Deane Drug Discovery Institute

Durham, NC, United States

Deane Drug Discovery Institute

Durham, NC, United States
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Caselli R.J.,Arizona Alzheimer Research Consortium | Huentelman M.J.,Arizona Alzheimer Research Consortium | Huentelman M.J.,Translational Genomics Research Institute | Lutz M.W.,Duke University | And 8 more authors.
Alzheimer's and Dementia | Year: 2012

Background: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline. Methods: An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two. Results: There were significant effects overall for both TOMM40 (linear effect, P =.04; quadratic effect, P =.03) and APOE (linear effect, P =.06; quadratic effect, P =.008), with no significant interaction (P =.63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P =.009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P =.006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect. Conclusion: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other. © 2012 The Alzheimer's Association. All rights reserved.

Grossman I.,Cabernet Pharmaceuticals | Lutz M.W.,Duke University | Lutz M.W.,Deane Drug Discovery Institute | Crenshaw D.G.,Duke University | And 9 more authors.
EPMA Journal | Year: 2010

Alzheimer's disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subtype for the purpose of disease monitoring or differential diagnosis, a biomarker for reliable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine. Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset when coupled with a subject's current age. This finding offers hope for reliable assignment of disease risk within a 5-7 year window, and is expected to guide enrichment of clinical trials in order to speed development of preventative medicines. © 2010 The Author(s).

Roses A.D.,Duke University | Roses A.D.,Deane Drug Discovery Institute | Lutz M.W.,Duke University | Lutz M.W.,Deane Drug Discovery Institute | And 13 more authors.
Pharmacogenomics Journal | Year: 2010

The£4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE£3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE £3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE£3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE£3 (70.5±1.2 years versus 77.6±2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Heinzen E.L.,Duke University | Need A.C.,Duke University | Hayden K.M.,Duke University | Chiba-Falek O.,Duke University | And 6 more authors.
Journal of Alzheimer's Disease | Year: 2010

Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation. © 2010 - IOS Press and the authors. All rights reserved.

Makeeva O.A.,Russian Academy of Medical Sciences | Markova V.V.,Russian Academy of Medical Sciences | Roses A.D.,Deane Drug Discovery Institute | Roses A.D.,Duke University | Puzyrev V.P.,Russian Academy of Medical Sciences
Personalized Medicine | Year: 2010

Many new genetic tests for common multifactorial disorders are becoming available to individuals, including direct-to-consumer genotyping services. Typically, studies of public attitudes reveal a high level of interest for individual genotyping. In a Russian urban population, 85% of 2000 respondents answered positively to a question about their own willingness to undergo predictive genetic testing for preventable health conditions. Gender, age and health status significantly influenced response. Multivariate discriminant analyses revealed that wanting to know about probable future diseases, readiness to improve lifestyles and an interest in learning about individual genome characteristics are the most important predictors for wanting to be tested. Along with the high level of interest, highly overestimated expectations were encountered in many studies. With the low predictive abilities of currently available genetic tests for common disorders, proper interpretation of the data and genetic counseling are essential. There is a need for prospective validation of genetic panels for risk assessments, and for efforts to measure the effects of genetic information disclosure and how this information might contribute to lifestyle changes. © 2010 Future Medicine Ltd.

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