@article {1441, title = {Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group.}, journal = {Circulation}, volume = {88}, year = {1993}, month = {1993 Sep}, pages = {837-45}, abstract = {

BACKGROUND: Peripheral arterial disease measured noninvasively by the ankle-arm index (AAI) is common in older adults, largely asymptomatic, and associated with clinically manifest cardiovascular disease (CVD). The criteria for an abnormal AAI have varied in previous studies. To determine whether there is an inverse dose-response relation between the AAI and clinical CVD, subclinical disease, and risk factors, we examined the relation of the AAI to cardiovascular risk factors, other noninvasive measures of subclinical atherosclerosis using carotid ultrasound, echocardiography and electrocardiography, and clinical CVD.

METHODS AND RESULTS: The AAI was measured in 5084 participants > or = 65 years old at the baseline examination of the Cardiovascular Health Study. All subjects had detailed assessment of prevalent CVD, measures of cardiovascular risk factors, and noninvasive measures of disease. Participants were stratified by baseline clinical CVD status and AAI (< 0.8, > or = 0.8 to < 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.5). Analyses tested for a dose-response relation of the AAI with clinical CVD, risk factors, and subclinical disease. The cumulative frequency of a low AAI was 7.4\% of participants < 0.8, 12.4\% < 0.9, and 23.6\% < 1.0. participants with an AAI < 0.8 were more than twice as likely as those with an AAI of 1.0 to 1.5 to have a history of myocardial infarction, angina, congestive heart failure, stroke, or transient ischemic attack (all P < .01). In participants free of clinical CVD at baseline, the AAI was inversely related to history of hypertension, history of diabetes, and smoking, as well as systolic blood pressure, serum creatinine, fasting glucose, fasting insulin, measures of pulmonary function, and fibrinogen level (all P < .01). Risk factor associations with the AAI were similar in men and women free of CVD except for serum total and low-density lipoprotein cholesterol, which were inversely associated with AAI level only in women. Risk factors associated with an AAI of < 1.0 in multivariate analysis included smoking (odds ratio [OR], 2.55), history of diabetes (OR, 3.84), increasing age (OR, 1.54), and nonwhite race (OR, 2.36). In the 3372 participants free of clinical CVD, other noninvasive measures of subclinical CVD, including carotid stenosis by duplex scanning, segmental wall motion abnormalities by echocardiogram, and major ECG abnormalities were inversely related to the AAI (all P < .01).

CONCLUSIONS: There was an inverse dose-response relation of the AAI with CVD risk factors and subclinical and clinical CVD among older adults. The lower the AAI, the greater the increase in CVD risk; however, even those with modest, asymptomatic reductions in the AAI (0.8 to 1.0) appear to be at increased risk of CVD.

}, keywords = {Aged, Ankle, Arm, Arteriosclerosis, Blood Pressure Determination, Cardiovascular Diseases, Female, Humans, Male, Multivariate Analysis, Peripheral Vascular Diseases, Population Surveillance, Predictive Value of Tests, Risk Factors}, issn = {0009-7322}, author = {Newman, A B and Siscovick, D S and Manolio, T A and Polak, J and Fried, L P and Borhani, N O and Wolfson, S K} } @article {1468, title = {Hypertension and outcomes research. From clinical trials to clinical epidemiology.}, journal = {Am J Hypertens}, volume = {9}, year = {1996}, month = {1996 Feb}, pages = {178-83}, abstract = {

Outcomes research seeks to identify effective evidence-based methods of providing the best medical care. While randomized clinical trials (RCT) usually provide the clearest answers, they are often not done or not practicable. More than a decade after the introduction of calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors, clinical trial data about their effect on major disease endpoints in patients with hypertension are still not available. The primary alternatives are the use of randomized trials that include surrogate endpoints, such as level of blood pressure or extent of carotid atherosclerosis, and the use of observational studies that include major disease endpoints. Both approaches, their strengths and limitations, are discussed in detail. The possibility of residual confounding limits the strength of inferences that can be drawn from observational studies. Similarly, the possibility of important drug effects, other than those involving the surrogate endpoint, limits the inferences that can be drawn from randomized trials that rely solely on surrogate outcomes as guides to therapy. In the absence of evidence from large clinical trials that include major disease endpoints, treatment decisions and guidelines need to synthesize the best available information from a variety of sources. Consistency of findings across various study designs, outcomes, and populations is critical to the practice of evidence-based medicine and the effort to maximize the health benefits of antihypertensive therapies.

