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51 results on '"Lutsey, Pamela L."'

1. Sleep Irregularity and Subclinical Markers of Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.

Author: Full, Kelsie M, Full, Kelsie M, Huang, Tianyi, Shah, Neomi A, Allison, Matthew A, Michos, Erin D, Duprez, Daniel A, Redline, Susan, Lutsey, Pamela L, Full, Kelsie M, Full, Kelsie M, Huang, Tianyi, Shah, Neomi A, Allison, Matthew A, Michos, Erin D, Duprez, Daniel A, Redline, Susan, and Lutsey, Pamela L
Abstract: Background Sleep irregularity has been linked to incident cardiovascular disease. Less is known about associations of sleep regularity with atherosclerosis. We examined cross-sectional associations of actigraphy-assessed sleep duration and sleep timing regularity with subclinical atherosclerosis in the community-based MESA (Multi-Ethnic Study of Atherosclerosis). Methods and Results MESA Sleep Ancillary Study participants (N=2032; mean age, 68.6±9.2 years; 37.9% White) completed 7-day wrist actigraphy. Participants underwent assessments of coronary artery calcium, carotid plaque presence, carotid intima-media thickness, and the ankle-brachial index. Sleep regularity was quantified by the 7-day with-in person SD of sleep duration and sleep onset timing. Relative risk regression models were used to calculate prevalence ratios and 95% CIs. Models are adjusted for demographics, cardiovascular disease risk factors, and other objectively assessed sleep characteristics including obstructive sleep apnea, sleep duration, and sleep fragmentation. After adjustment, compared with participants with more regular sleep durations (SD ≤60 minutes), participants with greater sleep duration irregularity (SD >120 minutes) were more likely to have high coronary artery calcium burden (>300; prevalence ratio, 1.33 [95% CI, 1.03-1.71]) and abnormal ankle-brachial index (<0.9; prevalence ratio, 1.75 [95% CI, 1.03-2.95]). Compared with participants with more regular sleep timing (SD ≤30 minutes), participants with irregular sleep timing (SD >90 minutes) were more likely to have high coronary artery calcium burden (prevalence ratio, 1.39 [95% CI, 1.07-1.82]). Associations persisted after adjustment for cardiovascular disease risk factors and average sleep duration, obstructive sleep apnea, and sleep fragmentation. Conclusions Sleep irregularity, particularly sleep duration irregularity, was associated with several measures of subclinical atherosclerosis. Sleep regularity may be a
Published: 2023

2. Changes in Cardiovascular Health Across Midlife and Late-Life and Magnetic Resonance Imaging Markers of Cerebral Vascular Disease in Late-Life

Author: MS Interne Geneeskunde, Circulatory Health, Sedaghat, Sanaz, Ji, Yuekai, Empana, Jean-Philippe, Hughes, Timothy M, Mosley, Thomas H, Gottesman, Rebecca F, Griswold, Michael, Jack, Clifford R, Lutsey, Pamela L, van Sloten, Thomas T, MS Interne Geneeskunde, Circulatory Health, Sedaghat, Sanaz, Ji, Yuekai, Empana, Jean-Philippe, Hughes, Timothy M, Mosley, Thomas H, Gottesman, Rebecca F, Griswold, Michael, Jack, Clifford R, Lutsey, Pamela L, and van Sloten, Thomas T
Published: 2023

3. Association of change in cardiovascular risk factors with incident dementia

Author: MS Interne Geneeskunde, Sedaghat, Sanaz, Lutsey, Pamela L, Ji, Yuekai, Empana, Jean-Philippe, Sorond, Farzaneh, Hughes, Timothy M, Mosley, Thomas H, Gottesman, Rebecca F, Knopman, David S, Walker, Keenan A, Gudnason, Vilmundur, Launer, Lenore J, van Sloten, Thomas T, MS Interne Geneeskunde, Sedaghat, Sanaz, Lutsey, Pamela L, Ji, Yuekai, Empana, Jean-Philippe, Sorond, Farzaneh, Hughes, Timothy M, Mosley, Thomas H, Gottesman, Rebecca F, Knopman, David S, Walker, Keenan A, Gudnason, Vilmundur, Launer, Lenore J, and van Sloten, Thomas T
Published: 2023

4. Relationship Between Age at Menopause, Obesity, and Incident Heart Failure: The Atherosclerosis Risk in Communities Study.

Author: Ebong, Imo A, Ebong, Imo A, Wilson, Machelle D, Appiah, Duke, Michos, Erin D, Racette, Susan B, Villablanca, Amparo, Breathett, Khadijah, Lutsey, Pamela L, Wellons, Melissa, Watson, Karol E, Chang, Patricia, Bertoni, Alain G, Ebong, Imo A, Ebong, Imo A, Wilson, Machelle D, Appiah, Duke, Michos, Erin D, Racette, Susan B, Villablanca, Amparo, Breathett, Khadijah, Lutsey, Pamela L, Wellons, Melissa, Watson, Karol E, Chang, Patricia, and Bertoni, Alain G
Abstract: Background The mechanisms linking menopausal age and heart failure (HF) incidence are controversial. We investigated for heterogeneity by obesity on the relationship between menopausal age and HF incidence. Methods and Results Using postmenopausal women who attended the Atherosclerosis Risk in Communities Study Visit 4, we estimated hazard ratios of incident HF associated with menopausal age using Cox proportional hazards models, testing for effect modification by obesity and adjusting for HF risk factors. Women were categorized by menopausal age: <45 years, 45 to 49 years, 50 to 54 years, and ≥55 years. Among 4441 postmenopausal women, aged 63.5±5.5 years, there were 903 incident HF events over a mean follow-up of 16.5 years. The attributable risk of generalized and central obesity for HF incidence was greatest among women who experienced menopause at age ≥55 years: 11.09/1000 person-years and 7.38/1000 person-years, respectively. There were significant interactions of menopausal age with body mass index and waist circumference for HF incidence, Pinteraction 0.02 and 0.001, respectively. The hazard ratios of incident HF for a SD increase in body mass index was elevated in women with menopausal age <45 years [1.39 (1.05-1.84)]; 45-49 years [1.33, (1.06-1.67)]; and ≥55 years [2.02, (1.41-2.89)]. The hazard ratio of incident HF for a SD increase in waist circumference was elevated only in women with menopausal age ≥55 years [2.93, (1.85-4.65)]. Conclusions As obesity worsened, the risk of developing HF became significantly greater when compared with women with lower body mass index and waist circumference, particularly among those who had experienced menopause at age ≥55 years.
Published: 2022

5. Association of Carotid Intima-Media Thickness and Other Carotid Ultrasound Features With Incident Dementia in the ARIC-NCS.

