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1.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
The funding sources are cited at the end of the paper.
PMCID: PMC4322187  PMID: 25262344
2.  Social support and physical activity as moderators of life stress in predicting baseline depression and change in depression over time in the Women’s Health Initiative 
Social psychiatry and psychiatric epidemiology  2013;48(12):10.1007/s00127-013-0693-z.
To determine whether social support and/or physical activity buffer the association between stressors and increasing risk of depression symptoms at baseline and at 3 year follow-up.
This is a secondary analysis of data from the Women’s Health Initiative Observational Study. 91,912 community-dwelling post-menopausal women participated in this prospective cohort study. Depression symptoms were measured at baseline and 3 years later; social support, physical activity, and stressors were measured at baseline.
Stressors at baseline, including verbal abuse, physical abuse, caregiving, social strain, negative life events, financial stress, low income, acute pain, and a greater number of chronic medical conditions, were all associated with higher levels of depression symptoms at baseline and new onset elevated symptoms at three year follow-up. Social support and physical activity were associated with lower levels of depressive symptoms. Contrary to expectation, more social support at baseline strengthened the association between concurrent depression and physical abuse, social strain, caregiving, and low income. Similarly, more social support at baseline increased the association between financial stress, income, and pain on new-onset depression 3 years later. Physical activity similarly moderated the effect of caregiving, income, and pain on depression symptoms at baseline.
Stressors, social support, and physical activity showed predicted main effect associations with depression. Multiplicative interactions were small in magnitude and in the opposite direction of what was expected.
PMCID: PMC3796164  PMID: 23644722
depression; risk factors; acute stress; chronic stress; protective factors; effect moderation
3.  No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population 
Human genetics  2013;132(12):1427-1431.
Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype–phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
PMCID: PMC3895337  PMID: 24100633
4.  Longitudinal Use of Complementary and Alternative Medicine among Older Adults with Radiographic Knee Osteoarthritis 
Clinical therapeutics  2013;35(11):10.1016/j.clinthera.2013.09.022.
Osteoarthritis (OA) accounts for more mobility issues in older adults than any other disease. OA is a chronic and often painful disease for which there is no cure. Cross-sectional studies have shown that older adults frequently use complementary and alternative medicine (CAM) and arthritis is the most common reason for CAM use. While previous research has profiled the sociodemographic and clinical characteristics of CAM users, few have provided information on variation in CAM use over time and most only considered use of any CAM, which was often a mixture of heterogeneous therapies.
This study sought to describe the longitudinal patterns of CAM use among older adults with knee OA, and to identify correlates/predictors of different commonly-used CAM therapies.
The Osteoarthritis Initiative included 1,121 adults aged 65 years and above with radiographic tibiofemoral OA in one or both knees at baseline. Annual surveys captured current use of conventional therapies and 25 CAM modalities (grouped into 6 categories) for joint pain or arthritis at baseline and during the 4-year follow-up. We assessed longitudinal use of CAM modalities by summing the number of visits with participants reporting use of each modality. Correlates of CAM use under consideration included sociodemographic indicators, body mass index, overall measures of mental and physical wellbeing, and clinical indices of knee OA. Generalized estimation equations provided adjusted odds ratio estimates and 95% confidence intervals.
Nearly one third of older adults reported using ≥ one CAM modality for treating OA at all assessments. With the exception of glucosamine and chondroitin (18%), few were persistent users of other CAM modalities. One in five of those using NSAIDs or glucosamine/chondroitin were using them concurrently. Adjusted models showed: 1) adults aged ≥75 years were less likely to use dietary supplements than those aged between 65 and 75 years; 2) persons with more severe knee pain or stiffness reported more CAM use; 3) better knee-related physical function was correlated with more use of chiropractic/massage; 4) older adults with more comorbidities were less likely to report use of dietary supplements.
Patterns of CAM use are, to some extent, inconsistent with current guidelines for OA treatment. Evaluating the potential risks and benefits in older adults from commonly-used CAM modalities, with or without combination use of conventional analgesics, is warranted.
PMCID: PMC3880574  PMID: 24145044
complementary and alternative medicine; osteoarthritis; pain; older adults
5.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
clinical Identifier: NCT00000611
PMCID: PMC3963523  PMID: 24084921
6.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
7.  Post genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study 
Annals of human genetics  2013;77(5):416-425.
Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or post-menopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet<0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet=1.74E-03, I2=89.8), with a significant association in older males (P=1.39E-06) but not younger males (P=0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
PMCID: PMC3796061  PMID: 23808484
PAGE; modifier; age; lipids; genetic association
8.  The Relationship of Sedentary Behavior and Physical Activity to Incident Cardiovascular Disease: Results from the Women’s Health Initiative 
The aim was to examine the independent and joint associations of sitting time and physical activity with risk of incident cardiovascular disease (CVD).
Sedentary behavior is recognized as a distinct construct beyond lack of leisure-time physical activity, but limited data exists on the interrelationship between these two components of energy balance.
Participants in the prospective Women’s Health Initiative Observational Study (N = 71,018), aged 50–79 and free of CVD at baseline (1993–1998), provided information on sedentary behavior, defined as hours of sitting per day, and usual physical activity at baseline and during follow-up through September 2010. First CVD (coronary heart disease or stroke) events were centrally adjudicated.
Sitting ≥ 10 hours/day compared to ≤ 5 hours/day was associated with increased CVD risk (HR=1.18, 95% CI 1.09, 1.29) in multivariable models including physical activity. Low physical activity was also associated with higher CVD risk (P, trend <0.001). When women were cross-classified by sitting time and physical activity (P, interaction = 0.94), CVD risk was highest in inactive women (≤1.7 MET-hrs/week) who also reported ≥10 hrs/day of sitting. Results were similar for CHD and stroke when examined separately. Associations between prolonged sitting and risk of CVD were stronger in overweight versus normal weight women and women aged 70 years and older compared to younger women.
Prolonged sitting time was associated with increased CVD risk, independent of leisure-time physical activity, in postmenopausal women without a history of CVD. A combination of low physical activity and prolonged sitting augments CVD risk.
PMCID: PMC3676694  PMID: 23583242
cardiovascular disease; women; physical activity; sedentary behavior
9.  The Association of Whole Grain Consumption with Incident Type 2 Diabetes: The Women's Health Initiative Observational Study 
Annals of epidemiology  2013;23(6):321-327.
Whole grains may offer protection from diabetes by decreasing energy intake, preventing weight gain, and direct effects on insulin resistance. This study examined associations of whole and refined grains with incident type 2 diabetes (T2D) ascertained by self-reported medication use in a cohort of post-menopausal women.
72,215 women free of diabetes at baseline from the Women's Health Initiative Observational Study were included. Whole grain consumption was categorized as 0, <0.5, 0.5-1.0, 1.0-<1.5, 1.5-<2.0, and ≥2.0 servings/day. Proportional hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals adjusting for potential confounders.
There were 3,465 cases of incident T2D over median 7.9 years follow-up. Adjusted for age and energy intake/day, successively increasing categories of whole grain consumption were associated with statistically significant reduced risk of incident T2D (HRs= 1.00, 0.83, 0.73, 0.69, 0.61, 0.57, p for trend <0.0001). Results were attenuated after adjustment for confounders and other dietary components. Non-smokers and those who maintained their weight within 5 pounds had a greater reduced risk of T2D with higher consumption of whole grains than smokers and women who gained more weight.
This large, prospective study found an inverse, dose-response relationship between whole grain consumption and incident T2D in postmenopausal women.
PMCID: PMC3662533  PMID: 23608304
type 2 diabetes; whole grains; cohort studies
10.  Sleep Duration, Insomnia, and Coronary Heart Disease Among Postmenopausal Women in the Women's Health Initiative 
Journal of Women's Health  2013;22(6):477-486.
Long and short sleep duration are associated with increased risk for coronary heart disease (CHD) and cardiovascular disease (CVD); however, evidence is inconsistent. We sought to identify whether self-reported sleep duration and insomnia, based on a validated questionnaire, are associated with increased incident CHD and CVD among postmenopausal women.
Women's Health Initiative Observational Study Participants (N=86,329; 50–79 years) who reported on sleep at baseline were followed for incident CVD events. Associations of sleep duration and insomnia with incident CHD and CVD were evaluated using Cox proportional hazards models over 10.3 years.