}, keywords = {Clinical Trials as Topic, Epidemiologic Methods, Evidence-Based Medicine, Humans, Hypertension, Outcome Assessment (Health Care)}, issn = {0895-7061}, author = {Psaty, B M and Siscovick, D S and Weiss, N S and Koepsell, T D and Rosendaal, F R and Lin, D and Heckbert, S R and Wagner, E H and Furberg, C D} } @article {1482, title = {Exercise intensity and subclinical cardiovascular disease in the elderly. The Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {145}, year = {1997}, month = {1997 Jun 01}, pages = {977-86}, abstract = {

The authors assessed the cross-sectional association between intensity of exercise in later life and coronary heart disease risk factors and subclinical disease among 2,274 men and women, 65 years of age and older, who were participants in the Cardiovascular Health Study (CHS) during 1989-1990. Subjects were free of prior clinical cardiovascular disease or impairment of physical function. Exercise intensity was characterized as low, moderate, or high, based on highest intensity exercise reported over the 2 weeks prior to the CHS baseline examination. After adjustment for age, education, and postmenopausal hormone therapy (among women), there was an inverse dose-response relationship of exercise intensity with selected risk factors. By low, moderate, and high exercise intensity, respectively: fasting insulin-men, 15.6 microU/ml, 14.1 microU/ml, and 12.6 microU/ml, p for trend <0.001; women, 14.8 microU/ml, 13.8 microU/ml, and 12.0 microU/ml, p for trend = 0.01; serum fibrinogen-men, 316.2 mg/dl, 315.4 mg/dl, and 300.0 mg/dl, p for trend = 0.01; women, 327.3 mg/dl, 317.0 mg/dl, and 310.7 mg/dl, p for trend = 0.01; lower extremity arterial disease by percent with ankle-arm index <0.9-men, 18.3, 5.5, and 3.7, p for trend = 0.01; women, 10.0, 5.7, and 2.8, p for trend = 0.02; evidence of myocardial injury by cardiac infarction/injury score (CIIS)-men, 8.0, 6.0, 3.9, p for trend <0.001; women, 4.6, 3.9, and 3.6, p for trend = 0.03. Adjustment for smoking, alcohol consumption, and total kilocalories expended in exercise altered the findings only slightly. The authors conclude that intensity of exercise in later life is associated with favorable coronary disease risk factor levels and a reduced prevalence of several markers of subclinical disease.

}, keywords = {Aged, Cardiovascular Diseases, Cross-Sectional Studies, Energy Metabolism, Exercise, Female, Fibrinogen, Humans, Insulin, Life Style, Longitudinal Studies, Male, Prevalence, Risk Factors}, issn = {0002-9262}, author = {Siscovick, D S and Fried, L and Mittelmark, M and Rutan, G and Bild, D and O{\textquoteright}Leary, D H} } @article {596, title = {Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.}, journal = {N Engl J Med}, volume = {341}, year = {1999}, month = {1999 Jul 15}, pages = {142-7}, abstract = {

BACKGROUND: Although aortic-valve stenosis is clearly associated with adverse cardiovascular outcomes, it is unclear whether valve sclerosis increases the risk of cardiovascular events.

METHODS: We assessed echocardiograms obtained at base line from 5621 men and women 65 years of age or older who were enrolled in a population-based prospective study. On echocardiography, the aortic valve was normal in 70 percent (3919 subjects), sclerotic without outflow obstruction in 29 percent (1610), and stenotic in 2 percent (92). The subjects were followed for a mean of 5.0 years to assess the risk of death from any cause and of death from cardiovascular causes. Cardiovascular morbidity was defined as new episodes of myocardial infarction, angina pectoris, congestive heart failure, or stroke.

RESULTS: There was a stepwise increase in deaths from any cause (P for trend, <0.001) and deaths from cardiovascular causes (P for trend, <0.001) with increasing aortic-valve abnormality; the respective rates were 14.9 and 6.1 percent in the group with normal aortic valves, 21.9 and 10.1 percent in the group with aortic sclerosis, and 41.3 and 19.6 percent in the group with aortic stenosis. The relative risk of death from cardiovascular causes among subjects without coronary heart disease at base line was 1.66 (95 percent confidence interval, 1.23 to 2.23) for those with sclerotic valves as compared with those with normal valves, after adjustment for age and sex. The relative risk remained elevated after further adjustment for clinical factors associated with sclerosis (relative risk, 1.52; 95 percent confidence interval, 1.12 to 2.05). The relative risk of myocardial infarction was 1.40 (95 percent confidence interval, 1.07 to 1.83) among subjects with aortic sclerosis, as compared with those with normal aortic valves.

CONCLUSIONS: Aortic sclerosis is common in the elderly and is associated with an increase of approximately 50 percent in the risk of death from cardiovascular causes and the risk of myocardial infarction, even in the absence of hemodynamically significant obstruction of left ventricular outflow.

}, keywords = {Aged, Angina Pectoris, Aortic Valve, Calcinosis, Cardiovascular Diseases, Cerebrovascular Disorders, Female, Heart Failure, Heart Valve Diseases, Humans, Male, Mortality, Myocardial Infarction, Prospective Studies, Risk, Risk Factors, Ultrasonography, United States, Ventricular Outflow Obstruction}, issn = {0028-4793}, doi = {10.1056/NEJM199907153410302}, author = {Otto, C M and Lind, B K and Kitzman, D W and Gersh, B J and Siscovick, D S} } @article {625, title = {Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study.}, journal = {Circulation}, volume = {102}, year = {2000}, month = {2000 Nov 07}, pages = {2335-40}, abstract = {

BACKGROUND: Whether serological evidence of prior infection with Chlamydia pneumoniae, herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy.