Author: Wang, Wendy, Wang, Wendy, Norby, Faye L, George, Kristen M, Alonso, Alvaro, Mosley, Thomas H, Gottesman, Rebecca F, Meyer, Michelle L, Lutsey, Pamela L, Wang, Wendy, Wang, Wendy, Norby, Faye L, George, Kristen M, Alonso, Alvaro, Mosley, Thomas H, Gottesman, Rebecca F, Meyer, Michelle L, and Lutsey, Pamela L
Abstract: Background Increased carotid intima-media thickness, interadventitial diameter, presence of carotid plaque, and lower distensibility are predictors for cardiovascular disease. These indices likely relate to cerebrovascular disease, and thus may constitute a form of vascular contributions to dementia and Alzheimer disease-related dementia. Therefore, we assessed the relationship of carotid measurements and arterial stiffness with incident dementia in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results A total of 12 459 ARIC participants with carotid arterial ultrasounds in 1990 to 1992 were followed through 2017 for dementia. Dementia cases were identified using in-person and phone cognitive status assessments, hospitalization discharge codes, and death certificate codes. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident dementia. Participants were aged 57±6 at baseline, 57% were women, and 23% were Black individuals. Over a median follow-up time of 24 years, 2224 dementia events were ascertained. After multivariable adjustments, the highest quintile of carotid intima-media thickness and interadventitial diameter in midlife was associated with increased risk of dementia (HR [95% CIs], 1.25 [1.08-1.45]; and 1.22 [1.04-1.43], respectively) compared with its respective lowest quintile. Presence of carotid plaque did not have a significant association with dementia (HR [95% CI], 1.06 [0.97-1.15]). Higher distensibility was associated with lower risk of dementia (HR [95% CI] highest versus lowest quintile, 0.76 [0.63-0.91]). Conclusions Greater carotid intima-media thickness, interadventitial diameter, and lower carotid distensibility are associated with an increased risk of incident dementia. These findings suggest that both atherosclerosis and carotid stiffness may be implicated in dementia risk.
Published: 2021

6. Association of Carotid Intima-Media Thickness and Other Carotid Ultrasound Features With Incident Dementia in the ARIC-NCS.

Author: Wang, Wendy, Wang, Wendy, Norby, Faye L, George, Kristen M, Alonso, Alvaro, Mosley, Thomas H, Gottesman, Rebecca F, Meyer, Michelle L, Lutsey, Pamela L, Wang, Wendy, Wang, Wendy, Norby, Faye L, George, Kristen M, Alonso, Alvaro, Mosley, Thomas H, Gottesman, Rebecca F, Meyer, Michelle L, and Lutsey, Pamela L
Abstract: Background Increased carotid intima-media thickness, interadventitial diameter, presence of carotid plaque, and lower distensibility are predictors for cardiovascular disease. These indices likely relate to cerebrovascular disease, and thus may constitute a form of vascular contributions to dementia and Alzheimer disease-related dementia. Therefore, we assessed the relationship of carotid measurements and arterial stiffness with incident dementia in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results A total of 12 459 ARIC participants with carotid arterial ultrasounds in 1990 to 1992 were followed through 2017 for dementia. Dementia cases were identified using in-person and phone cognitive status assessments, hospitalization discharge codes, and death certificate codes. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident dementia. Participants were aged 57±6 at baseline, 57% were women, and 23% were Black individuals. Over a median follow-up time of 24 years, 2224 dementia events were ascertained. After multivariable adjustments, the highest quintile of carotid intima-media thickness and interadventitial diameter in midlife was associated with increased risk of dementia (HR [95% CIs], 1.25 [1.08-1.45]; and 1.22 [1.04-1.43], respectively) compared with its respective lowest quintile. Presence of carotid plaque did not have a significant association with dementia (HR [95% CI], 1.06 [0.97-1.15]). Higher distensibility was associated with lower risk of dementia (HR [95% CI] highest versus lowest quintile, 0.76 [0.63-0.91]). Conclusions Greater carotid intima-media thickness, interadventitial diameter, and lower carotid distensibility are associated with an increased risk of incident dementia. These findings suggest that both atherosclerosis and carotid stiffness may be implicated in dementia risk.
Published: 2021

7. Association of Carotid Intima-Media Thickness and Other Carotid Ultrasound Features With Incident Dementia in the ARIC-NCS.

Author: Wang, Wendy, Wang, Wendy, Norby, Faye L, George, Kristen M, Alonso, Alvaro, Mosley, Thomas H, Gottesman, Rebecca F, Meyer, Michelle L, Lutsey, Pamela L, Wang, Wendy, Wang, Wendy, Norby, Faye L, George, Kristen M, Alonso, Alvaro, Mosley, Thomas H, Gottesman, Rebecca F, Meyer, Michelle L, and Lutsey, Pamela L
Abstract: Background Increased carotid intima-media thickness, interadventitial diameter, presence of carotid plaque, and lower distensibility are predictors for cardiovascular disease. These indices likely relate to cerebrovascular disease, and thus may constitute a form of vascular contributions to dementia and Alzheimer disease-related dementia. Therefore, we assessed the relationship of carotid measurements and arterial stiffness with incident dementia in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results A total of 12 459 ARIC participants with carotid arterial ultrasounds in 1990 to 1992 were followed through 2017 for dementia. Dementia cases were identified using in-person and phone cognitive status assessments, hospitalization discharge codes, and death certificate codes. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident dementia. Participants were aged 57±6 at baseline, 57% were women, and 23% were Black individuals. Over a median follow-up time of 24 years, 2224 dementia events were ascertained. After multivariable adjustments, the highest quintile of carotid intima-media thickness and interadventitial diameter in midlife was associated with increased risk of dementia (HR [95% CIs], 1.25 [1.08-1.45]; and 1.22 [1.04-1.43], respectively) compared with its respective lowest quintile. Presence of carotid plaque did not have a significant association with dementia (HR [95% CI], 1.06 [0.97-1.15]). Higher distensibility was associated with lower risk of dementia (HR [95% CI] highest versus lowest quintile, 0.76 [0.63-0.91]). Conclusions Greater carotid intima-media thickness, interadventitial diameter, and lower carotid distensibility are associated with an increased risk of incident dementia. These findings suggest that both atherosclerosis and carotid stiffness may be implicated in dementia risk.
Published: 2021

8. Hemostatic factors, inflammatory markers, and risk of incident venous thromboembolism: The Multi-Ethnic Study of Atherosclerosis.

