[show abstract][hide abstract] ABSTRACT: The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
[show abstract][hide abstract] ABSTRACT: Low vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse.
To evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women's Health Initiative randomized, placebo-controlled, clinical trial.
In post hoc analyses, the results of the Women's Health Initiative randomized clinical trial in which 36,282 postmenopausal women were randomized to receive calcium carbonate (1,000 mg as elemental calcium) with vitamin D-3 (400 IU) daily or placebo were examined in the 6% subgroup of 1,911 participants, oversampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups.
At baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared with 75.1% [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared with 32.4% [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using nonprotocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P=0.02).
Joint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1,000 mg calcium carbonate and 400 IU vitamin D-3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms.
Journal of the American Academy of Nutrition and Dietetics 08/2013; · 3.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Low 25-hydroxyvitamin D (25(OH) D) concentrations have been associated with radiologic worsening of osteoarthritis in some reports. However, the results are mixed and few studies have evaluated associations between 25(OH) D concentrations and both total vitamin D intake and clinical joint symptoms.
Cross-sectional analyses of information from a subset of 1993 postmenopausal women obtained at baseline entry in the Women's Health Initiative Calcium plus Vitamin D clinical trial.
25(OH) D concentration, total vitamin D intake (diet plus supplements), presence and severity of joint pain and joint swelling.
The 25(OH) D levels were commonly low with 53% having deficient (<50 nmol/L) and only 17% having sufficient (>72 nmol/L) levels. Joint pain (reported by 74%) and joint swelling (reported by 34%) were also commonly reported. 25(OH) D concentrations were modestly correlated with total vitamin D intake (R=0.29, p<0.0001); however, considerable variability in 25(OH) D concentrations for a given vitamin D intake was seen. In adjusted linear regression models, lower serum 25(OH) D concentrations were associated with higher average joint pain score (P=0.01 for trend) with differences most apparent in the lowest 25(OH) D levels sextile.
Relatively low 25(OH) D levels and a high frequency of joint symptoms were common in this population of postmenopausal women. Total vitamin D intake was only modestly associated with 25(OH) D. Low serum 25(OH) D concentrations were associated with higher joint pain scores. These findings can inform the design of future intervention trials.
[show abstract][hide abstract] ABSTRACT: The immune and blood coagulation systems have been implicated in the pathophysiology of the geriatric syndrome of frailty, but limited prospective data examining the relationship of clotting/inflammation biomarkers to risk of incident frailty exist.
This prospective analysis was derived from a nested case-control study within the Women's Health Initiative. Among women 65 to 79 years free of frailty at enrollment, we randomly selected 900 incident cases from those developing frailty within 3 years; 900 non-frail controls were individually matched on age, ethnicity, and blood collection date. Biomarkers assessed for risk of incident frailty included fibrinogen, factor VIII, D-dimer, C-reactive protein, interleukin-6, and tissue plasminogen activator (t-PA).
When examined by quartiles in multivariable adjusted models, higher D-dimer and t-PA levels were each associated with increased risk of frailty (P trend = .04). Relative to the lowest quartile, the odds ratios for frailty compared with the upper quartile were 1.52 (95% confidence interval, 1.05-2.22) for t-PA and 1.57 (95% confidence interval, 1.11-2.22) for D-dimer. For women having high t-PA and high D-dimer compared with women having lower levels of both biomarkers, the odds of frailty was 2.20 (1.29-3.75). There was little evidence for association between coagulation factor VIII, fibrinogen, C-reactive protein, or interleukin-6 levels and incident frailty.
This prospective analysis supports the role of markers of fibrin turnover and fibrinolysis as independent predictors of incident frailty in postmenopausal women.
The American Journal of Medicine 09/2009; 122(10):947-54. · 4.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: To examine the associations between current use, duration, and potency of angiotensin-converting enzyme (ACE) inhibitors and incident frailty in women aged 65 and older who were not frail at baseline.
Data were from the Women's Health Initiative Observational Study (WHI-OS), a prospective study conducted at 40 U.S. clinical centers.
Women aged 65 to 79 at baseline who were not frail (N=27,378).
Current ACE inhibitor use was ascertained through direct inspection of medicine containers at baseline. Components of frailty were self-reported low physical function or impaired walking, exhaustion, low physical activity, and unintended weight. Frailty was ascertained through self-reported and physical measurements data at baseline and 3-year clinic contacts.
By the 3-year follow-up, 3,950 (14.4%) women had developed frailty. Current ACE inhibitor use had no association with incident frailty (multivariate adjusted odds ratio=0.96, 95% confidence interval=0.82-1.13). Duration and potency of ACE inhibitor use were also not significantly associated with incident frailty. A similar pattern of results was observed when incident cardiovascular disease events were studied as a separate outcome or when the sample was restricted to subjects with hypertension.