Women with high insomnia scores had elevated risk of CHD (38%) and CVD (27%) after adjustment for age and race, and in fully adjusted models (hazard ratio [HR]=1.19, 95% confidence interval [CI] 1.09–1.30; 1.11 95% CI 1.03–2.00). Shorter (≤5 hours) and longer (≥10 hours) sleep duration demonstrated significantly higher incident CHD (25%) and CVD (19%) in age- and race-adjusted models, but this was not significant in fully adjusted models. Formal tests for interaction indicated significant interactions between sleep duration and insomnia for risk of CHD (p<0.01) and CVD (p=0.02). Women with high insomnia scores and long sleep demonstrated the greatest risk of incident CHD compared to midrange sleep duration (HR=1.93, 95% CI 1.06—3.51) in fully adjusted models.
Sleep duration and insomnia are associated with CHD and CVD risk, and may interact to cause almost double the risk of CHD and CVD. Additional research is needed to understand how sleep quality modifies the association between prolonged sleep and cardiovascular outcomes.
PMCID: PMC3678565  PMID: 23651054
11.  Estrogen Alone and Joint Symptoms in the Women’s Health Initiative Randomized Trial 
Menopause (New York, N.Y.)  2013;20(6):10.1097/GME.0b013e31828392c4.
While joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen influence on joint symptoms provide mixed results. Against this background, estrogen alone effects on joint symptoms were examined in post hoc analyses in the Women’s Health Initiative randomized, placebo-controlled clinical trial.
10,739 postmenopausal women with prior hysterectomy were randomized to receive daily oral conjugated equine estrogen (0.625 mg/d) or matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire at entry and year 1 from all participants and in a random 9.9% subsample (n=1062) following years 3 and 6. Logistic regression models were used to compare frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms.
At baseline, joint pain and swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After one year, joint pain frequency was significantly lower in the estrogen alone compared to the placebo group (76.3% vs 79.2%, P=0.001) as was joint pain severity and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen alone group (42.1% vs 39.7%, P=0.02). Adherence adjusted analyses strengthen the estrogen association with reduced joint pain but attenuated the estrogen association with increased joint swelling.
The current findings suggest that estrogen alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.
PMCID: PMC3855295  PMID: 23511705
Estrogen; joint pain; joint swelling; Women’s Health Initiative; postmenopausal women; randomized clinical trial
12.  Validation of quantitative magnetic resonance imaging-based apparent bone volume fraction in peri-articular tibial bone of cadaveric knees 
In the knee, high-resolution magnetic resonance (MR) imaging has demonstrated that increased apparent bone volume fraction (trabecular bone volume per total volume; BV/TV) in the peri-articular proximal medial tibia is associated with joint space narrowing and the presence of bone marrow lesions. However, despite evidence of construct validity, MR-based apparent BV/TV has not yet been cross-validated in the proximal medial tibia by comparison with a gold standard (e.g., micro-computed tomography [microCT]). In this cadaveric validation study we explored the association between MR-based apparent BV/TV and microCT-based BV/TV in the proximal peri-articular medial tibia.
Fresh cadaveric whole knee specimens were obtained from individuals 51 to 80 years of age with no knee pathology other than osteoarthritis. Ten knees were collected from five cadavers within 10 hours of death and underwent a 3-Tesla MR exam including a coronal-oblique 3-dimensional fast imaging with steady state precession (3D FISP) sequence within 36 hours of death. The specimens were placed in a 4% paraformaldehyde in phosphate buffer within 58 hours of death. After preservation, a subchondral region from the tibial plateau was collected and underwent microCT imaging with a voxel size of 9 μm x 9 μm x 9 μm. A single reader analyzed the microCT images in a similar volume of interest as selected in the MR measures. A different reader analyzed the MR-based trabecular morphometry using a custom analysis tool. To analyze the MR-based trabecular morphometry, a rectangular region of interest (ROI) was positioned on the 20 central images in the proximal medial tibial subchondral bone. The primary outcome measures were MR-based and microCT-based trabecular BV/TV in the proximal medial tibia.
The MR-based apparent BV/TV was strongly correlated with microCT-based BV/TV (r = 0.83, confidence interval = 0.42 to 0.96), despite the MR-based apparent BV/TV being systematically lower than measured using microCT.
MR-based apparent BV/TV in the proximal peri-articular medial tibia has good construct validity and may represent an alternative for CT-based BV/TV.
PMCID: PMC4021054  PMID: 24779374
Micro-computed tomography; Validation; Magnetic resonance; Osteoarthritis; Trabecula
13.  Documentation and management of overweight and obesity in primary care 
We examine overweight/obesity management in primary care in relation to body mass index (BMI), documentation of weight status, and comorbidities.