Author: Evensen, Line H, Evensen, Line H, Folsom, Aaron R, Pankow, James S, Hansen, John-Bjarne, Allison, Matthew A, Cushman, Mary, Lutsey, Pamela L, Evensen, Line H, Evensen, Line H, Folsom, Aaron R, Pankow, James S, Hansen, John-Bjarne, Allison, Matthew A, Cushman, Mary, and Lutsey, Pamela L
Abstract: BackgroundSeveral hemostatic factors and inflammatory markers are associated with the risk of incident venous thromboembolism (VTE), however, most existing data are from case-control studies in Caucasian populations.ObjectivesWe aimed to prospectively confirm previous findings and explore less studied biomarkers in relation to VTE risk in a multi-racial/multi-ethnic cohort.MethodsCirculating levels of factor VIII, fibrinogen, D-dimer, plasmin-antiplasmin complex (PAP), C-reactive protein (CRP), and interleukin-6 (IL-6) were measured at baseline (2000-2002) in 6706 participants of the Multi-Ethnic Study of Atherosclerosis. Incident VTE was identified using hospitalization discharge codes from baseline to December 31, 2015. Hazard ratios (HRs) of VTE were estimated in Cox regression models.ResultsThere were 227 events during a median of 14 years of follow-up. Compared with participants in the lowest quartile, the HRs for those above the 95th percentile and p for trend across categories were 3.50 (95% confidence interval [CI] 1.98-6.19; p < .001) for D-dimer, 1.49 (95% CI 0.84-2.63; p = .02) for factor VIII, 1.32 (95% CI 0.76-2.28; p = .99) for fibrinogen, 1.92 (95% CI 1.08-3.42; p = .15) for PAP, 1.68 (95% CI 0.81-3.48; p = .08) for CRP, and 2.55 (95% CI 1.15-5.66; p = .07) for IL-6, after adjustment for demographics and body mass index. For CRP and IL-6, follow-up was restricted to 10 years because of violations of the proportional hazards assumption. No significant interactions by age/ethnicity were observed.ConclusionsWe demonstrated a fairly novel association between PAP and risk of incident VTE, and contributed further prospective confirmation regarding the associations of D-dimer, factor VIII, and IL-6 with VTE.
Published: 2021

9. Life-Course Individual and Neighborhood Socioeconomic Status and Risk of Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study.

Author: George, Kristen M, George, Kristen M, Lutsey, Pamela L, Kucharska-Newton, Anna, Palta, Priya, Heiss, Gerardo, Osypuk, Theresa, Folsom, Aaron R, George, Kristen M, George, Kristen M, Lutsey, Pamela L, Kucharska-Newton, Anna, Palta, Priya, Heiss, Gerardo, Osypuk, Theresa, and Folsom, Aaron R
Abstract: We examined associations of individual- and neighborhood-level life-course (LC) socioeconomic status (SES) with incident dementia in the Atherosclerosis Risk in Communities cohort. Individual- and neighborhood-level SES were assessed at 3 life epochs (childhood, young adulthood, midlife) via questionnaire (2001-2002) and summarized into LC-SES scores. Dementia was ascertained through 2013 using cognitive exams, telephone interviews, and hospital and death certificate codes. Cox regression was used to estimate hazard ratios of dementia by LC-SES scores in race-specific models. The analyses included data from 12,599 participants (25% Black) in the United States, with a mean age of 54 years and median follow-up of 24 years. Each standard-deviation greater individual LC-SES score was associated with a 14% (hazard ratio (HR) = 0.86, 95% confidence interval (CI): 0.81, 0.92) lower risk of dementia in White and 21% (HR = 0.79, 95% CI: 0.71, 0.87) lower risk in Black participants. Education was removed from the individual LC-SES score and adjusted for separately to assess economic factors of LC-SES. A standard-deviation greater individual LC-SES score, without education, was associated with a 10% (HR = 0.90, 95% CI: 0.84, 0.97) lower dementia risk in White and 15% (HR = 0.85, 95% CI: 0.76, 0.96) lower risk in Black participants. Neighborhood LC-SES was not associated with dementia. We found that individual LC-SES is a risk factor for dementia, whereas neighborhood LC-SES was not associated.
Published: 2020

10. Migraine Headache and Risk of Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study.

Author: George, Kristen M, George, Kristen M, Folsom, Aaron R, Sharrett, A Richey, Mosley, Thomas H, Gottesman, Rebecca F, Hamedani, Ali G, Lutsey, Pamela L, George, Kristen M, George, Kristen M, Folsom, Aaron R, Sharrett, A Richey, Mosley, Thomas H, Gottesman, Rebecca F, Hamedani, Ali G, and Lutsey, Pamela L
Abstract: ObjectiveWe aimed to assess the association between migraine headache and incident dementia.BackgroundMigraine is a risk factor for white matter hyperintensities and ischemic stroke, which are both associated with increased risk of dementia. However, it is unknown whether migraine is independently associated with dementia.MethodsHistory of migraine was ascertained via questionnaire. Adjudicated cases of dementia were identified using cognitive tests, neuropsychological exams, and clinician review of suspected cases. Incident dementia was identified using adjudicated cases, follow-up calls, and surveillance of hospital and death codes. We assessed hazards of incident dementia by migraine status. Sex differences were also examined and stratified results were presented.ResultsAnalysis included 12,495 White and African American participants ages 51-70 with a median follow-up time of 21 years. Prevalence of dementia was 18.5% (1821/9955) among those with no migraine history, 15.8% (196/1243) among those with severe non-migraine heading, and 16.7% (233/1397) among migraineurs. There was no association between migraine and incident dementia [hazard ratio: 1.04 (0.91, 1.20)]. There was also no statistically significant interaction between sex and migraine status on risk of dementia.ConclusionDespite evidence of brain abnormalities in migraineurs, there was no association between migraine and incident dementia in this prospective cohort.
Published: 2020

11. No Association Found Between Midlife Seropositivity for Infection and Subsequent Cognitive Decline: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