METHODS AND RESULTS: We conducted a nested case-control study among participants in the Cardiovascular Health Study, a cohort study of persons aged >/=65 years. Cases experienced an incident MI and CHD death (n=213). Control subjects were matched to cases by age, sex, clinic, year of enrollment, and month of blood draw (n=405). Serum was analyzed for IgG antibodies to C pneumoniae, HSV-1, and CMV. After adjustment for other risk factors, the risk of MI and CHD death was associated with the presence of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95\% CI 1.1 to 3.6) but was not associated with the presence of IgG antibodies to either C pneumoniae (OR 1.1, 95\% CI 0.7 to 1.8) or CMV (OR 1.2, 95\% CI 0.7 to 1.9). Although there was little association with low to moderate C pneumoniae antibody titers (

CONCLUSIONS: Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae, only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.

}, keywords = {Adult, Age Factors, Aged, Antibodies, Bacterial, Antibodies, Viral, Case-Control Studies, Chlamydophila pneumoniae, Coronary Disease, Cytomegalovirus, Female, Herpesvirus 1, Human, HIV Antibodies, Humans, Immunoglobulin G, Male, Myocardial Infarction, Risk Factors}, issn = {1524-4539}, doi = {10.1161/01.cir.102.19.2335}, author = {Siscovick, D S and Schwartz, S M and Corey, L and Grayston, J T and Ashley, R and Wang, S P and Psaty, B M and Tracy, R P and Kuller, L H and Kronmal, R A} } @article {660, title = {Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study.}, journal = {Stroke}, volume = {32}, year = {2001}, month = {2001 Sep}, pages = {1939-46}, abstract = {

BACKGROUND AND PURPOSE: Subclinical findings on MRI of the brain are associated with poorer cognitive and neurological function among older adults. We sought to determine how alcohol consumption is related to these findings.

METHODS: As part of the Cardiovascular Health Study, 3660 adults aged 65 years and older underwent MRI of the brain from 1992 to 1994. We excluded 284 participants with a confirmed history of cerebrovascular disease. We assessed self-reported intake of beer, wine, and liquor at the annual clinic visit closest to the date of the MRI and grouped participants into 6 categories: abstainers, former drinkers, <1 drink weekly, 1 to <7 drinks weekly, 7 to <15 drinks weekly, and >/=15 drinks weekly. Neuroradiologists assessed white matter grade, infarcts, ventricular size, and sulcal size in a standardized and blinded manner. We used multivariate regression to control for sociodemographic and clinical characteristics.

RESULTS: We found a U-shaped relationship between alcohol consumption and white matter abnormalities. Compared with abstainers, individuals consuming 1 to <7 drinks had an OR of 0.68, and those consuming >/=15 drinks weekly had an OR of 0.95 (p for quadratic term=0.01). Heavier alcohol consumption was associated with a lower prevalence of infarcts (OR for >/=15 drinks weekly relative to abstainers 0.59; P for trend=0.004), but larger ventricular size (OR for >/=15 drinks weekly relative to abstainers 1.32; P for trend=0.006) and sulcal size (OR for >/=15 drinks weekly relative to abstainers 1.53; P for trend=0.007).

CONCLUSIONS: Moderate alcohol consumption is associated with a lower prevalence of white matter abnormalities and infarcts, thought to be of vascular origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older adults. The extent to which these competing associations influence overall brain function will require further study.

}, keywords = {Aged, Aging, Alcohol Drinking, Atrophy, Brain, Brain Diseases, Cerebral Infarction, Comorbidity, Demography, Female, Health Surveys, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Odds Ratio, Prospective Studies, Sensitivity and Specificity, United States}, issn = {1524-4628}, doi = {10.1161/hs0901.095723}, author = {Mukamal, K J and Longstreth, W T and Mittleman, M A and Crum, R M and Siscovick, D S} } @article {699, title = {Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study.}, journal = {Br J Ophthalmol}, volume = {86}, year = {2002}, month = {2002 Sep}, pages = {1007-13}, abstract = {

AIM: To examine the relation between blood pressure and retinal microvascular abnormalities in older people.

METHODS: The Cardiovascular Health Study is a prospective cohort study conducted in four US communities initiated in 1989 to 1990. Blood pressure was measured according to standardised protocols at each examination. During the 1997-8 examination, retinal photographs were taken of 2405 people aged 69-97 years (2056 without diabetes and 349 with diabetes). Signs of focal microvascular abnormalities (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) were evaluated from photographs according to standardised methods. To quantify generalised arteriolar narrowing, the photographs were digitised and diameters of individual arterioles were measured and summarised.

RESULTS: In non-diabetic people, elevated concurrent blood pressure taken at the time of retinal photography was strongly associated with presence of all retinal microvascular lesions. The multivariable adjusted odds ratios, comparing the highest to lowest quintile of concurrent systolic blood pressure, were 4.0 (95\% confidence intervals (CI): 2.4 to 6.9, p test of trend<0.001) for focal arteriolar narrowing, 2.9 (95\% CI: 1.6 to 5.3, p<0.001) for arteriovenous nicking, 2.8 (95\% CI: 1.5 to 5.2, p<0.001) for retinopathy, and 2.1 (95\% CI: 1.4 to 3.1, p<0.001) for generalised arteriolar narrowing. Generalised arteriolar narrowing and possibly arteriovenous nicking were also significantly associated with past blood pressure measured up to 8 years before retinal photography, even after adjustment for concurrent blood pressure. These associations were somewhat weaker in people with diabetes.