This analysis of baseline data from the Cholesterol Education and Research Trial included 2,330 overweight and obese adult primary care patients from southeastern New England. Data were obtained via a telephone interview and abstraction of subjects’ medical record. BMI (kg/m2) was calculated from measured height and weight. Management of overweight/obesity included advice to lose weight, physical activity recommendations, dietary recommendations, and referral for nutrition counseling.
Documentation of weight status was more common with increasing BMI (13% of overweight patients, 39% of mildly obese, and 77% of moderately/severely obese). Documentation of overweight/obesity was associated with increased behavioral treatment; the biggest increase was seen for advice to lose weight (ORs were 7.2 for overweight patients, 3.3 for patients with mild obesity, and 4.0 for moderate/severe obesity). While weight-related comorbidities were associated with increased overweight/obesity management at all BMIs, the biggest increase in odds was for patients with moderate/severe obesity.
Documentation of weight management was more common among patients with documented overweight/obesity and with weight-related comorbidities. These insights may help in designing new interventions in primary care setting for overweight and obese patients.
PMCID: PMC3967526  PMID: 19734401
14.  Geriatric Syndromes and Incident Disability in Older Women: Results from the Women’s Health Initiative Observational Study 
Geriatric syndromes are common in older women and contribute to disability risk. Little is known about how the number of geriatric syndromes is associated with incident disability in community-based populations of older adults.
Longitudinal analysis from the Women’s Health Initiative Observational Study (WHI).
29,544 women aged 65 or older, who were enrolled in the WHI and free of disability in activities of daily living (ADL) at baseline.
Geriatric syndromes were self-reported at baseline and three year follow-up and included high depressive symptoms, dizziness, falls, hearing or visual impairment, osteoporosis, polypharmacy, syncope, sleep disturbance, and urinary incontinence. Disability was defined as dependence in any ADL and was assessed at baseline and follow-up. Chronic diseases were measured by a modified Charlson index.
Geriatric syndromes were common in this population of women; 76.3% had at least one syndrome present at baseline. Increased number of geriatric syndromes at baseline was significantly associated with increased risk of incident ADL disability at follow-up (p ≤ 0.001). The adjusted risk ratio (RR) and 95% confidence interval (CI) for a single syndrome compared to no syndromes was 1.21 (0.78, 1.87). For women with five or more geriatric syndromes, the RR (CI) was 6.64 (4.15, 10.62). These results were only slightly attenuated after adjustment for number of chronic diseases or pain.
Geriatric syndromes are significantly associated with onset of disability in older women; this association is not simply a result of chronic disease or pain. A better understanding of how these conditions contribute to disablement is needed. Geriatric syndrome assessment should be considered along with chronic disease management in the prevention of disability in older women.
PMCID: PMC3602348  PMID: 23452034
Geriatric syndromes; disability; aging; women’s health
15.  Self-reported Snoring and Risk of Cardiovascular Disease among Postmenopausal Women (From the Women’s Health Initiative) 
The American journal of cardiology  2012;111(4):540-546.
Habitual snoring may be associated with cardiovascular disease (CVD); however limited evidence exists among women. We investigated whether frequent snoring is a predictor of coronary heart disease (CHD) and stroke among 42,244 postmenopausal women participating in the Women’s Health Initiative Observational Study. Participants provided self-reported information regarding snoring habits at baseline (1993-1998) and were followed for outcomes through August 2009. Physician adjudicators confirmed CHD, defined as MI, CHD death, revascularization procedures, or hospitalized angina, and confirmed ischemic stroke. Cox proportional hazards models were used to evaluate whether snoring frequency is a significant predictor of adjudicated outcomes. We observed 2,401 incident cases of CHD over 437,899 person-years of follow up. After adjusting for age and race, frequent snoring was associated with incident CHD (HR=1.54, 95% CI 1.39-1.70) and stroke (HR=1.41, 95% CI 1.19-1.66), and all CVD (HR=1.46, 95% CI 1.34-1.60). In fully adjusted models that included CVD risk factors such as obesity, hypertension, and diabetes, frequent snoring was associated with a more modest increase in incident CHD (HR=1.14 95% CI 1.01-1.28), stroke (HR=1.19, 95% CI 1.02-1.40) and CVD (HR=1.12, 95% CI 1.01-1.24). In conclusion, snoring is associated with a modest increased risk of incident CHD, stroke and CVD after adjustment for CVD risk factors. Additional studies are needed to elucidate the mechanisms in which snoring may be associated with CVD risk factors and outcomes.