Author: George, Kristen M, George, Kristen M, Folsom, Aaron R, Norby, Faye L, Lutsey, Pamela L, George, Kristen M, George, Kristen M, Folsom, Aaron R, Norby, Faye L, and Lutsey, Pamela L
Abstract: Infections of herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), Helicobacter pylori, and Chlamydia pneumoniae may play a role in cognitive decline via systemic inflammation. We hypothesized that Atherosclerosis Risk in Communities study participants who were seropositive in midlife for antibodies to HSV-1, CMV, H pylori, or C pneumoniae would have an accelerated rate of cognitive decline over 20 years. Atherosclerosis Risk in Communities performed a case-cohort study involving a stratified random sample of participants tested for serum immunoglobulin G antibodies to the pathogens of interest. We conducted a longitudinal study using this cohort. Cognitive change was measured using Z scores from the Delayed Word Recall (DWR), Digit Symbol Substitution (DSS), and Word Fluency (WF) Tests administered at visits 2 (1990-1992), 4 (1996-1998), and 5 (2011-2013). Linear regression models with generalized estimating equations and inverse probability of attrition weights were used to evaluate associations between infection and cognitive performance. Four hundred twenty-six participants were analyzed, of which 3% were seronegative for all 4 infections, 14% seropositive for one, 33% and 34% seropositive for 2 and 3, respectively, and 16% seropositive for all infections. At baseline, test scores were significantly lower for participants seropositive for H pylori and C pneumoniae. After baseline covariate adjustment, the rate of decline in DWR, DSS, WF, and global Z scores did not differ significantly by infection status for any of the 4 infections. There was also no significant association between the number of infections for which participants were seropositive and cognitive decline. Our study provides no evidence supporting a longitudinal relationship between seropositivity and cognitive decline.
Published: 2020

12. Association Between Thyroid Dysfunction and Incident Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study.

Author: George, Kristen M, George, Kristen M, Lutsey, Pamela L, Selvin, Elizabeth, Palta, Priya, Windham, Beverly Gwen, Folsom, Aaron R, George, Kristen M, George, Kristen M, Lutsey, Pamela L, Selvin, Elizabeth, Palta, Priya, Windham, Beverly Gwen, and Folsom, Aaron R
Abstract: BackgroundAbnormal thyroid hormone levels (high or low) and autoimmunity from autoimmune thyroid disease (AITD) may increase dementia risk.MethodsWe examined the associations of thyroid dysfunction or possible AITD in 1990 - 1992 with dementia through 2017 in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. Thyroid dysfunction (subclinical and overt hypo- or hyperthyroidism and euthyroidism) was categorized from serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) cut-points and AITD from anti-thyroid peroxidase (anti-TPO) antibody positivity. Dementia was identified primarily based on cognitive test performance, neuropsychological examinations and clinician review of suspected cases. Additional cases of dementia were ascertained through telephone interviews or relevant hospital and death certificate codes. Cox regression with multivariable adjustment was used for analysis.ResultsAfter exclusions for missing data, 12,481 participants were included in the analysis (mean index exam age 57 ± 5.7 (44% male, 25% black)), and 2,235 incident dementia cases were identified. AITD was not significantly associated with dementia. Subclinical hypothyroidism was associated with a lower risk of dementia (hazard ratio (HR) (95% confidence interval (CI)): 0.74 (0.60 - 0.92)), while overt hyperthyroidism was associated with a higher risk of dementia (HR (95% CI): 1.40 (1.02 - 1.92)) compared to euthyroid participants. Participants with serum FT4 concentrations above the 95th percentile were at an increased risk of dementia compared to those in the middle 90% of FT4 (HR (95% CI): 1.23 (1.02 - 1.48)).ConclusionsSubclinical hypothyroidism was associated with reduced risk of dementia, whereas overt hyperthyroidism, particularly very elevated FT4, was associated with increased risk of dementia. The association between subclinical hypothyroidism and reduced risk of dementia cannot be explained, but may have been an artifact due to change. By extrapolation, e
Published: 2019

13. Association Between Thyroid Dysfunction and Incident Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study.

Author: George, Kristen M, George, Kristen M, Lutsey, Pamela L, Selvin, Elizabeth, Palta, Priya, Windham, Beverly Gwen, Folsom, Aaron R, George, Kristen M, George, Kristen M, Lutsey, Pamela L, Selvin, Elizabeth, Palta, Priya, Windham, Beverly Gwen, and Folsom, Aaron R
Abstract: BackgroundAbnormal thyroid hormone levels (high or low) and autoimmunity from autoimmune thyroid disease (AITD) may increase dementia risk.MethodsWe examined the associations of thyroid dysfunction or possible AITD in 1990 - 1992 with dementia through 2017 in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. Thyroid dysfunction (subclinical and overt hypo- or hyperthyroidism and euthyroidism) was categorized from serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) cut-points and AITD from anti-thyroid peroxidase (anti-TPO) antibody positivity. Dementia was identified primarily based on cognitive test performance, neuropsychological examinations and clinician review of suspected cases. Additional cases of dementia were ascertained through telephone interviews or relevant hospital and death certificate codes. Cox regression with multivariable adjustment was used for analysis.ResultsAfter exclusions for missing data, 12,481 participants were included in the analysis (mean index exam age 57 ± 5.7 (44% male, 25% black)), and 2,235 incident dementia cases were identified. AITD was not significantly associated with dementia. Subclinical hypothyroidism was associated with a lower risk of dementia (hazard ratio (HR) (95% confidence interval (CI)): 0.74 (0.60 - 0.92)), while overt hyperthyroidism was associated with a higher risk of dementia (HR (95% CI): 1.40 (1.02 - 1.92)) compared to euthyroid participants. Participants with serum FT4 concentrations above the 95th percentile were at an increased risk of dementia compared to those in the middle 90% of FT4 (HR (95% CI): 1.23 (1.02 - 1.48)).ConclusionsSubclinical hypothyroidism was associated with reduced risk of dementia, whereas overt hyperthyroidism, particularly very elevated FT4, was associated with increased risk of dementia. The association between subclinical hypothyroidism and reduced risk of dementia cannot be explained, but may have been an artifact due to change. By extrapolation, e
Published: 2019

14. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk

Author: Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, Allen, Naomi E, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, and Allen, Naomi E
Published: 2019

15. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk

Author: Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, Allen, Naomi E, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, and Allen, Naomi E
Published: 2019

