Brent Anderson

C3 R102G polymorphism increases risk of age-related macular degeneration

Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H (CFH) and complement factor B (CFB) genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk. These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls. The C3 polymorphisms were in strong LD (r(2) = 0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT P = 0.02, case-control genotypic P = 0.004; L314P genoPDT P = 0.001, case-control genotypic P = 0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (P = 0.01), but there was no effect of L314P in the R102G risk allele carriers (P = 0.2). After adjusting for age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong [P = 0.015, odds ratio = 1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR(population attributable risk) = 0.17]. Therefore, while the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data.

Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration.

The objective of this study was to determine if MTND2*LHON4917G (4917G), a specific non-synonymous polymorphism in the mitochondrial genome previously associated with neurodegenerative phenotypes, is associated with increased risk for age-related macular degeneration (AMD). A preliminary study of 393 individuals (293 cases and 100 controls) ascertained at Vanderbilt revealed an increased occurrence of 4917G in cases compared to controls (15.4% vs.9.0%, p = 0.11). Since there was a significant age difference between cases and controls in this initial analysis, we extended the study by selecting Caucasian pairs matched at the exact age at examination. From the 1547 individuals in the Vanderbilt/Duke AMD population association study (including 157 in the preliminary study), we were able to match 560 (280 cases and 280 unaffected) on exact age at examination. This study population was genotyped for 4917G plus specific AMD-associated nuclear genome polymorphisms in CFH, LOC387715 and ApoE. Following adjustment for the listed nuclear genome polymorphisms, 4917G independently predicts the presence of AMD (OR = 2.16, 95%CI 1.20–3.91, p = 0.01). In conclusion, a specific mitochondrial polymorphism previously implicated in other neurodegenerative phenotypes (4917G) appears to convey risk for AMD independent of recently discovered nuclear DNA polymorphisms.

Genomic convergence to identify candidate genes for Alzheimer disease on chromosome 10

A broad region of chromosome 10 (chr10) has engendered continued interest in the etiology of late‐onset Alzheimer Disease (LOAD) from both linkage and candidate gene studies. However, there is a very extensive heterogeneity on chr10. We converged linkage analysis and gene expression data using the concept of genomic convergence that suggests that genes showing positive results across multiple different data types are more likely to be involved in AD. We identified and examined 28 genes on chr10 for association with AD in a Caucasian case‐control dataset of 506 cases and 558 controls with substantial clinical information. The cases were all LOAD (minimum age at onset ≥60 years). Both single marker and haplotypic associations were tested in the overall dataset and 8 subsets defined by age, gender, ApoE and clinical status. PTPLA showed allelic, genotypic and haplotypic association in the overall dataset. SORCS1 was significant in the overall data sets (p=0.0025) and most significant in the female subset (allelic association p=0.00002, a 3‐locus haplotype had p=0.0005). Odds Ratio of SORCS1 in the female subset was 1.7 (p<0.0001). SORCS1 is an interesting candidate gene involved in the Aβ pathway. Therefore, genetic variations in PTPLA and SORCS1 may be associated and have modest effect to the risk of AD by affecting Aβ pathway. The replication of the effect of these genes in different study populations and search for susceptible variants and functional studies of these genes are necessary to get a better understanding of the roles of the genes in Alzheimer disease. 30, 463–471, 2009.

Examination of association to autism of common genetic variationin genes related to dopamine

Autism is a severe neurodevelopmental disorder characterized by a triad of complications. Autistic individuals display significant disturbances in language and reciprocal social interactions, combined with repetitive and stereotypic behaviors. Prevalence studies suggest that autism is more common than originally believed, with recent estimates citing a rate of one in 150. Although multiple genetic linkage and association studies have yielded multiple suggestive genes or chromosomal regions, a specific risk locus has yet to be identified and widely confirmed. Because many etiologies have been suggested for this complex syndrome, we hypothesize that one of the difficulties in identifying autism genes is that multiple genetic variants may be required to significantly increase the risk of developing autism. Thus, we took the alternative approach of examining 14 prominent dopamine pathway candidate genes for detailed study by genotyping 28 single nucleotide polymorphisms. Although we did observe a nominally significant association for rs2239535 (P=0.008) on chromosome 20, single‐locus analysis did not reveal any results as significant after correction for multiple comparisons. No significant interaction was identified when Multifactor Dimensionality Reduction was employed to test specifically for multilocus effects. Although genome‐wide linkage scans in autism have provided support for linkage to various loci along the dopamine pathway, our study does not provide strong evidence of linkage or association to any specific gene or combination of genes within the pathway. These results demonstrate that common genetic variation within the tested genes located within this pathway at most play a minor to moderate role in overall autism pathogenesis.