CONCLUSIONS: Retinal microvascular abnormalities are related to elevated concurrent blood pressure in older people. Additionally, generalised retinal arteriolar narrowing and possibly arteriovenous nicking are related to previously elevated blood pressure, independent of concurrent blood pressure. These data suggest that retinal microvascular changes reflect severity and duration of hypertension.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Cohort Studies, Diabetic Retinopathy, Eye, Female, Humans, Male, Microcirculation, Prospective Studies, Retina, Retinal Diseases}, issn = {0007-1161}, doi = {10.1136/bjo.86.9.1007}, author = {Wong, T Y and Hubbard, L D and Klein, R and Marino, E K and Kronmal, R and Sharrett, A R and Siscovick, D S and Burke, G and Tielsch, J M} } @article {944, title = {Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study.}, journal = {Osteoporos Int}, volume = {18}, year = {2007}, month = {2007 May}, pages = {593-602}, abstract = {

INTRODUCTION: Previous studies have found inconsistent relationships of alcohol consumption with risk of hip fracture, and the importance of bone mineral density and risk of falls in mediating such a relationship has not been determined.

METHODS: As part of the Cardiovascular Health Study, a population-based cohort study of adults aged 65 years and older from four U.S. communities, 5,865 participants reported their use of beer, wine, and liquor yearly. We identified cases of hip fracture unrelated to malignancy or motor vehicle accidents using hospitalization discharge diagnoses. A subgroup of 1,567 participants in two communities underwent dual-energy x-ray absorptiometry scans to assess bone mineral density.

RESULTS: A total of 412 cases of hip fracture occurred during an average of 12 years of follow-up. There was a significant U-shaped relationship between alcohol intake and risk of hip fracture (p quadratic 0.02). Compared with long-term abstainers, the adjusted hazard ratios for hip fracture were 0.78 (95\% confidence interval [CI], 0.61-1.00) among consumers of up to 14 drinks per week and 1.18 (95\% CI, 0.77-1.81) among consumers of 14 or more drinks per week. Alcohol intake was associated with bone mineral density of the total hip and femoral neck in a stepwise manner, with approximately 5\% (95\% CI, 1\%-9\%) higher bone density among consumers of 14 or more drinks per week than among abstainers. These relationships were all similar among men and women.

CONCLUSIONS: Among older adults, moderate alcohol consumption has a U-shaped relationship with risk of hip fracture, but a graded positive relationship with bone mineral density at the hip.

}, keywords = {Absorptiometry, Photon, Aged, Alcohol Drinking, Alcoholic Beverages, Apolipoproteins E, Bone Density, Female, Femur Neck, Genotype, Hip, Hip Fractures, Humans, Longitudinal Studies, Male, Risk Assessment, Risk Factors, Sex Distribution, United States}, issn = {0937-941X}, doi = {10.1007/s00198-006-0287-7}, author = {Mukamal, K J and Robbins, J A and Cauley, J A and Kern, L M and Siscovick, D S} } @article {1046, title = {Fish consumption and risk of subclinical brain abnormalities on MRI in older adults.}, journal = {Neurology}, volume = {71}, year = {2008}, month = {2008 Aug 05}, pages = {439-46}, abstract = {

OBJECTIVE: To investigate the association between fish consumption and subclinical brain abnormalities.

METHODS: In the population-based Cardiovascular Health Study, 3,660 participants age > or =65 underwent an MRI scan in 1992-1994. Five years later, 2,313 were scanned. Neuroradiologists assessed MRI scans in a standardized and blinded manner. Food frequency questionnaires were used to assess dietary intakes. Participants with known cerebrovascular disease were excluded from the analyses.

RESULTS: After adjustment for multiple risk factors, the risk of having one or more prevalent subclinical infarcts was lower among those consuming tuna/other fish > or =3 times/week, compared to <1/month (relative risk 0.74, 95\% CI = 0.54-1.01, p = 0.06, p trend = 0.03). Tuna/other fish consumption was also associated with trends toward lower incidence of subclinical infarcts. Additionally, tuna/other fish intake was associated with better white matter grade, but not with sulcal and ventricular grades, markers of brain atrophy. No significant associations were found between fried fish consumption and any subclinical brain abnormalities.

CONCLUSIONS: Among older adults, modest consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examinations. Our results add to prior evidence that suggest that dietary intake of fish with higher eicosapentaenoic acid and docosahexaenoic acid content, and not fried fish intake, may have clinically important health benefits.