16. Association Between Thyroid Dysfunction and Incident Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study.

Author: George, Kristen M, George, Kristen M, Lutsey, Pamela L, Selvin, Elizabeth, Palta, Priya, Windham, Beverly Gwen, Folsom, Aaron R, George, Kristen M, George, Kristen M, Lutsey, Pamela L, Selvin, Elizabeth, Palta, Priya, Windham, Beverly Gwen, and Folsom, Aaron R
Abstract: BackgroundAbnormal thyroid hormone levels (high or low) and autoimmunity from autoimmune thyroid disease (AITD) may increase dementia risk.MethodsWe examined the associations of thyroid dysfunction or possible AITD in 1990 - 1992 with dementia through 2017 in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. Thyroid dysfunction (subclinical and overt hypo- or hyperthyroidism and euthyroidism) was categorized from serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) cut-points and AITD from anti-thyroid peroxidase (anti-TPO) antibody positivity. Dementia was identified primarily based on cognitive test performance, neuropsychological examinations and clinician review of suspected cases. Additional cases of dementia were ascertained through telephone interviews or relevant hospital and death certificate codes. Cox regression with multivariable adjustment was used for analysis.ResultsAfter exclusions for missing data, 12,481 participants were included in the analysis (mean index exam age 57 ± 5.7 (44% male, 25% black)), and 2,235 incident dementia cases were identified. AITD was not significantly associated with dementia. Subclinical hypothyroidism was associated with a lower risk of dementia (hazard ratio (HR) (95% confidence interval (CI)): 0.74 (0.60 - 0.92)), while overt hyperthyroidism was associated with a higher risk of dementia (HR (95% CI): 1.40 (1.02 - 1.92)) compared to euthyroid participants. Participants with serum FT4 concentrations above the 95th percentile were at an increased risk of dementia compared to those in the middle 90% of FT4 (HR (95% CI): 1.23 (1.02 - 1.48)).ConclusionsSubclinical hypothyroidism was associated with reduced risk of dementia, whereas overt hyperthyroidism, particularly very elevated FT4, was associated with increased risk of dementia. The association between subclinical hypothyroidism and reduced risk of dementia cannot be explained, but may have been an artifact due to change. By extrapolation, e
Published: 2019

17. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk

Author: Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, Allen, Naomi E, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, and Allen, Naomi E
Published: 2019

18. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk.

Author: Travis, Ruth C, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, Allen, Naomi E, Travis, Ruth C, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, and Allen, Naomi E
Abstract: Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a hig
Published: 2019

19. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk

Author: Epi Kanker Team 1, Cancer, JC onderzoeksprogramma Kanker, MS MDL 1, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, Allen, Naomi E, Epi Kanker Team 1, Cancer, JC onderzoeksprogramma Kanker, MS MDL 1, Travis, Ruth C, Perez-Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Joshu, Corinne E, Lutsey, Pamela L, Mondul, Alison M, Platz, Elizabeth A, Weinstein, Stephanie J, Layne, Tracy M, Helzlsouer, Kathy J, Visvanathan, Kala, Palli, Domenico, Peeters, Petra H, Bueno-de-Mesquita, Bas, Trichopoulou, Antonia, Gunter, Marc J, Tsilidis, Konstantinos K, Sánchez, Maria-Jose, Olsen, Anja, Brenner, Hermann, Schöttker, Ben, Perna, Laura, Holleczek, Bernd, Knekt, Paul, Rissanen, Harri, Yeap, Bu B, Flicker, Leon, Almeida, Osvaldo P, Wong, Yuen Yee Elizabeth, Chan, June M, Giovannucci, Edward L, Stampfer, Meir J, Ursin, Giske, Gislefoss, Randi E, Bjørge, Tone, Meyer, Haakon E, Blomhoff, Rune, Tsugane, Shoichiro, Sawada, Norie, English, Dallas R, Eyles, Darryl W, Heath, Alicia K, Williamson, Elizabeth J, Manjer, Jonas, Malm, Johan, Almquist, Martin, Marchand, Loic Le, Haiman, Christopher A, Wilkens, Lynne R, Schenk, Jeannette M, Tangen, Cathy M, Black, Amanda, Cook, Michael B, Huang, Wen-Yi, Ziegler, Regina G, Martin, Richard M, Hamdy, Freddie C, Donovan, Jenny L, Neal, David E, Touvier, Mathilde, Hercberg, Serge, Galan, Pilar, Deschasaux, Mélanie, Key, Timothy J, and Allen, Naomi E
Published: 2019

20. Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

Author: Robinson-Cohen, Cassianne, Bartz, Traci M., Lai, Dongbing, Ikizler, T. Alp, Peacock, Munro, Imel, Erik A., Michos, Erin D., Foroud, Tatiana M., Åkesson, Kristina, Taylor, Kent D., Malmgren, Linnea, Matsushita, Kunihiro, Nethander, Maria, Eriksson, Joel, Ohlsson, Claes, Mellström, Daniel, Wolf, Myles, Ljunggren, Östen, McGuigan, Fiona, Rotter, Jerome I., Karlsson, Magnus, Econs, Michael J., Ix, Joachim H., Lutsey, Pamela L., Psaty, Bruce M., de Boer, Ian H., Kestenbaum, Bryan R., Robinson-Cohen, Cassianne, Bartz, Traci M., Lai, Dongbing, Ikizler, T. Alp, Peacock, Munro, Imel, Erik A., Michos, Erin D., Foroud, Tatiana M., Åkesson, Kristina, Taylor, Kent D., Malmgren, Linnea, Matsushita, Kunihiro, Nethander, Maria, Eriksson, Joel, Ohlsson, Claes, Mellström, Daniel, Wolf, Myles, Ljunggren, Östen, McGuigan, Fiona, Rotter, Jerome I., Karlsson, Magnus, Econs, Michael J., Ix, Joachim H., Lutsey, Pamela L., Psaty, Bruce M., de Boer, Ian H., and Kestenbaum, Bryan R.
Abstract: Background: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. Methods: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m(2) to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. Results: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0x10(-24)), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. Conclusions: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
Published: 2018
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21. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author: Jiang, Xia, O'Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josee, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Voelzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, de Groot, Lisette C. P. G. M., Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, van Heemst, Diana, Kleber, Marcus E., Maerz, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Kahonen, Mika, Raitakari, Olli T., Mikkila, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hypponen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O'Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josee, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Voelzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, de Groot, Lisette C. P. G. M., Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, van Heemst, Diana, Kleber, Marcus E., Maerz, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Kahonen, Mika, Raitakari, Olli T., Mikkila, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hypponen, Elina, Kraft, Peter, and Kiel, Douglas P.
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Published: 2018
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22. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.

