@article {866, title = {Quantitative measures of gait characteristics indicate prevalence of underlying subclinical structural brain abnormalities in high-functioning older adults.}, journal = {Neuroepidemiology}, volume = {26}, year = {2006}, month = {2006}, pages = {52-60}, abstract = {

Abnormal gait in high-functioning older adults may indicate underlying subtle structural brain abnormalities. We tested the hypothesis that temporal and spatial parameters of gait, including speed, stride length and double support time, are cross-sectionally associated with white matter hyperintensity, subcortical infarcts or brain atrophy on brain MRI. We examined 321 men and women (mean age = 78.3) participating to the Cardiovascular Health Study who were free of dementia or stroke at the time of the gait assessment. Analyses were set with gait as independent variable and brain MRIs as dependent variables. Gait measures were determined from the footfalls recorded on a 4-meter-long instrumented walking surface, the GaitMat II. Brain MRIs were examined for the presence of white matter hyperintensity (WMG, graded from 0 to 9), brain infarcts (predominantly subcortical) and ventricular enlargement (graded from 0 to 9). Slower gait, shorter stride length and longer double support times were associated with greater prevalence of white matter grade > or =3 (p = 0.02), and at least 1 brain infarct (p = 0.04) independent of age. In multivariate logistic regression models adjusted for demographics and clinical cardiovascular diseases, those with gait speed <1.02 m/s were more likely to have WMG > or =3 and at least 1 brain infarct, compared with those with faster gait - odds ratio (OR): 2.85, 95\% confidence interval (95\% CI): 1.35, 6.02, and OR: 2.09, 95\% CI: 1.04, 4.19. Shorter stride length was also associated with greater probability of having at least 1 brain infarct (gait stride <0.88 vs. >1.10 m: OR: 3.20, 95\% CI: 1.49, 6.88), while longer double support times were associated with a greater probability of having WMG > or =3 (double support time >0.19 vs. <0.14 s: OR: 2.3, 95\% CI: 1.1, 4.7) independent of demographics and clinical cardiovascular diseases. Gait parameters were not significantly associated with ventricular grade. In summary, in this group of high-functioning older adults, poorer gait speed, shorter stride and longer double support time are associated with high white matter disease and subclinical strokes.

}, keywords = {Aged, Brain, Cerebral Infarction, Cerebral Ventricles, Cerebrovascular Disorders, Cohort Studies, Dementia, Female, Gait, Gait Disorders, Neurologic, Humans, Hypertension, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Stroke, United States}, issn = {0251-5350}, doi = {10.1159/000089240}, author = {Rosano, Caterina and Brach, Jennifer and Longstreth, William T and Newman, Anne B} } @article {929, title = {Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {166}, year = {2006}, month = {2006 Nov 27}, pages = {2388-94}, abstract = {

BACKGROUND: Small vessel disease may contribute to the risk of cardiovascular disease in older persons. We describe the relation of retinal vascular caliber to incident coronary heart disease (CHD) and stroke in elderly persons.

METHODS: Prospective population-based cohort study composed of 1992 men and women aged 69 to 97 years living in 4 US communities. Retinal arteriolar and venular calibers were measured from retinal photographs using a computer-assisted method. Incident CHD and stroke events were ascertained using standardized methods.

RESULTS: After 5 years of follow-up, there were 115 incident CHD events and 113 incident stroke events. Participants with larger retinal venular caliber had a higher incidence of CHD (11.7\%; 95\% confidence interval [CI], 8.7\%-15.8\%, vs 8.1\%; 95\% CI, 5.7\%-11.6\%), comparing largest with smallest venular caliber quartiles, and stroke (8.4\%; 95\% CI, 6.0-11.7, vs 5.8\%; 95\% CI, 3.9-8.4). At multivariable analysis, controlling for age, sex, race, arteriolar caliber, systolic and diastolic blood pressure, diabetes, glucose concentration, cigarette smoking, pack-years of smoking, and high-density-lipoprotein and low-density lipoprotein cholesterol levels, larger retinal venular caliber was associated with incident CHD (rate ratio, 3.0; 95\% CI, 1.6-5.7, comparing largest with smallest venular caliber quartiles; P(trend) = .001) and incident stroke (rate ratio, 2.2; 95\% CI, 1.1-4.3; P(trend) = .02). Additional adjustment for C-reactive protein and common and internal carotid artery intimal-media thickness had minimal effect on these associations. At multivariable analysis, smaller retinal arteriolar caliber was associated with incident CHD (rate ratio, 2.0; 95\% CI, 1.1-3.7, comparing largest with smallest arteriolar caliber quartiles; P = .03) but not stroke (rate ratio,1.1; 95\% CI, 0.5-2.2; P = .73).