}, keywords = {Aged, Animals, Brain, Brain Infarction, Cooking, Cross-Sectional Studies, Diet, Female, Fish Products, Fishes, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, Risk}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000324414.12665.b0}, author = {Virtanen, J K and Siscovick, D S and Longstreth, W T and Kuller, L H and Mozaffarian, D} } @article {1070, title = {Hypertension genes and retinal vascular calibre: the Cardiovascular Health Study.}, journal = {J Hum Hypertens}, volume = {23}, year = {2009}, month = {2009 Sep}, pages = {578-84}, abstract = {

We examined the associations of single nucleotide polymorphisms (SNPs) in three candidate hypertension genes, alpha-adducin (ADD1/G460W), beta2-adrenergic receptor (ADRB2/Arg16Gly and Gln27Glu) and G-protein beta3 subunit (GNB3/C825T), with retinal arteriolar calibre (an intermediate marker of chronic hypertension) and venular calibre. Data in 1842 participants (1554 whites and 288 African Americans) aged 69-96 years from the Cardiovascular Health Study with genotype and retinal vascular calibre data were included. A computer-assisted method was used to measure retinal vascular calibre. We analysed four SNPs and multilocus interaction for three genes. All SNPs were in Hardy-Weinberg equilibrium in whites and African Americans. The study had sufficient power to detect 0.5\% of the total variance of retinal vascular calibre contributed by each SNP in the total population, except for the GNB3 gene variant. No significant associations between these SNPs in the genes studied and mean retinal arteriolar and venular calibre were found in single-gene or multilocus analysis (for example, age-, gender-, race-adjusted mean retinal arteriolar calibre was similar between participants who were ADD1/460W homozygotes and ADD1/G allele carriers, 166.2 vs 167.7 microm). In conclusion, this study found no evidence of an association of SNPs in candidate hypertension genes studied here with retinal vascular calibre.

}, keywords = {African Americans, Aged, Aged, 80 and over, Arterioles, Calmodulin-Binding Proteins, European Continental Ancestry Group, Heterotrimeric GTP-Binding Proteins, Humans, Hypertension, Longitudinal Studies, Polymorphism, Single Nucleotide, Receptors, Adrenergic, beta-2, Retinal Vessels}, issn = {1476-5527}, doi = {10.1038/jhh.2008.168}, author = {Sun, C and Wang, J J and Islam, F M and Heckbert, S R and Klein, R and Siscovick, D S and Klein, B E K and Wong, T Y} } @article {1091, title = {Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly.}, journal = {Nutr Metab Cardiovasc Dis}, volume = {20}, year = {2010}, month = {2010 Jan}, pages = {15-21}, abstract = {

BACKGROUND AND AIMS: Glycosylated hemoglobin (HbA(1c)) has been associated with incident cardiovascular disease (CVD), but the findings are inconsistent. We tested the hypothesis that HbA(1c) may be associated with an increased risk of death and cardiovascular mortality in older adults.

METHODS AND RESULTS: We evaluated the association between HbA(1c) with all-cause and cardiovascular mortality in 810 participants without a history of diabetes in a sub-study of the Cardiovascular Health Study (CHS), a community cohort study of individuals > or =65 years of age. Glycosylated hemoglobin was measured at baseline and all-cause and cardiovascular mortality was assessed during the follow-up period. The relation between baseline HbA(1c) and death was evaluated with multivariate Cox proportional hazards regression models. After a median follow-up of 14.2 years, 416 deaths were observed. The crude incidence rates of all-cause mortality across HbA(1c) groups were: 4.4\% per year, 4.3\% per year and 4.6\% per year for tertile 1 (< or =5.6\%), tertile 2 (5.61-6.20\%) and tertile 3 (> or =6.21\%), respectively. In unadjusted and fully adjusted analyses, baseline HbA(1c) was not associated with all-cause mortality and cardiovascular mortality (hazard ratio: 1.16 [95\% confidence interval 0.91-1.47] and hazard ratio: 1.31 [95\% confidence interval 0.90-1.93], respectively for the highest HbA(1c) tertile compared with the lowest).

CONCLUSION: These results suggest that HbA(1c) does not significantly predict all-cause and cardiovascular mortality in non-diabetic community-dwelling older adults.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Disease Progression, Female, Glycated Hemoglobin A, Health Surveys, Heart Failure, Humans, Incidence, Male, Myocardial Infarction, Risk Factors, Statistics as Topic, Stroke, United States}, issn = {1590-3729}, doi = {10.1016/j.numecd.2009.02.007}, author = {Chonchol, M and Katz, R and Fried, L F and Sarnak, M J and Siscovick, D S and Newman, A B and Strotmeyer, E S and Bertoni, A and Shlipak, M G} } @article {1561, title = {Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism.}, journal = {Diabetologia}, volume = {55}, year = {2012}, month = {2012 Feb}, pages = {331-9}, abstract = {

AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.

METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.

RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 {\texttimes} 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.

CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

}, keywords = {Adult, Aged, Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Disease Progression, Fasting, Female, Genetic Variation, Genotype, Humans, Male, Middle Aged, Models, Genetic, Polymorphism, Single Nucleotide, Proportional Hazards Models, Regression Analysis, Risk}, issn = {1432-0428}, doi = {10.1007/s00125-011-2353-8}, author = {Walford, G A and Green, T and Neale, B and Isakova, T and Rotter, J I and Grant, S F A and Fox, C S and Pankow, J S and Wilson, J G and Meigs, J B and Siscovick, D S and Bowden, D W and Daly, M J and Florez, J C} } @article {6281, title = {Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies.}, journal = {Int J Obes (Lond)}, volume = {37}, year = {2013}, month = {2013 Sep}, pages = {1211-20}, abstract = {

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids.

DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800).

RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed.

CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

}, keywords = {Adipose Tissue, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Body Mass Index, Europe, European Continental Ancestry Group, Fatty Acids, Female, Gene Frequency, Gene-Environment Interaction, Genetic Predisposition to Disease, Genotype, Humans, Low Density Lipoprotein Receptor-Related Protein-1, Male, Middle Aged, Obesity, Phenotype, Polymorphism, Single Nucleotide, Prevalence, United States}, issn = {1476-5497}, doi = {10.1038/ijo.2012.215}, author = {Smith, C E and Ngwa, J and Tanaka, T and Qi, Q and Wojczynski, M K and Lemaitre, R N and Anderson, J S and Manichaikul, A and Mikkil{\"a}, V and van Rooij, F J A and Ye, Z and Bandinelli, S and Frazier-Wood, A C and Houston, D K and Hu, F and Langenberg, C and McKeown, N M and Mozaffarian, D and North, K E and Viikari, J and Zillikens, M C and Djouss{\'e}, L and Hofman, A and K{\"a}h{\"o}nen, M and Kabagambe, E K and Loos, R J F and Saylor, G B and Forouhi, N G and Liu, Y and Mukamal, K J and Chen, Y-D I and Tsai, M Y and Uitterlinden, A G and Raitakari, O and van Duijn, C M and Arnett, D K and Borecki, I B and Cupples, L A and Ferrucci, L and Kritchevsky, S B and Lehtim{\"a}ki, T and Qi, Lu and Rotter, J I and Siscovick, D S and Wareham, N J and Witteman, J C M and Ordov{\'a}s, J M and Nettleton, J A} } @article {5859, title = {Prediction and classification of cardiovascular disease risk in older adults with diabetes.}, journal = {Diabetologia}, volume = {56}, year = {2013}, month = {2013 Feb}, pages = {275-83}, abstract = {

AIMS/HYPOTHESIS: We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis.

METHODS: As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged >=65~years, we examined the 10~year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7~years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred.

RESULTS: The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol, creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle-brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima-media thickness modestly improved discrimination (C statistic 0.68; p = 0.002) and classification (net reclassification improvement [NRI] 0.12; p = 0.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures.

CONCLUSIONS/INTERPRETATION: Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better understanding of the pathophysiology and determinants of CVD in this patient group is needed.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Biomarkers, Blood Pressure, Cardiovascular Diseases, Carotid Intima-Media Thickness, Cholesterol, HDL, Diabetes Mellitus, Female, Humans, Male, Myocardial Infarction, Regression Analysis, Risk Factors, Stroke}, issn = {1432-0428}, doi = {10.1007/s00125-012-2772-1}, author = {Mukamal, K J and Kizer, J R and Djouss{\'e}, L and Ix, J H and Zieman, S and Siscovick, D S and Sibley, C T and Tracy, R P and Arnold, A M} } @article {5978, title = {Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.}, journal = {Pharmacogenomics J}, volume = {14}, year = {2014}, month = {2014 Feb}, pages = {6-13}, abstract = {

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the {\textquoteright}missing heritability{\textquoteright} of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0\%), tri/tetracyclic antidepressants (2.6\%), sulfonylurea hypoglycemic agents (2.9\%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4\%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 {\texttimes} 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

}, keywords = {Computer Simulation, Cross-Sectional Studies, Drug-Related Side Effects and Adverse Reactions, Electrocardiography, European Continental Ancestry Group, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Linear Models, Long QT Syndrome, Markov Chains, Pharmacogenetics, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable}, issn = {1473-1150}, doi = {10.1038/tpj.2013.4}, author = {Avery, C L and Sitlani, C M and Arking, D E and Arnett, D K and Bis, J C and Boerwinkle, E and Buckley, B M and Ida Chen, Y-D and de Craen, A J M and Eijgelsheim, M and Enquobahrie, D and Evans, D S and Ford, I and Garcia, M E and Gudnason, V and Harris, T B and Heckbert, S R and Hochner, H and Hofman, A and Hsueh, W-C and Isaacs, A and Jukema, J W and Knekt, P and Kors, J A and Krijthe, B P and Kristiansson, K and Laaksonen, M and Liu, Y and Li, X and Macfarlane, P W and Newton-Cheh, C and Nieminen, M S and Oostra, B A and Peloso, G M and Porthan, K and Rice, K and Rivadeneira, F F and Rotter, J I and Salomaa, V and Sattar, N and Siscovick, D S and Slagboom, P E and Smith, A V and Sotoodehnia, N and Stott, D J and Stricker, B H and St{\"u}rmer, T and Trompet, S and Uitterlinden, A G and van Duijn, C and Westendorp, R G J and Witteman, J C and Whitsel, E A and Psaty, B M} } @article {6606, title = {Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 May}, pages = {647-56}, abstract = {