PMCID: PMC3563849  PMID: 23219175
Snoring; Cardiovascular Disease; Coronary Heart Disease; Menopause
16.  Magnetic resonance imaging evaluation of weight-bearing subchondral trabecular bone in the knee 
Skeletal radiology  2010;40(1):10.1007/s00256-010-0943-z.
Changes in weight-bearing subchondral bone are central to osteoarthritis (OA) pathophysiology. Using MR, knee trabecular bone is typically assessed in the axial plane, however partial volume artifacts limit the utility of MR methods for femorotibial compartment subchondral bone analysis. Oblique-coronal acquisitions may enable direct visualization and quantification of the expected increases in femorotibial subchondral trabecular bone.
MR acquisition parameters were first optimized at 3 Tesla. Thereafter, five volunteers underwent axial and coronal exams of their right knee. Each image series was evaluated visually and quantitatively. An anatomically standardized region-of-interest was placed on both the medial and lateral tibial plateaus of all coronal slices containing subchondral bone. Mean and maximum marrow signal was measured, and “bone signal” was calculated.
The MR acquisition had spatial resolution 0.2× 0.2×1.0 mm and acquisition time 10.5 min. The two asymptomatic knees exhibited prominent horizontal trabeculae in the tibial subchondral bone, while the one confirmed OA knee had disorganized subchondral bone and absent horizontal trabeculae. The subchondral bone signal was 8–14% higher in both compartments of the OA knee than the asymptomatic knees.
The weight-bearing femorotibial subchondral trabecular bone can be directly visualized and changes quantified in the coronal-oblique plane. Qualitative and quantitative assessments can be performed using the resultant images and may provide a method to discriminate between the healthy and OA knees. These methods should enable a quantitative evaluation of the role of weight-bearing subchondral bone in the natural history of knee OA to be undertaken.
PMCID: PMC3886640  PMID: 20449585
Knee; MR; Subchondral bone; Osteoarthritis; Trabecular bone; Osteoporosis
17.  Obesity and Other Modifiable Factors for Physical Inactivity Measured by Accelerometer in Adults with Knee Osteoarthritis: Data from the Osteoarthritis Initiative (OAI) 
Arthritis care & research  2013;65(1):53-61.
To investigate the public health impact of obesity and other modifiable risk factors related to physical inactivity in adults with knee osteoarthritis (OA).
The frequency of inactivity as defined by the United States Department of Health and Human Services was assessed from objective accelerometer monitoring of 1089 participants with radiographic knee OA aged 49 to 84 years during the OAI 48 month visit (2008–2010). The relationship between modifiable factors (weight status, dietary fat, fiber, smoking, depressive symptoms, knee function, knee pain, knee confidence) with inactivity was assessed using odds ratios (OR) and attributable fractions (AF) controlling for descriptive factors (age, gender, race, education, live alone, employment, frequent knee symptoms, comorbidity).
Almost half (48.9%) of participants with knee OA were inactive. Being overweight (OR=1.8, CI: 1.2, 2.5) or obese (OR=3.9, CI: 2.6, 5.7), inadequate dietary fiber intake (OR =1.6, 95% CI: 1.2, 2.2), severe knee dysfunction (OR=1.9, 95% CI: 1.3, 2.8), and severe pain (OR=1.7, 95% CI: 1.1, 2.5) were significantly related to inactivity, controlling for descriptive factors. Modifiable factors with significant average AFs were being overweight or obese (AF=23.8%, 95% CI: 10.5%, 38.6%) and inadequate dietary fiber (AF=12.1%, 95% CI: 0.1%, 24.5%) controlling for all factors.
Being obese or overweight, the quality of the diet, severe pain, and severe dysfunction are significantly associated with physical inactivity in adults with knee OA. All components should be considered in designing physical activity interventions that target arthritis populations with low activity levels.
PMCID: PMC3449019  PMID: 22674911
18.  Bone Marrow Lesions are Associated with Altered Trabecular Morphometry 
Bone marrow lesions (BMLs) are a common magnetic resonance (MR) feature in patients with osteoarthritis, however their pathological basis remains poorly understood and has not been evaluated in vivo. Our aim was to evaluate the trabecular structure associated with the presence and size of BMLs present in the same regions of interest (ROI) using quantitative MR-based trabecular morphometry.