Author: Jiang, Xia, Jiang, Xia, O'Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, Jiang, Xia, Jiang, Xia, O'Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, and Danesh, John
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Published: 2018

23. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author: Jiang, Xia, O'Reilly, Paul F., Aschard, Hugues, Hsu, Yi Hsiang, Richards, J.B., Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen Yi, van Schoor, Natasja M., van der Velde, Nathalie, de Groot, Lisette C.P.G.M., Enneman, Anke, Cupples, L.A., Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M.K., Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, van Heemst, Diana, Kleber, Marcus E., März, Winfried, De Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, Den Heijer, Martin, Jarvelin, Marjo Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M.C., Uitterlinden, Andre G., Rivadeneira, Fernando, Jiang, Xia, O'Reilly, Paul F., Aschard, Hugues, Hsu, Yi Hsiang, Richards, J.B., Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen Yi, van Schoor, Natasja M., van der Velde, Nathalie, de Groot, Lisette C.P.G.M., Enneman, Anke, Cupples, L.A., Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M.K., Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, van Heemst, Diana, Kleber, Marcus E., März, Winfried, De Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, Den Heijer, Martin, Jarvelin, Marjo Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M.C., Uitterlinden, Andre G., and Rivadeneira, Fernando
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 -9 at rs8018720 in SEC23A, and P = 1.9×10 -14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Published: 2018

24. Objectively measured sleep characteristics and prevalence of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis Sleep study.

Author: Lutsey, Pamela L, Lutsey, Pamela L, McClelland, Robyn L, Duprez, Daniel, Shea, Steven, Shahar, Eyal, Nagayoshi, Mako, Budoff, Matthew, Kaufman, Joel D, Redline, Susan, Lutsey, Pamela L, Lutsey, Pamela L, McClelland, Robyn L, Duprez, Daniel, Shea, Steven, Shahar, Eyal, Nagayoshi, Mako, Budoff, Matthew, Kaufman, Joel D, and Redline, Susan
Abstract: BackgroundWe tested whether objectively measured indices of obstructive sleep apnoea (OSA) and sleep quality are associated with coronary artery calcification (CAC) prevalence independent of obesity, a classic confounder.Methods1465 Multi-Ethnic Study of Atherosclerosis participants (mean age 68 years), who were free of clinical cardiovascular disease, had both coronary CT and in-home polysomnography and actigraphy performed. OSA categories were defined by the Apnea-Hypopnea Index (AHI). Prevalence ratios (PRs) for CAC >0 and >400 (high burden) were calculated.ResultsParticipants with severe OSA (AHI ≥30; 14.6%) were more likely to have prevalent CAC, relative to those with no evidence of OSA, after adjustment for demographics and smoking status (PR 1.16; 95% CI 1.06 to 1.26), body mass index (1.11; 1.02 to 1.21) and traditional cardiovascular risk factors (1.10; 1.01 to 1.19). Other markers of hypoxaemia tended to be associated with a higher prevalence of CAC >0. For CAC >400, a higher prevalence was observed with both a higher arousal index and less slow-wave sleep. Overall, associations were somewhat stronger among younger participants, but did not vary by sex or race/ethnicity.ConclusionsIn this population-based multi-ethnic sample, severe OSA was associated with subclinical coronary artery disease (CAC >0), independent of obesity and traditional cardiovascular risk factors. Furthermore, the associations of the arousal index and slow-wave sleep with high CAC burden suggest that higher nightly sympathetic nervous system activation is also a risk factor. These findings highlight the potential importance of measuring disturbances in OSA as well as sleep fragmentation as possible risk factors for coronary artery disease.
Published: 2015

25. Genetic Variants Associated with Circulating Parathyroid Hormone.

Author: Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, Kestenbaum, Bryan, Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, and Kestenbaum, Bryan
Abstract: Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
Published: 2017

26. Relation of Serum Vitamin D to Risk of Mitral Annular and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis).

Author: Tibuakuu, Martin, Tibuakuu, Martin, Zhao, Di, de Boer, Ian H, Guallar, Eliseo, Bortnick, Anna E, Lutsey, Pamela L, Budoff, Matthew J, Kizer, Jorge R, Kestenbaum, Bryan R, Michos, Erin D, Tibuakuu, Martin, Tibuakuu, Martin, Zhao, Di, de Boer, Ian H, Guallar, Eliseo, Bortnick, Anna E, Lutsey, Pamela L, Budoff, Matthew J, Kizer, Jorge R, Kestenbaum, Bryan R, and Michos, Erin D
Abstract: Serum 25-hydroxyvitamin D [25(OH)D] concentration has been identified as a possible modifiable risk factor for cardiovascular disease (CVD). We hypothesized that serum 25(OH)D concentration would be associated with calcifications of the left-sided heart valves, which are markers of CVD risk. Aortic valve calcium (AVC) and mitral annular calcium (MAC) were quantified from cardiac computed tomography scans performed on 5,530 Multi-Ethnic Study of Atherosclerosis participants at the baseline examination (2000 to 2002) and at a follow-up visit at either Examination 2 (2002 to 2004) or Examination 3 (2004 to 2005). 25(OH)D was measured from serum samples collected at the baseline examination. Using relative risk regression, we evaluated the multivariable-adjusted risk of prevalent and incident AVC and MAC in this ethnically diverse population free of clinical CVD at baseline. The mean age of participants was 62 ± 10 years; 53% were women, 40% white, 26% black, 21% Hispanic, and 12% Chinese. Prevalent AVC and MAC were observed in 12% and 9% of study sample, respectively. There were no significant associations between 25(OH)D and prevalent AVC or MAC. Over a mean follow-up of 2.5 years, 4% developed incident AVC and 5% developed incident MAC. After adjusting for demographic variables, each 10 ng/ml higher serum 25(OH)D was associated with a 15% (relative risk 0.85, 95% confidence interval 0.74 to 0.98) lower risk of incident MAC but not AVC. However, this association was no longer significant after adjusting for lifestyle and CVD risk factors. Results suggest a possible link between serum 25(OH)D and the risk for incident MAC, but future studies with longer follow-up are needed to further test this association.
Published: 2017

27. Genetic Variants Associated with Circulating Parathyroid Hormone.

Author: Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, Kestenbaum, Bryan, Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, and Kestenbaum, Bryan
Abstract: Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
Published: 2017

28. Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies.

