4 research outputs found
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Fine Mapping of 10q and 18q for Familial Alzheimer's Disease in Caribbean Hispanics
Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18
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APOE and APOC1 Promoter Polymorphisms and the Risk of Alzheimer Disease in African American and Caribbean Hispanic Individuals
Background: The APOE ε4 allele is a genetic risk factor for Alzheimer disease (AD), though the strength of the association varies by ethnic group. Polymorphisms in regulatory sequences of APOE have also been related to AD, but the effects are inconsistent across studies.
Methods: We examined the association between AD and variants in 3 APOE promoters and in the promoter of the adjacent APOC1 gene in African American and Caribbean Hispanic individuals. Polymorphisms tested were the −491A/T, −427T/C, and −219G/T (Th1/E47cs) in the APOE promoter and the HpaI variant in the APOC1 promoter. Using standard research criteria for AD, overall odds ratios were computed and repeated stratified by presence or absence of APOE ε4.
Results: The APOC1 HpaI+ variant was associated with AD in Caribbean Hispanic individuals, but strong linkage disequilibrium with the APOE ε4 allele indicated that this was not an independent effect. No promoter variant in APOE or APOC1 was associated with AD before or after adjusting for age, education, sex, and multiple comparisons. Estimated haplotypes including −219G/T, APOE, and APOC1 differed significantly in Caribbean Hispanic patients and controls but not in African American participants. This effect was primarily owing to the −219G/T-APOE haplotype, but we did not detect significant allele-specific differences in promoter activity comparing reporter constructs containing the APOE −219G and −219 T alleles.
Conclusion: These findings exclude a strong or independent influence of APOE or APOC1 promoter polymorphisms on the variation in APOE-related risk of AD in African American and Caribbean Hispanic individuals.
The ε4 variant of the APOE gene is a well-established risk factor for sporadic and familial Alzheimer disease (AD),1,2 although risk appears less consistent among African American and Caribbean Hispanic individuals with sporadic AD.2,3 An attractive hypothesis has been that genetic polymorphisms in regulatory sequences of the APOE locus, either in the immediate upstream promoter region or in the downstream enhancer regions, or a nearby gene might modify the APOE-associated risk. Thus, overexpression of the ε4 allele in the aging brain may be detrimental, possibly by promoting the extracellular aggregation of amyloid-β peptide, whereas overexpression of the ε3 or ε2 alleles may be neutral or protective. Data from transgenic mice that express human APOE protein have tended to support this hypothesis.4,5 An association between 1 or more APOE promoter polymorphisms and AD has been reported.6-15 Promoter polymorphisms associated with AD in 1 or more of these studies are, numbered relative to the transcriptional start site: −491A/T, −427T/C, and −219G/T (also known as Th1/E47cs). However, for each of these markers there are conflicting data.13,16-22 The HpaI+ variant in the promoter of the APOC1 gene, located closely downstream of APOE, has also been associated with AD.23-25 It is not clear whether this is an independent association or due to linkage disequilibrium with the APOE ε4 allele. Herein we report the allele frequencies of each of these polymorphisms in a large sample of African American and Caribbean Hispanic patients with AD and elderly controls, and we test for APOE promoter activity of 1 variant, −219G/T
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Familial Alzheimer Disease Among Caribbean Hispanics: A Reexamination of Its Association With APOE
Objectives: To reexamine the association between the apolipoprotein E ϵ4 allele (APOE ϵ4) and familial Alzheimer disease (AD), and to search for novel genes that may be associated with susceptibility in Caribbean Hispanic families with a history of AD.
Methods: Families were identified in Caribbean Hispanic communities in the greater New York City area, the Dominican Republic, and Puerto Rico. Each family in the study cohort included at least 2 living relatives with a history of dementia. All family members underwent neuropsychological testing and medical and neurological examinations to establish the presence or absence of dementia and to specify the type of dementia.
Results: Over a 2½-year period, 203 families were identified. Of these, 19 families had at least 1 family member with onset of dementia before age 55 years, with 8 of the 19 families showing an association with a previously unreported presenilin mutation. Multiple cases of AD were identified in 29 families. Overall, there were 236 affected sibling pairs with AD available for analysis. The average age at onset was 74 years. The presence of APOE ϵ4 was strongly associated with AD.
Conclusions: Both early-onset and late-onset familial AD occur in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics is strongly associated with APOE ϵ4. Future attempts to identify additional susceptibility genes should consider the effects of APOE ϵ4.
A FAMILY HISTORY of Alzheimer disease (AD) is one of the strongest risk factors for the disease. The lifetime risk of AD for family members of patients approaches 50% in some studies, which suggests an age-dependent autosomal dominant mode of inheritance.1,2 Mutations in genes on chromosomes 1, 14, and 21 are associated with familial early-onset AD, often with an autosomal dominant pattern of inheritance.3,4 However, these genes account for only 10% of all AD. The discovery that a polymorphism in the APOE (apolipoprotein E) gene on chromosome 19 was associated with susceptibility to both sporadic and familial late-onset AD5 led to the search for other potential susceptibility genes. Sites for potential susceptibility genes on chromosome 12 have been identified,6 and, more recently, sites on chromosome 10 have also been identified.7-9 Attempts to confirm the linkage between chromosome 12 and AD have been variable,10-12 and the association with α2-macroglobulin, a candidate gene in the area, has also been inconsistent.13-16 Familial AD may be the result of complex inheritance involving many genes with incomplete penetrance or a combination of genetic and environmental factors.
Hispanics are one of the most rapidly increasing ethnic groups in the United States. The elderly Hispanic population is expected to double in the United States by the year 2010 and increase 11-fold by 2050.17 Compared with other ethnic groups, Caribbean Hispanics have an increased prevalence and incidence of AD,18-20 as do Mexican Americans.21 Yet the reason for this increase in disease frequency is unknown. No specific environmental factors have been identified, which suggests a genetic explanation.
The association between AD and the APOE ϵ4 allelic polymorphism has been weaker in late-onset AD among Caribbean Hispanics compared with whites in New York City20,22,23 but not in Miami, Fla.24,25 We began the family study not only to identify the chromosomal location of additional susceptibility genes in Caribbean Hispanics, but also to reinvestigate the heterogeneity of the APOE association in this population