158 participants in the Osteoarthritis Initiative (OAI) were imaged with a coronal 3D FISP sequence for trabecular morphometry in the same session as the OAI 3T MR knee evaluation. The proximal medial tibial subchondral bone in the central weight-bearing ROI on these knee 3D FISP images were quantitatively evaluated for apparent bone volume fraction, trabecular number, spacing, and thickness. BMLs were also evaluated in the subchondral bone immediately adjacent to the articular cartilage. BML volume was also evaluated within the same trabecular morphometry ROI and semi-quantitatively classified as none, small, or large. Kruskal-Wallis test was used to determine if mean apparent bone volume fraction, trabecular number, spacing, or thickness differed by BML score.
Compared to knees with ROIs containing no BMLs, knees with small or large BMLs had statistically higher apparent bone volume fraction (p<0.01), trabecular number (p<0.01), and thickness (p=0.02), and lower trabecular spacing (p<0.01).
Compared to knees with ROIs containing no BMLs, knees with ROIs containing small or large BMLs had higher apparent bone volume fraction, trabecular number and thickness, but lower trabecular spacing. These findings may represent areas of locally increased bone remodeling or compression.
PMCID: PMC3478500  PMID: 22940708
magnetic resonance imaging; osteoarthritis; knee
19.  Circulating Levels of 25Hydroxy-Vitamin D and Risk of Cardiovascular Disease: A Meta-Analysis of Prospective Studies 
Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25hydroxy-vitamin D (25(OH)-vitamin D) levels for potential cardiovascular health benefits remain unclear.
Methods and Results
We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6,123 CVD cases in 65,994 participants were included for a meta-analysis. Comparing the lowest to the highest 25(OH)-vitamin D categories, the pooled relative risks (RR) was 1.52 (95% CI: 1.30-1.77) for total CVD, 1.42 (95% CI: 1.19-1.71) for CVD mortality, 1.38 (95% CI: 1.21-1.57) for coronary heart disease, and 1.64 (95% CI: 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and had better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below approximately 60 nmol/L, with a RR of 1.03 (95% CI: 1.00-1.06) per 25 nmol/L decrement in 25(OH)-vitamin D.
This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D in the range of 20-60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.
PMCID: PMC3510675  PMID: 23149428
25hydroxy-vitamin D; cardiovascular disease; meta-analysis; prospective study
20.  Short Sleep Duration is Associated with Carotid Intima-Media Thickness Among Men in the CARDIA Study 
Background and purpose
Carotid intima-media thickness (CIMT) is a subclinical marker of cardiovascular disease (CVD). Recent studies suggest that shorter sleep duration is a risk factor for CVD, but there is limited evidence regarding this association using high-quality, objective assessments of sleep. The aim of this study is to determine whether sleep duration is associated with CIMT.
The study used an observational cohort consisting of 617 black and white middle-aged healthy participants (37–52 y; 58% female) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Multivariable-adjusted linear regression analyses were performed. Sleep duration was measured using wrist actigraphy monitors. CIMT was calculated using the average of 20 measurements of the mean common carotid, bulb and internal CIMT, which was assessed using ultrasound images.
After adjusting for covariates, one hour of longer sleep duration was associated with 0.026 mm less CIMT among men (p=0.02, 95% CI -0.047, -0.005), and 0.001 mm less CIMT among women (p=0.91, 95% CI -0.020, 0.022). Segment-specific analyses indicated that the carotid bulb was a key driver of the observed association.
Shorter objectively assessed sleep duration was associated with greater CIMT among men but not women.
PMCID: PMC3479367  PMID: 22935396
Sleep; carotid intima-media thickness; atherosclerosis; cardiovascular disease
21.  Bone marrow lesion volume reduction is not associated with improvement of other periarticular bone measures: data from the Osteoarthritis Initiative 
Arthritis Research & Therapy  2013;15(5):R153.
We evaluated the associations between bone marrow lesion (BML) volume change and changes in periarticular bone mineral density (paBMD) as well as subchondral sclerosis to determine whether BML change is associated with other local bone changes.
