Citations

Abstract Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-186.

The role of the Alzheimer's Disease Neuroimaging Initiative Genetics Core is to facilitate the investigation of genetic influences on disease onset and trajectory as reflected in structural, functional, and molecular imaging changes; fluid biomarkers; and cognitive status. Major goals include (1) blood sample processing, genotyping, and dissemination, (2) genome‐wide association studies (GWAS) of longitudinal phenotypic data, and (3) providing a central resource, point of contact and planning group for genetics within the Alzheimer's Disease Neuroimaging Initiative. Genome‐wide array data have been publicly released and updated, and several neuroimaging GWAS have recently been reported examining baseline magnetic resonance imaging measures as quantitative phenotypes. Other preliminary investigations include copy number variation in mild cognitive impairment and Alzheimer's disease and GWAS of baseline cerebrospinal fluid biomarkers and longitudinal changes on magnetic resonance imaging. Blood collection for RNA studies is a new direction. Genetic studies of longitudinal phenotypes hold promise for elucidating disease mechanisms and risk, development of therapeutic strategies, and refining selection criteria for clinical trials.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Background— Right ventricular pacing increases the risk of heart failure in adults with structural heart disease. The impact of prolonged right ventricular pacing in adults without structural heart disease is not fully characterized and may depend on interactions of pacing with abnormal substrate predisposing to ventricular dysfunction. Methods and Results— We assessed the effect of right ventricular pacing in patients who underwent pacemaker implantation for isolated congenital atrioventricular block between 1964 and 2005. To assess for immunologic contribution to cardiac dysfunction, outcomes were compared between patients with (Ab + ) and without (Ab − ) antinuclear antibody during adulthood and an age- and sex-matched Olmsted County, Minnesota, population. Of 103 patients (mean±SD age, 32±19 years), 18 were Ab + . Long-term survival free of new heart failure after pacemaker implantation in isolated congenital atrioventricular block patients was worse than in the matched population ( P <0.001). This difference was attributable to the development of heart failure in 12 Ab + patients (67%; P <0.001), without differences between Ab − patients (2%) and the matched population (2%; P =0.7). Compared with baseline, at last follow-up, left ventricular ejection fraction did not decline in Ab − (53±9% to 57±12%) but decreased in Ab + (52±10% to 38±12%; P =0.03) patients. Survival was similar in Ab − patients and the Minnesota population (98%; P =0.7) but worse in Ab + patients (79%; P <0.01). Conclusions— The natural history of patients with isolated congenital atrioventricular block who require pacing depends upon their antibody status. Antinuclear antibody status was a predictor for the development of heart failure and death. Long-term right ventricular pacing alone does not appear to be associated with development of heart failure, deterioration in ventricular function, or reduced survival in Ab − isolated congenital atrioventricular block patients.

Background— The risk of syncope occurring while driving has obvious implications for personal and public safety. We aimed to define the clinical characteristics, causes, and prognosis of syncope while driving. Methods and Results— In this case-control study of consecutive patients evaluated for syncope from 1996 through 1998 at an academic medical center, we documented causes, clinical characteristics, and recurrence of syncope while driving. Of 3877 patients identified, 381 (9.8%) had syncope while driving (driving group). Compared with the 3496 patients (90.2%) who did not have syncope while driving, the driving group was younger ( P =0.01) and had higher percentages of male patients ( P <0.001) and patients with a history of any cardiovascular disease ( P =0.01) and stroke ( P =0.02). Syncope while driving was commonly caused by neurally mediated syncope (37.3%) and cardiac arrhythmias (11.8%). Long-term survival in the driving group was comparable to that of an age- and sex-matched cohort from the Minnesota population ( P =0.15). Among the driving group, syncope recurred in 72 patients, 35 of whom (48.6%) had recurrence >6 months after the initial evaluation. Recurrences during driving happened in 10 patients in the driving group, 7 of which (70%) were >12 months after the initial evaluation. Conclusions— In our study, neurally mediated syncope was the most common type of syncope while driving. The causes of syncope, the late recurrences of syncope (during ≥6 months of follow-up), and the overall low incidence of recurrent syncope while driving provide useful information to supplement current recommendations on driving for these patients.

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

Abstract Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081–9)