Author: Mahmoodi, Bakhtawar K, Mahmoodi, Bakhtawar K, Cushman, Mary, Anne Næss, Inger, Allison, Matthew A, Bos, Willem J, Brækkan, Sigrid K, Cannegieter, Suzanne C, Gansevoort, Ron T, Gona, Philimon N, Hammerstrøm, Jens, Hansen, John-Bjarne, Heckbert, Susan, Holst, Anders G, Lakoski, Susan G, Lutsey, Pamela L, Manson, JoAnn E, Martin, Lisa W, Matsushita, Kunihiro, Meijer, Karina, Overvad, Kim, Prescott, Eva, Puurunen, Marja, Rossouw, Jacques E, Sang, Yingying, Severinsen, Marianne T, Ten Berg, Jur, Folsom, Aaron R, Zakai, Neil A, Mahmoodi, Bakhtawar K, Mahmoodi, Bakhtawar K, Cushman, Mary, Anne Næss, Inger, Allison, Matthew A, Bos, Willem J, Brækkan, Sigrid K, Cannegieter, Suzanne C, Gansevoort, Ron T, Gona, Philimon N, Hammerstrøm, Jens, Hansen, John-Bjarne, Heckbert, Susan, Holst, Anders G, Lakoski, Susan G, Lutsey, Pamela L, Manson, JoAnn E, Martin, Lisa W, Matsushita, Kunihiro, Meijer, Karina, Overvad, Kim, Prescott, Eva, Puurunen, Marja, Rossouw, Jacques E, Sang, Yingying, Severinsen, Marianne T, Ten Berg, Jur, Folsom, Aaron R, and Zakai, Neil A
Abstract: BackgroundMuch controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE).MethodsWe performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis.ResultsThe studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively.ConclusionsExcept for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood p
Published: 2017

29. Relation of Serum Vitamin D to Risk of Mitral Annular and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis).

Author: Tibuakuu, Martin, Tibuakuu, Martin, Zhao, Di, de Boer, Ian H, Guallar, Eliseo, Bortnick, Anna E, Lutsey, Pamela L, Budoff, Matthew J, Kizer, Jorge R, Kestenbaum, Bryan R, Michos, Erin D, Tibuakuu, Martin, Tibuakuu, Martin, Zhao, Di, de Boer, Ian H, Guallar, Eliseo, Bortnick, Anna E, Lutsey, Pamela L, Budoff, Matthew J, Kizer, Jorge R, Kestenbaum, Bryan R, and Michos, Erin D
Abstract: Serum 25-hydroxyvitamin D [25(OH)D] concentration has been identified as a possible modifiable risk factor for cardiovascular disease (CVD). We hypothesized that serum 25(OH)D concentration would be associated with calcifications of the left-sided heart valves, which are markers of CVD risk. Aortic valve calcium (AVC) and mitral annular calcium (MAC) were quantified from cardiac computed tomography scans performed on 5,530 Multi-Ethnic Study of Atherosclerosis participants at the baseline examination (2000 to 2002) and at a follow-up visit at either Examination 2 (2002 to 2004) or Examination 3 (2004 to 2005). 25(OH)D was measured from serum samples collected at the baseline examination. Using relative risk regression, we evaluated the multivariable-adjusted risk of prevalent and incident AVC and MAC in this ethnically diverse population free of clinical CVD at baseline. The mean age of participants was 62 ± 10 years; 53% were women, 40% white, 26% black, 21% Hispanic, and 12% Chinese. Prevalent AVC and MAC were observed in 12% and 9% of study sample, respectively. There were no significant associations between 25(OH)D and prevalent AVC or MAC. Over a mean follow-up of 2.5 years, 4% developed incident AVC and 5% developed incident MAC. After adjusting for demographic variables, each 10 ng/ml higher serum 25(OH)D was associated with a 15% (relative risk 0.85, 95% confidence interval 0.74 to 0.98) lower risk of incident MAC but not AVC. However, this association was no longer significant after adjusting for lifestyle and CVD risk factors. Results suggest a possible link between serum 25(OH)D and the risk for incident MAC, but future studies with longer follow-up are needed to further test this association.
Published: 2017

30. Kidney function, bone-mineral metabolism markers, and future risk of peripheral artery disease.

Author: Yang, Chao, Yang, Chao, Kwak, Lucia, Ballew, Shoshana H, Garimella, Pranav S, Jaar, Bernard G, Folsom, Aaron R, Heiss, Gerardo, Selvin, Elizabeth, Lutsey, Pamela L, Coresh, Josef, Matsushita, Kunihiro, Yang, Chao, Yang, Chao, Kwak, Lucia, Ballew, Shoshana H, Garimella, Pranav S, Jaar, Bernard G, Folsom, Aaron R, Heiss, Gerardo, Selvin, Elizabeth, Lutsey, Pamela L, Coresh, Josef, and Matsushita, Kunihiro
Abstract: Background and aimsReduced kidney function is a risk factor for lower-extremity peripheral artery disease (PAD). However, the associations of novel filtration markers with PAD are yet to be quantified. Moreover, little is known on whether bone-mineral metabolism (BMM) markers are related to incident PAD beyond kidney function.MethodsUsing data from 12,472 participants at baseline (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) study, we comprehensively quantified the associations of kidney related markers with incident PAD (defined as hospitalizations with diagnosis of lower-extremity atherosclerosis, revascularization, or amputation). Kidney related markers of interest included estimated glomerular filtration rate (eGFR) (based on creatinine, cystatin C, and both), cystatin C, beta-2 microglobulin (B2M), and BMM markers (serum fibroblast growth factor 23, parathyroid hormone, calcium, and phosphorus).ResultsDuring a median follow-up of 21 years, 471 participants developed incident PAD. Low eGFR was significantly associated with future PAD risk, with slightly stronger relationship when cystatin C was used (adjusted hazard ratio [HR] 6.3-8.3 for eGFR <30 and 2.4-3.5 for eGFR 30-59 vs. eGFR ≥90 mL/min/1.73 m2). Among all filtration markers, B2M had the strongest association with incident PAD (HR for top vs. bottom quartile 2.60 [95% CI: 1.91-3.54] for B2M vs. 1.20 [0.91-1.58] for creatinine-based eGFR). Among BMM markers, only phosphorus remained significant for PAD risk beyond potential confounders, including kidney function (HR 1.47 [1.11-1.94] in top quartile).ConclusionsKidney dysfunction was independently associated with future PAD risk, particularly when assessed with cystatin C and B2M. Among the BMM markers tested, phosphorus was most robustly associated with incident PAD beyond kidney function. Our results suggest the potential usefulness of novel filtration markers for PAD risk assessment and the possible role of phosphorus in the
Published: 2017