The convenience sample comprised participants in the Osteoarthritis Initiative (OAI) with weight-bearing posterior-anterior knee radiographs and magnetic resonance images (MRIs) at the 24- and 48-month visits and dual-energy x-ray absorptiometry (DXA) at the 30-/36-month and 48-month visits. The right knee was assessed unless contraindicated for MRI. We used knee DXA scans to measure medial tibia paBMD and medial/lateral paBMD ratio (M:L paBMD). Knee radiographs were scored for sclerosis (grades 0 to 3) in the medial tibia. Two raters determined BML volume on sagittal fat-suppressed MRI by using a semiautomated segmentation method. To focus on knees with only medial tibia BML changes, knees with lateral tibial BMLs were excluded. Medial tibial BML volume change was classified into three groups: BML regression (lowest quartile of medial tibial BML volume change), no-to-minimal change (middle two quartiles), and BML progression (highest quartile). We used proportional odds logistic regression models to evaluate the association between quartiles of changes in medial paBMD or M:L paBMD ratio, as outcomes, and BML volume change.
The sample (n = 308) included 163 (53%) female subjects, 212 (69%) knees with radiographic osteoarthritis, and participants with a mean age of 63.8 ± 9.3 years and mean body mass index of 29.8 ± 4.7 kg/m2. We found an association between greater increases in medial tibia paBMD and BML regression (OR = 1.7 (95% confidence interval (CI) = 1.1 to 2.8)) and a similar trend for BML progression (OR = 1.6 (95% CI = 1.0 to 2.6]). We also detected associations between greater increase in M:L paBMD and BML regression (OR = 1.6 (95% CI = 1.0 to 2.7]) and BML progression (OR = 1.8 (95% CI = 1.1 to 3.0)), although BML regression had borderline statistical significance. The frequency of sclerosis progression in the medial tibia (n = 14) was greater among knees with BML progression or regression compared with knees without BML change (P = 0.01 and P = 0.04, respectively).
BML regression and BML progression are characterized by concurrent increases in paBMD and sclerosis, which are characteristic of increased radiographic osteoarthritis severity. At least during 24 months, BML regression is not representative of improvement in other periarticular bone measures.
PMCID: PMC3978480  PMID: 24432365
22.  Gender-Specific Correlates of Complementary and Alternative Medicine Use for Knee Osteoarthritis 
Journal of Women's Health  2012;21(10):1091-1099.
Knee osteoarthritis (OA) increases healthcare use and cost. Women have higher pain and lower quality of life measures compared to men even after accounting for differences in age, body mass index (BMI), and radiographic OA severity. Our objective was to describe gender-specific correlates of complementary and alternative medicine (CAM) use among persons with radiographically confirmed knee OA.
Using data from the Osteoarthritis Initiative, 2,679 women and men with radiographic tibiofemoral OA in at least one knee were identified. Treatment approaches were classified as current CAM therapy (alternative medical systems, mind-body interventions, manipulation and body-based methods, energy therapies, and three types of biologically based therapies) or conventional medication use (over-the-counter or prescription). Gender-specific multivariable logistic regression models identified sociodemographic and clinical/functional correlates of CAM use.
CAM use, either alone (23.9% women, 21.9% men) or with conventional medications (27.3% women, 19.0% men), was common. Glucosamine use (27.2% women, 28.2% men) and chondroitin sulfate use (24.8% women; 25.7% men) did not differ by gender. Compared to men, women were more likely to report use of mind-body interventions (14.1% vs. 5.7%), topical agents (16.1% vs. 9.5%), and concurrent CAM strategies (18.0% vs. 9.9%). Higher quality of life measures and physical function indices in women were inversely associated with any therapy, and higher pain scores were positively associated with conventional medication use. History of hip replacement was a strong correlate of conventional medication use in women but not in men.
Women were more likely than men to use CAM alone or concomitantly with conventional medications.
PMCID: PMC3466916  PMID: 22946630
23.  CAM use among overweight and obese persons with radiographic knee osteoarthritis 
Obesity is associated with knee pain and is an independent predictor of incident knee osteoarthritis (OA); increased pain with movement often leads patients to adopt sedentary lifestyles to avoid pain. Detailed descriptions of pain management strategies by body mass index (BMI) level among OA patients are lacking. The objectives were to describe complementary and alternative medicine (CAM) and conventional medication use by BMI level and identify correlates of CAM use by BMI level.
Using Osteoarthritis Initiative baseline data, 2,675 patients with radiographic tibiofemoral OA in at least one knee were identified. Use of CAM therapies and conventional medications was determined by interviewers. Potential correlates included SF-12, CES-D, Western Ontario and McMaster Universities Osteoarthritis Index, and Knee injury and Osteoarthritis Outcome Score quality of life. Multinomial logistic regression models adjusting for sociodemographic and clinical factors provided estimates of the association between BMI levels and treatment use; binary logistic regression identified correlates of CAM use.
