Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age‐matched controls

Abstract

Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.

Regional European differences in allele and genotype frequencies of low density lipoprotein receptor‐related protein 1 polymorphism in Alzheimer's disease

“…However, a post hoc power calculation revealed that the present study has only sufficient statistical power to exclude an allele frequency difference of about 6% and the power is even less considering the fact that genegene interaction were investigated. Our data, however, support the findings of several other studies in which no increased AD risk was found to be associated with LRP1 CC genotype frequency [Woodward et al, 1998;Beffert et al, 1999;Bullido et al, 2000;Hatanaka et al, 2000;Hu et al, 2000;McIlroy et al, 2001;Perry et al, 2001;Sanchez-Guerra et al, 2001]. Kang et al [1997] also reported that, when APOE e4 homozygotes were left out of the analysis, the correlation between LRP1 gene and AD was strengthened.…”

“…This result has been confirmed by some subsequent studies [Baum et al, 1998;Hollenbach et al, 1998;Kamboh et al, 1998;Lambert et al, 1998], although the strength of association with AD was not a particularly strong one. Contradictory results have been reported from other studies [Woodward et al, 1998;Beffert et al, 1999;Bullido et al, 2000;Hatanaka et al, 2000;Hu et al, 2000;McIlroy et al, 2001;Perry et al, 2001;Sanchez-Guerra et al, 2001], while some authors found an association between exon 3 LRP1 gene polymorphism and AD modulated by APOE e4 allele and gender [Bullido et al, 2000;Hatanaka et al, 2000].…”

“…However, it is noteworthy that the original association was only described in family history-positive AD patients [Kang et al, 1997], while subsequent studies comprised mainly sporadic or unrelated AD cases. Moreover, several conflicting studies did not support this association [Woodward et al, 1998;Beffert et al, 1999;Bullido et al, 2000;Hatanaka et al, 2000;Hu et al, 2000;McIlroy et al, 2001;Perry et al, 2001;Sanchez-Guerra et al, 2001], Lambert et al [1998] and Baum et al [1998] reported only a weak association between exon 3 LRP1 gene polymorphism and AD [Beffert et al, 1999;Bullido et al, 2000], and two metaanalysis based on seven and eight studies on exon 3 LRP1 gene polymorphism and AD showed that the C allele remains over-represented in AD patients when compared to controls (86.7% vs. 82.8%), but only with weak correlation to the disease (C allele: OR 1.34; CC genotype: OR 1.35) [Beffert et al, 1999;Bullido et al, 2000]. Therefore, it is possible that a moderate effect associated with the exon 3 LRP1 gene polymorphism is due to its non-random association with a functional mutation present somewhere in the gene.…”

Racial Differences in the Influence of the APOE Epsilon 4 Allele on Cognitive Decline in a Sample of Community-Dwelling Older Adults

“…Thus, it is important to control for such variables in analyses examining racial differences in the effect of APOE genotype on CD. Moreover, it is of interest to note that in cross-sectional studies restricted to African American samples (thus decreasing between-group variability on SES and health variables) researchers have been more likely to find an association of APOE genotype and AD [24][25][26] .…”

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

“…Isolation of genomic DNA and general procedures for PCR-RFLP genotyping have been described [74]. Reagents and conditions to amplify the XmnI polymorphism (C →T) at bp −158 of HBG2 were, 0.5 pmole each of left (5'-GCACTGAAACTGTTGCTTTATAGGAT-3') and right primers (5'-GCGTCTGGACTAGGAGCTTATTG-3'), 0.5 U of Taq (Promega, Madison, WI) and 37 cycles of 94°C/40 sec, 55°C/30 sec, 72°C/1 min.…”