ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.

OBJECTIVE: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. METHODS: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. RESULTS: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. CONCLUSIONS: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.

INTRODUCTION: African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. METHODS: We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. RESULTS: Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. DISCUSSION: Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Relationship between depressive symptoms and cognition in older, non-demented African Americans.

Knowledge of the relationship between depressive symptoms and cognition in older adults has primarily come from studies of clinically depressed, functionally impaired or cognitively impaired individuals, and in predominately White samples. Limited minority representation in depression research exposes the need to examine these associations in more ethnic/racially diverse populations. We sought to examine the relationship between depressive symptoms and cognition in a sample of non-demented older African Americans recruited from surrounding U.S. cities of New York, Greensboro, Miami, and Nashville (N=944). Depressive symptoms were evaluated with the Geriatric Depression Scale (GDS). Cognition was evaluated with a comprehensive neuropsychological battery. Test scores were summarized into attention, executive function, memory, language, and processing speed composites. Controlling for age, education, reading level, and sex, African American older adults who endorsed more symptoms obtained significantly lower scores on measures of memory, language, processing speed, and executive functioning. Further investigation of the causal pathway underlying this association, as well as potential mediators of the relationship between depressive symptoms and cognitive test performance among older African Americans, such as cardiovascular and cerebrovascular disease, may offer potential avenues for intervention.

Food expenditure patterns in the Canadian Arctic show cause for concern for obesity and chronic disease.

BACKGROUND: Little is understood about the economic factors that have influenced the nutrition transition from traditional to store-bought foods that are typically high in fat and sugar amongst people living in the Canadian Arctic. This study aims to determine the pattern of household food expenditure in the Canadian Arctic. METHOD: Local food prices were collected over 12 months in six communities in Nunavut and the Northwest Territories. Dietary intake data were collected from 441 adults using a validated quantitative food frequency questionnaire. Money spent on six food groups was calculated along with the cost of energy and selected nutrients per person. RESULTS: Participants spent approximately 10% of total food expenditure on each of the food groups of fruit/vegetables, grains and potatoes, and dairy, 17% on traditional meats (e.g. caribou, goose, char, and seal liver), and 20% on non-traditional meats (e.g. beef, pork, chicken, fish, and processed meats). Non-nutrient-dense foods (NNDF) accounted for 34% of food expenditure. Younger participants (<30 years) spent more on NNDF and less on traditional meats compared with the older age groups. Participants with higher levels of formal education spent more on fruit and vegetables and less on traditional meats, when compared with participants with lower levels of formal education. CONCLUSIONS: Participants spent most household income on NNDF, a possible consequence of generation discrepancy between younger and older participants. The tendency toward NNDF, particularly among youth, should be addressed with an assessment of predictive factors and the development of targeted approaches to population-based interventions.

African American participation in health-related research studies: indicators for effective recruitment.

OBJECTIVE: To elucidate factors that influence African American willingness to participate in health-related research studies. METHODS: The African American Alzheimer disease research study group at North Carolina A&T State University designed an in-person questionnaire and surveyed more than 700 African American adults on their willingness to participate in health-related research studies. The questionnaire was distributed and collected in a nonclinical setting during the years 2008 and 2009. This study was approved by the North Carolina A&T State University Institutional Review Board. RESULTS: Of the 733 valid respondents, 16% had previously participated in a health-related research study. Of these, more than 90% were willing to participate again in future research studies. Of the 614 who had never participated in a research study, more than 70% expressed willingness to participate. The majority (75%) of experienced research study participants (RSP) were older than 40 years compared with 45% of non-research study participants. Experienced research participants were also twice as likely to have a college degree compared with non-research study participants. Seventy-three percent of non-research study participants were willing to participate in research studies in the future. The factors that were probable impediments to participation included lack of time and trust. Men with knowledge of the Tuskegee Syphilis Study were 50% less likely to be willing to participate compared with those who had not heard of Tuskegee Syphilis Study. CONCLUSIONS: African Americans are willing to participate in health-related research studies. Several factors such as the appropriate incentives, community trust building, outreach, and community partnership creation are necessary for engaging minority participants. Incorporating factors that target African American enrollment in research design and implementation, such as increased training of minority health ambassadors and African American researchers and public health specialists, are needed to better engage minorities across generations, in research.

Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.

Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.

Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy has been associated with several mutations in the gene encoding human cardiac troponin I (HCTnI). A missense mutation in the inhibitory region of TnI replaces an arginine residue at position 145 with a glycine and cosegregates with the disease. Results from several assays indicate that the inhibitory function of HCTnI(R145G) is significantly reduced. When HCTnI(R145G) was incorporated into whole troponin, Tn(R145G) (HCTnT small middle dotHCTnI(R145G) small middle dotHCTnC), only partial inhibition of the actin-tropomyosin-myosin ATPase activity was observed in the absence of Ca(2+) compared with wild type Tn (HCTnT small middle dotHCTnI small middle dotHCTnC). Maximal activation of actin-tropomyosin-myosin ATPase in the presence of Ca(2+) was also decreased in Tn(R145G) when compared with Tn. Using skinned cardiac muscle fibers, we determined that in comparison with the wild type complex 1) the complex containing HCTnI(R145G) only inhibited 84% of Ca(2+)-unregulated force, 2) the recovery of Ca(2+)-activated force was decreased, and 3) there was a significant increase in the Ca(2+) sensitivity of force development. Computer modeling of troponin C and I variables predicts that the primary defect in TnI caused by these mutations would lead to diastolic dysfunction. These results suggest that severe diastolic dysfunction and somewhat decreased contractility would be prominent clinical features and that hypertrophy could arise as a compensatory mechanism.