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 {\texttimes} 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

}, keywords = {Adaptor Proteins, Signal Transducing, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Brain-Derived Neurotrophic Factor, Coffea, Cytochrome P-450 CYP1A2, Food Habits, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide}, issn = {1476-5578}, doi = {10.1038/mp.2014.107}, author = {Cornelis, M C and Byrne, E M and Esko, T and Nalls, M A and Ganna, A and Paynter, N and Monda, K L and Amin, N and Fischer, K and Renstrom, F and Ngwa, J S and Huikari, V and Cavadino, A and Nolte, I M and Teumer, A and Yu, K and Marques-Vidal, P and Rawal, R and Manichaikul, A and Wojczynski, M K and Vink, J M and Zhao, J H and Burlutsky, G and Lahti, J and Mikkil{\"a}, V and Lemaitre, R N and Eriksson, J and Musani, S K and Tanaka, T and Geller, F and Luan, J and Hui, J and M{\"a}gi, R and Dimitriou, M and Garcia, M E and Ho, W-K and Wright, M J and Rose, L M and Magnusson, P K E and Pedersen, N L and Couper, D and Oostra, B A and Hofman, A and Ikram, M A and Tiemeier, H W and Uitterlinden, A G and van Rooij, F J A and Barroso, I and Johansson, I and Xue, L and Kaakinen, M and Milani, L and Power, C and Snieder, H and Stolk, R P and Baumeister, S E and Biffar, R and Gu, F and Bastardot, F and Kutalik, Z and Jacobs, D R and Forouhi, N G and Mihailov, E and Lind, L and Lindgren, C and Micha{\"e}lsson, K and Morris, A and Jensen, M and Khaw, K-T and Luben, R N and Wang, J J and M{\"a}nnist{\"o}, S and Per{\"a}l{\"a}, M-M and K{\"a}h{\"o}nen, M and Lehtim{\"a}ki, T and Viikari, J and Mozaffarian, D and Mukamal, K and Psaty, B M and D{\"o}ring, A and Heath, A C and Montgomery, G W and Dahmen, N and Carithers, T and Tucker, K L and Ferrucci, L and Boyd, H A and Melbye, M and Treur, J L and Mellstr{\"o}m, D and Hottenga, J J and Prokopenko, I and T{\"o}njes, A and Deloukas, P and Kanoni, S and Lorentzon, M and Houston, D K and Liu, Y and Danesh, J and Rasheed, A and Mason, M A and Zonderman, A B and Franke, L and Kristal, B S and Karjalainen, J and Reed, D R and Westra, H-J and Evans, M K and Saleheen, D and Harris, T B and Dedoussis, G and Curhan, G and Stumvoll, M and Beilby, J and Pasquale, L R and Feenstra, B and Bandinelli, S and Ordov{\'a}s, J M and Chan, A T and Peters, U and Ohlsson, C and Gieger, C and Martin, N G and Waldenberger, M and Siscovick, D S and Raitakari, O and Eriksson, J G and Mitchell, P and Hunter, D J and Kraft, P and Rimm, E B and Boomsma, D I and Borecki, I B and Loos, R J F and Wareham, N J and Vollenweider, P and Caporaso, N and Grabe, H J and Neuhouser, M L and Wolffenbuttel, B H R and Hu, F B and Hypponen, E and J{\"a}rvelin, M-R and Cupples, L A and Franks, P W and Ridker, P M and van Duijn, C M and Heiss, G and Metspalu, A and North, K E and Ingelsson, E and Nettleton, J A and van Dam, R M and Chasman, D I} } @article {7124, title = {Brain natriuretic peptide and insulin resistance in older adults.}, journal = {Diabet Med}, year = {2016}, month = {2016 Apr 21}, abstract = {

AIMS: Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established.

METHODS: N-Terminal (NT)-proBNP was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance.

RESULTS: Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P~<~0.001 for all four indices). Although the genetic score was strongly related to measured NT-proBNP levels amongst European Americans (F statistic~=~71.08), we observed no association of genetically determined NT-proBNP with insulin resistance (P~=~0.38; P~=~0.01 for comparison with the association of measured levels of NT-proBNP).

CONCLUSIONS: In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. This article is protected by copyright. All rights reserved.

}, issn = {1464-5491}, doi = {10.1111/dme.13139}, author = {Kim, F and Biggs, M L and Kizer, J R and Brutsaert, E F and de Fillipi, C and Newman, A B and Kronmal, R A and Tracy, R P and Gottdiener, J S and Djouss{\'e}, L and de Boer, I H and Psaty, B M and Siscovick, D S and Mukamal, K J} } @article {6806, title = {Fibrosis markers, hip fracture risk, and bone density in older adults.}, journal = {Osteoporos Int}, volume = {27}, year = {2016}, month = {2016 Feb}, pages = {815-20}, abstract = {

UNLABELLED: We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-β1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-β1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome.

INTRODUCTION: TGF-β1 serves several roles in bone formation and resorption. A consequence of TGF-β1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels.

METHODS: Participants were from the Cardiovascular Health Study (mean age 78~years; mean follow-up 8.3~years). We included 1681 persons with measured levels of TGF-β1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures).

