revealed significant associations with these three (ZC3H12C, DLGAP2, and GPR1) genes. These findings suggest possible role of imprinted genes in AD pathogenesis that show specific expression in the brain. In this study, 14 significant SNPs from single locus analysis of 93 imprinted genes and 23 non-APOE SNPs (genotyped using TaqMan assays) were investigated for their potential regulatory function. Functional significance of SNPs in LD (r2≥0.80) with these 33 SNPs was also examined. Two publicly available bioinformatics tools (SNAP and RegulomeDB) were used. There were total of 22 SNPs with RegulomeDB score of less than 3. This score indicates that these SNPs are likely to affect binding and have functional significance. However, only two of them have been previously identified as genome wide significant. These are ABCA7/rs3764650 and CLU/rs1532278 with RegulomeDB scores of 2a and 2b, respectively. A reported suggestive SNP (HRK/rs17429217) had a RegulomeDB score of 2b. Except DLGAP2 (RegulomeDB score: 2b), none of these variants showed significant association with LOAD/dementia risk in present study. This suggests for conducting additional well designed studies focusing on expression and pathway analysis of these genes in larger sample size.
Gov't Doc #: 16603
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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