CONCLUSION: Larger retinal venular caliber is independently associated with risk of cardiovascular disease in elderly persons.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Cardiovascular Diseases, Cohort Studies, Female, Humans, Image Processing, Computer-Assisted, Incidence, Male, Photography, Prospective Studies, Retinal Diseases, Retinal Vein, Retinal Vessels, Risk Factors, Stroke, United States}, issn = {0003-9926}, doi = {10.1001/archinte.166.21.2388}, author = {Wong, Tien Yin and Kamineni, Aruna and Klein, Ronald and Sharrett, A Richey and Klein, Barbara E and Siscovick, David S and Cushman, Mary and Duncan, Bruce B} } @article {5998, title = {The QT interval and risk of incident atrial fibrillation.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Oct}, pages = {1562-8}, abstract = {

BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.

OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.

METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.

RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95\% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95\% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95\% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.

CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Humans, Incidence, Long QT Syndrome, Male, Middle Aged, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.07.023}, author = {Mandyam, Mala C and Soliman, Elsayed Z and Alonso, Alvaro and Dewland, Thomas A and Heckbert, Susan R and Vittinghoff, Eric and Cummings, Steven R and Ellinor, Patrick T and Chaitman, Bernard R and Stocke, Karen and Applegate, William B and Arking, Dan E and Butler, Javed and Loehr, Laura R and Magnani, Jared W and Murphy, Rachel A and Satterfield, Suzanne and Newman, Anne B and Marcus, Gregory M} } @article {6565, title = {Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Apr 15}, pages = {1957-63}, abstract = {

The study of genetic influences on drug response and efficacy ({\textquoteright}pharmacogenetics{\textquoteright}) has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual{\textquoteright}s responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75\% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7\% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

}, keywords = {Cytochrome P-450 Enzyme System, Databases, Genetic, European Continental Ancestry Group, Exome, Humans, Pharmaceutical Preparations, Pharmacogenetics, Polymorphism, Genetic}, issn = {1460-2083}, doi = {10.1093/hmg/ddt588}, author = {Gordon, Adam S and Tabor, Holly K and Johnson, Andrew D and Snively, Beverly M and Assimes, Themistocles L and Auer, Paul L and Ioannidis, John P A and Peters, Ulrike and Robinson, Jennifer G and Sucheston, Lara E and Wang, Danxin and Sotoodehnia, Nona and Rotter, Jerome I and Psaty, Bruce M and Jackson, Rebecca D and Herrington, David M and O{\textquoteright}Donnell, Christopher J and Reiner, Alexander P and Rich, Stephen S and Rieder, Mark J and Bamshad, Michael J and Nickerson, Deborah A} } @article {8523, title = {{Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis}, journal = {BMJ}, volume = {366}, year = {2019}, month = {07}, pages = {l4292}, abstract = {{To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.\ Individual participant data meta-analysis.\ Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.\ Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.\ Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95\% confidence interval 1.54 to 1.75}, author = {Merino, J. and Guasch-Ferr?, M. and Ellervik, C. and Dashti, H. S. and Sharp, S. J. and Wu, P. and Overvad, K. and Sarnowski, C. and Kuokkanen, M. and Lemaitre, R. N. and Justice, A. E. and Ericson, U. and Braun, K. V. E. and Mahendran, Y. and Frazier-Wood, A. C. and Sun, D. and Chu, A. Y. and Tanaka, T. and Luan, J. and Hong, J. and Tj?nneland, A. and Ding, M. and Lundqvist, A. and Mukamal, K. and Rohde, R. and Schulz, C. A. and Franco, O. H. and Grarup, N. and Chen, Y. I. and Bazzano, L. and Franks, P. W. and Buring, J. E. and Langenberg, C. and Liu, C. T. and Hansen, T. and Jensen, M. K. and S??ksj?rvi, K. and Psaty, B. M. and Young, K. L. and Hindy, G. and Sandholt, C. H. and Ridker, P. M. and Ordovas, J. M. and Meigs, J. B. and Pedersen, O. and Kraft, P. and Perola, M. and North, K. E. and Orho-Melander, M. and Voortman, T. and Toft, U. and Rotter, J. I. and Qi, L. and Forouhi, N. G. and Mozaffarian, D. and S?rensen, T. I. A. and Stampfer, M. J. and M?nnist?, S. and Selvin, E. and Imamura, F. and Salomaa, V. and Hu, F. B. and Wareham, N. J. and Dupuis, J. and Smith, C. E. and Kilpel?inen, T. O. and Chasman, D. I. and Florez, J. C.} }