BMI was inversely associated with CAM use (45% users had BMI ≥35 kg/m2; 54% had BMI <25 kg/m2), but positively associated with conventional medication use (54% users had BMI ≥35 kg/m2; 35.1% had BMI <25 kg/m2). Those with BMI ≥30 kg/m2 were less likely to use CAM alone or in combination with conventional medications when compared to patients with BMI <25 kg/m2.
CAM use is common among people with knee OA but is inversely associated with BMI. Understanding ways to further symptom management in OA among overweight and obese patients is warranted.
PMCID: PMC3850510  PMID: 24073985
Knee osteoarthritis; Obesity; Pain; Complementary and alternative medicine
24.  Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study 
PLoS Biology  2013;11(9):e1001661.
A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.
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.
Author Summary
The number of known associations between human diseases and common genetic variants has grown dramatically in the past decade, most being identified in large-scale genetic studies of people of Western European origin. But because the frequencies of genetic variants can differ substantially between continental populations, it's important to assess how well these associations can be extended to populations with different continental ancestry. Are the correlations between genetic variants, disease endpoints, and risk factors consistent enough for genetic risk models to be reliably applied across different ancestries? Here we describe a systematic analysis of disease outcome and risk-factor–associated variants (tagSNPs) identified in European populations, in which we test whether the effect size of a tagSNP is consistent across six populations with significant non-European ancestry. We demonstrate that although nearly all such tagSNPs have effects in the same direction across all ancestries (i.e., variants associated with higher risk in Europeans will also be associated with higher risk in other populations), roughly a quarter of the variants tested have significantly different magnitude of effect (usually lower) in at least one non-European population. We therefore advise caution in the use of tagSNP-based genetic disease risk models in populations that have a different genetic ancestry from the population in which original associations were first made. We then show that this differential strength of association can be attributed to population-dependent variations in the correlation between tagSNPs and the variant that actually determines risk—the so-called functional variant. Risk models based on functional variants are therefore likely to be more robust than tagSNP-based models.
PMCID: PMC3775722  PMID: 24068893
25.  Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker - longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative 
Arthritis Research & Therapy  2013;15(5):R112.
Bone marrow lesion (BML) size may be an important imaging biomarker for osteoarthritis-related clinical trials and reducing BML size may be an important therapeutic goal. However, data on the interrelationships between BML size, pain, and structural progression are inconsistent and rarely examined in the same cohort. Therefore, we evaluated the cross-sectional and longitudinal associations of BML volume with knee pain and joint space narrowing (JSN).
A BML volume assessment was performed on magnetic resonance images of the knee collected at the 24- and 48-month Osteoarthritis Initiative visits from a convenience sample of 404 participants in the progression cohort. During the same visits, knee pain was assessed with WOMAC pain scores and knee radiographs were acquired and scored for JSN. BML volume was summed to generate a total knee volume and an index tibiofemoral compartment volume (compartment with greater baseline JSN). Primary analyses included multiple linear regressions (outcome = pain, predictor = total knee BML volume) and logistic regressions (outcome = JSN, predictor = index tibiofemoral compartment BML volume).
This sample was 49% female with a mean age of 63 (9.2 standard deviation (SD)) years, and 71% had radiographic osteoarthritis in the study knee. Larger baseline BMLs were associated with greater baseline knee pain (P = 0.01), the presence of JSN at baseline (odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.23 to 1.83), and JSN progression (OR = 1.27, 95%CI = 1.11 to 1.46). Changes in total knee BML volume had a positive association with changes in knee pain severity (P = 0.004) and this association may be driven by knees that were progressing from no or small baseline BMLs to larger BMLs. In contrast, we found no linear positive relationship between BML volume change and JSN progression. Instead, regression of medial tibiofemoral BML volume was associated with JSN progression compared to knees with no or minimal changes in BML volume (OR = 3.36, 95%CI = 1.55 to 7.28). However, follow-up analyses indicated that the association between JSN progression and BML volume change may primarily be influenced by baseline BML volume.
Large baseline BMLs are associated with greater baseline knee pain, the presence of JSN at baseline, and disease progression. Additionally, BML regression is associated with decreased knee pain but not a reduced risk of concurrent JSN progression.
PMCID: PMC3978948  PMID: 24020939
Magnetic resonance imaging; symptoms; radiographs; joint space narrowing

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