Overall, incidence of frailty was similar in current ACE inhibitor users and nonusers.
Journal of the American Geriatrics Society 03/2009; 57(2):297-303. · 3.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the association between chronic kidney disease and incident hip fracture using serum cystatin-C as a biomarker of renal function calculated without reference to muscle mass.
Case-control study nested within a prospective study.
The Women's Health Initiative Observational Study conducted at 40 U.S. clinical centers.
From 93,676 women aged 50 to 79 followed for an average of 7 years, 397 incident hip fracture cases and 397 matched controls were studied.
Cystatin-C levels were measured on baseline serum using a particle-enhanced immunonepholometric assay. Estimated glomerular filtration rates (eGFR(cys-c)) were calculated using a validated equation and categorized into three groups (>or=90.0 mL/min per 1.73 m(2), 60.0-89.9 mL/min per 1.73 m(2), and <60.0 mL/min per 1.73 m(2) indicating chronic kidney disease Stages 3 to 4).
The odds ratio (OR) for hip fracture was 2.50 (95% confidence interval (CI)=1.32-4.72) for eGFR(cys-c) less than 60 mL/min per 1.73 m(2) compared with Stages 0 to 1, after adjustment for body mass, parental hip fracture, smoking, alcohol consumption, and physical function. No association was observed for eGFR(cys-c) of 60 to 90 mL/min per 1.73 m(2) (OR=1.04, 95% CI=0.66-1.64). Additional adjustment for poor health status, hemoglobin, serum 25-hydroxy vitamin D, and bone metabolism markers did not affect these associations. Adjustment for plasma homocysteine reduced the OR for eGFR(cys-c) less than 60 mL/min per 1.73 m(2) to 1.83 (95% CI=0.93-3.61).
Women with eGFR(cys-c) levels less than 60 mL/min per 1.73 m(2) have a substantially greater risk of hip fracture. Effects of renal function on homocysteine levels may partially mediate, or accompany, this association.
Journal of the American Geriatrics Society 07/2008; 56(8):1434-41. · 3.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inflammatory biomarkers have shown consistent associations with disability and frailty in older adults. Statin medications may reduce the incidence the frailty because of their anti-inflammatory effects. This study examines associations between current use, duration, and potency of statin medications and incident frailty in initially nonfrail women 65 years old or older.
The authors conducted a prospective analysis of data from the Women's Health Initiative Observational Study (WHI-OS) conducted at 40 clinical centers in the United States. Eligible women were nonfrail and 65-79 years old at baseline (n = 25,378). Current statin use at baseline was ascertained through direct inspection of medicine containers during clinic visits. Frailty was ascertained through self-reported indicators and physical measurements at baseline and 3-year clinic contacts. Components of frailty included self-reported low physical function, exhaustion, low physical activity, and unintended weight loss. Multinomial logistic regression models were used to adjust for covariates predicting incident frailty.
Among the 25,378 eligible women, 3453 (13.6%) developed frailty by the 3-year follow-up contact. Current statin use had no association with incident frailty (multivariate-adjusted odds ratio [OR] = 1.00; 95% confidence interval [CI], 0.85-1.16). Duration and potency of statin use were also not significantly associated with incident frailty. Among low potency statin users, longer duration of use was associated with reduced risk of frailty (p for trend =.02). A similar pattern of results was observed when frailty was studied in the absence of intervening, incident cardiovascular events.
Overall, incidence of frailty was similar in current statin users and nonusers.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2008; 63(4):369-75. · 4.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking.
We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [corrected] twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study.
The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P=0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics.
Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.).
New England Journal of Medicine 03/2006; 354(7):684-96. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: The combined use of free and total prostate-specific antigen (PSA) in early detection of prostate cancer has been controversial. This article systematically evaluates the discriminating capacity of a large number of combination tests.
Free and total PSA were analyzed in stored serum samples taken prior to diagnosis in 429 cases and 1,640 controls from the Physicians' Health Study. We used a classification algorithm called logic regression to search for clinically useful tests combining total and percent free PSA and receiver operating characteristic analysis and compared these tests with those based on total and complexed PSA. Data were divided into training and test subsets. For robustness, we considered 35 test-train splits of the original data and computed receiver operating characteristic curves for each test data set.
The average area under the receiver operating characteristic curve across test data sets was 0.74 for total PSA and 0.76 for the combination tests. Combination tests with higher sensitivity and specificity than PSA > 4.0 ng/mL were identified 29 out of 35 times. All these tests extended the PSA reflex range to below 4.0 ng/mL. Receiver operating characteristic curve analysis indicated that the overall diagnostic performance as expressed by the area under the curve did not differ significantly for the different tests.
Tests combining total and percent free PSA show modest overall improvements over total PSA. However, utilization of percent free PSA below a PSA threshold of 4 ng/mL could translate into a practically important reduction in unnecessary biopsies without sacrificing cancers detected.