Circulating Neuregulin-1β Levels Vary According to the Angiographic Severity of Coronary Artery Disease and Ischemia

BackgroundCoronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1&bgr; (NRG-1&bgr;) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1&bgr; is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1&bgr; would vary in relation to CAD severity and the presence of stress-induced ischemia. MethodsWe measured serum and plasma levels of NRG-1&bgr; and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score. ResultsSerum NRG-1&bgr; (sNRG-1&bgr;), plasma NRG-1&bgr; (pNRG-1&bgr;), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1&bgr; levels were approximately two-fold higher than sNRG-1&bgr;. Both sNRG-1&bgr; and pNRG-1&bgr; correlated inversely with CAD severity. pNRG-1&bgr; levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02). ConclusionBoth sNRG-1&bgr; and pNRG-1&bgr; correlated inversely with angiographic severity of CAD. pNRG-1&bgr; levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1&bgr; as a biomarker of CAD severity and ischemia.

Predicting and preventing the cardiotoxicity of cancer therapy

For the past 40 years, cardiovascular disease and malignant neoplasms have been the leading causes of death in the USA. As treatments for cancer, cardiovascular disease, diabetes and other chronic illnesses improve, we are seeing more complicated patients in our clinics. Cancer therapies such as anthracyclines and radiation therapy continue to pose a risk for delayed-onset cardiovascular disease, in spite of decades of research. It has been reported that the risk of congestive heart failure is the second most common, late, long-term disabling health condition among cancer survivors. Improved understanding of an individual’s risk for cardiovascular complications of these therapies and earlier intervention for selected patients may help to improve the overall outcome for patients requiring these therapies. New therapies targeting oncogenes and the process of angiogenesis have ‘off-target’ effects regarding the cardiovascular system that remain poorly understood. Our knowledge and experience in the cardiovascular care of patients with cancer must continue to grow if we are to assure the best possible outcome for these people. The aim of this review is to highlight the risk of chemotherapy-induced cardiotoxicity among several of the most commonly used cancer therapies, various ways to screen for patients at highest risk of cardiotoxicity and management of cardiac complications of cancer therapy. We spend a disproportionate amount of space and time on the subject of anthracycline toxicity due to its often devastating nature, and its persistence as a clinical problem despite decades of use and research.

Association Analysis of Genetic Polymorphisms in the CDC2 Gene with Late-Onset Alzheimer Disease

Background: Alzheimer disease (AD) is a complex neurodegenerative disorder resulting from multiple genetic and non-genetic factors. Linkage studies indicated that chromosome 10 has at least one locus for this disease. The cell division cycle 2 (CDC2) gene, which is close to one of the linkage regions, has previously been associated with the risk of AD with an odds ratio of 1.78. Biologically, CDC2, which is involved in paired helical filament-tau formation, is thought as a candidate gene in AD. Methods: In this study, six single nucleotide polymorphisms spanning the entire gene were selected and examined for association for late-onset AD (LOAD) in two large independent datasets. A family-based dataset including 1,337 Caucasian discordant sib pairs and an independent dataset of 745 Caucasian cases and 998 controls for LOAD were used. Family-based association tests and logistic regression conditional on the apolipoprotein E genotype and sex were applied to association study in family-based and case-control datasets, respectively. Results: Neither dataset demonstrated any association with LOAD in our samples with all p values >0.16. Conclusion: Our results suggest that if any contribution of common genetic variants in CDC2 to the risk of developing AD exists, it is likely to be very small.

P1-313: Examination of the effect of heterogeneity on the chromosome 10 risk in late-onset Alzheimer’s disease

The common apolipoprotein E (APOE) e4 allele is strongly associated with risk of dementia and age at onset, but studies are inconclusive as to whether the e4 allele affects rate of progression or survival in demented patients. Furthermore, previous observations suggest a contribution of two APOE promoter polymorphisms (-491 A/T and -219 G/T) in dementia, but the influence of these two polymorphisms on survival in demented patients have not been evaluated yet.