RESULTS: Among women, higher TGF-β1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95~\% CI 0.61, 0.91]). Among men, TGF-β1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-β1 on fracture risk). TGF-β1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women.

CONCLUSIONS: TGF-β1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-β1 levels and hip fracture risk and bone density require further investigation.

}, issn = {1433-2965}, doi = {10.1007/s00198-015-3269-9}, author = {Barzilay, J I and B{\r u}{\v z}kov{\'a}, P and Kizer, J R and Djouss{\'e}, L and Ix, J H and Fink, H A and Siscovick, D S and Cauley, J A and Mukamal, K J} } @article {7365, title = {Incident atrial fibrillation and the risk of fracture in the cardiovascular health study.}, journal = {Osteoporos Int}, volume = {28}, year = {2017}, month = {2017 Feb}, pages = {719-725}, abstract = {

In this prospective cohort of 4462 older adults, incident atrial fibrillation (AF) was not statistically significantly associated with subsequent risk of incident fracture.

INTRODUCTION: AF is associated with stroke, heart failure, dementia, and death, but its association with fracture is unknown. Therefore, we examined the association of incident AF with the risk of subsequent fracture in the Cardiovascular Health Study (CHS) cohort.

METHODS: Of the CHS participants aged >=65~years, 4462 were followed between 1991 and 2009, mean follow-up 8.8~years. Incident AF was identified by annual study electrocardiogram (ECG), hospital discharge diagnosis codes, or Medicare claims. Fractures of the hip, distal forearm, humerus, or pelvis were identified using hospital discharge diagnosis codes or Medicare claims. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95~\% confidence intervals (CIs) for the association between incident AF (time-varying) and the risk of subsequent fracture. We also evaluated whether AF was associated with risk of sustaining a fall.

RESULTS: Crude incident fracture rate was 22.9 per 1000 person-years in participants with AF and 17.7 per 1000 person-years in participants without AF. Individuals with incident AF were not at significantly higher risk of hip fracture (adjusted HR~=~1.09, 95~\% CI 0.83-1.42) or fracture at any selected site (adjusted HR~=~0.97, 95~\% CI 0.77-1.22) or risk of sustaining a fall (adjusted HR~=~1.00, 95~\% CI~=~0.87-1.16) compared with those without AF.

CONCLUSION: In this cohort of older, community-dwelling adults, incident AF was not shown to be associated with falls or hip or other fractures.

}, issn = {1433-2965}, doi = {10.1007/s00198-016-3778-1}, author = {Wallace, E R and Siscovick, D S and Sitlani, C M and Dublin, S and Mitchell, P and Robbins, J A and Fink, H A and Cauley, J A and B{\r u}{\v z}kov{\'a}, P and Carbone, L and Chen, Z and Heckbert, S R} } @article {8106, title = {Biochemical markers of bone turnover and risk of incident hip fracture in older women: the Cardiovascular Health Study.}, journal = {Osteoporos Int}, year = {2019}, month = {2019 Jun 21}, abstract = {

The relationships of osteocalcin (OC) and C-telopeptide of type I collagen (CTX) with long-term incidence of hip fracture were examined in 1680 post-menopausal women from a population-based study. CTX, but not OC, levels were associated with incident hip fracture in these participants, a relationship characterized by an inverted U-shape.

INTRODUCTION: We sought to investigate the relationships of OC, a marker of bone formation, and CTX, a marker of bone resorption, with long-term incidence of hip fracture in older women.

METHODS: We included 1680 women from the population-based Cardiovascular Health Study (mean [SD] age 74.5 [5.0] years). The longitudinal association of both markers with incidence of hip fracture was examined using multivariable Cox models.

RESULTS: During a median follow-up of 12.3~years, 288 incident hip fractures occurred. Linear spline analysis did not demonstrate an association between OC levels and incident hip fracture. By contrast, increasing levels of CTX up to the middle-upper range were associated with a significantly greater risk of hip fracture (HR = 1.52 per SD increment, 95\% CI = 1.10-2.09), while further increases were associated with a marginally non-significant lower risk (HR = 0.80 per SD increment, 95\% CI = 0.63-1.01), after full adjustment for potential confounders. In analyses of quartiles, CTX exhibited a similar inverted U-shaped relationship with incident fracture after adjustment, with a significant association observed only for the comparison of quartile 3 to quartile 1 (HR = 1.63, 95\% CI = 1.10-2.43). In a subset with available measures, both OC and CTX were inversely associated with bone mineral density of the hip.

CONCLUSION: CTX, but not OC, levels were associated with incident hip fracture in post-menopausal women, a relationship characterized by an inverted U-shape. These findings highlight the complex relationship of bone turnover markers with hip fracture risk.

}, issn = {1433-2965}, doi = {10.1007/s00198-019-05043-1}, author = {Massera, D and Xu, S and Walker, M D and Valderr{\'a}bano, R J and Mukamal, K J and Ix, J H and Siscovick, D S and Tracy, R P and Robbins, J A and Biggs, M L and Xue, X and Kizer, J R} }