31. Association of traditional cardiovascular risk factors with venous thromboembolism

Author: Mahmoodi, Bakhtawar K., Cushman, Mary, Næss, Inger Anne, Allison, Matthew A., Bos, Willem Jan, Brækkan, Sigrid K., Cannegieter, Suzanne C., Gansevoort, Ron T., Gona, Philimon N., Hammerstrøm, Jens, Hansen, John Bjarne, Heckbert, Susan, Holst, Anders G., Lakoski, Susan G., Lutsey, Pamela L., Manson, Jo Ann E., Martin, Lisa W., Matsushita, Kunihiro, Meijer, Karina, Overvad, Kim, Prescott, Eva, Puurunen, Marja, Rossouw, Jacques E., Sang, Yingying, Severinsen, Marianne T., Ten Berg, Jur, Folsom, Aaron R., Zakai, Neil A., Mahmoodi, Bakhtawar K., Cushman, Mary, Næss, Inger Anne, Allison, Matthew A., Bos, Willem Jan, Brækkan, Sigrid K., Cannegieter, Suzanne C., Gansevoort, Ron T., Gona, Philimon N., Hammerstrøm, Jens, Hansen, John Bjarne, Heckbert, Susan, Holst, Anders G., Lakoski, Susan G., Lutsey, Pamela L., Manson, Jo Ann E., Martin, Lisa W., Matsushita, Kunihiro, Meijer, Karina, Overvad, Kim, Prescott, Eva, Puurunen, Marja, Rossouw, Jacques E., Sang, Yingying, Severinsen, Marianne T., Ten Berg, Jur, Folsom, Aaron R., and Zakai, Neil A.
Abstract: Background: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE). Methods: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis. Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively. Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher sy
Published: 2017

32. Life's Simple 7's Cardiovascular Health Metrics are Associated with Hispanic/Latino Neurocognitive Function: HCHS/SOL Results.

Author: González, Hector M, González, Hector M, Tarraf, Wassim, Gouskova, Natalia, Rodríguez, Carlos J, Rundek, Tatjana, Grober, Ellen, Pirzada, Amber, González, Patricia, Lutsey, Pamela L, Camacho, Alvaro, Daviglus, Martha L, Wright, Clinton, Mosley, Thomas H, González, Hector M, González, Hector M, Tarraf, Wassim, Gouskova, Natalia, Rodríguez, Carlos J, Rundek, Tatjana, Grober, Ellen, Pirzada, Amber, González, Patricia, Lutsey, Pamela L, Camacho, Alvaro, Daviglus, Martha L, Wright, Clinton, and Mosley, Thomas H
Abstract: BackgroundHispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed.ObjectiveWe examined associations between neurocognition and cardiovascular health (CVH) metrics (Life's Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance).MethodsWe used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45-74 years) to examine neurocognition in relation to CVH LS7 scores.ResultsIn age and sex adjusted models, a one unit LS7 score increase (range = 0-14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p < 0.01]; range = 3-42), B-SEVLT recall (0.12 [p < 0.01]; range = 0-15), Word Fluency (phonemic; 0.46 (p < 0.01); range = 0-49), and Digit Symbol Substitution (0.49 (p < 0.01); range = 0-83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations.ConclusionsWe found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos.
Published: 2016

33. Life's Simple 7's Cardiovascular Health Metrics are Associated with Hispanic/Latino Neurocognitive Function: HCHS/SOL Results.

Author: González, Hector M, Libon, David1, González, Hector M, Tarraf, Wassim, Gouskova, Natalia, Rodríguez, Carlos J, Rundek, Tatjana, Grober, Ellen, Pirzada, Amber, González, Patricia, Lutsey, Pamela L, Camacho, Alvaro, Daviglus, Martha L, Wright, Clinton, Mosley, Thomas H, González, Hector M, Libon, David1, González, Hector M, Tarraf, Wassim, Gouskova, Natalia, Rodríguez, Carlos J, Rundek, Tatjana, Grober, Ellen, Pirzada, Amber, González, Patricia, Lutsey, Pamela L, Camacho, Alvaro, Daviglus, Martha L, Wright, Clinton, and Mosley, Thomas H
Abstract: BackgroundHispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed.ObjectiveWe examined associations between neurocognition and cardiovascular health (CVH) metrics (Life's Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance).MethodsWe used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45-74 years) to examine neurocognition in relation to CVH LS7 scores.ResultsIn age and sex adjusted models, a one unit LS7 score increase (range = 0-14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p < 0.01]; range = 3-42), B-SEVLT recall (0.12 [p < 0.01]; range = 0-15), Word Fluency (phonemic; 0.46 (p < 0.01); range = 0-49), and Digit Symbol Substitution (0.49 (p < 0.01); range = 0-83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations.ConclusionsWe found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos.
Published: 2016

34. Biomarkers of Vitamin D Status and Risk of ESRD.

Author: Rebholz, Casey M, Rebholz, Casey M, Grams, Morgan E, Lutsey, Pamela L, Hoofnagle, Andrew N, Misialek, Jeffrey R, Inker, Lesley A, Levey, Andrew S, Selvin, Elizabeth, Hsu, Chi-Yuan, Kimmel, Paul L, Vasan, Ramachandran S, Eckfeldt, John H, Coresh, Josef, Chronic Kidney Disease Biomarkers Consortium, Rebholz, Casey M, Rebholz, Casey M, Grams, Morgan E, Lutsey, Pamela L, Hoofnagle, Andrew N, Misialek, Jeffrey R, Inker, Lesley A, Levey, Andrew S, Selvin, Elizabeth, Hsu, Chi-Yuan, Kimmel, Paul L, Vasan, Ramachandran S, Eckfeldt, John H, Coresh, Josef, and Chronic Kidney Disease Biomarkers Consortium
Abstract: BackgroundDisordered mineral metabolism is characteristic of decreased kidney function. However, the prospective associations between circulating levels of vitamin D binding protein, vitamin D, and end-stage renal disease (ESRD) have not been extensively evaluated in epidemiologic studies.Study designNested case-control study.Setting & participantsMiddle-aged black and white men and women from 4 US communities.PredictorsBaseline levels of vitamin D binding protein, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) were measured in blood samples collected at study visit 4 (1996-1998) of the ARIC (Atherosclerosis Risk in Communities) Study.OutcomeESRD cases (n=184) were identified through hospitalization diagnostic codes from 1996 to 2008 and were frequency matched to controls (n=251) on categories of estimated glomerular filtration rate, albuminuria, diabetes mellitus, sex, and race.MeasurementsLogistic regression was used to estimate the association between mineral metabolism biomarkers (vitamin D binding protein, 25(OH)D, and 1,25(OH)2D) and incident ESRD, adjusting for age, sex, race, estimated glomerular filtration rate, albuminuria, diabetes mellitus, hypertension, education, specimen type, and serum levels of calcium, phosphate, and parathyroid hormone.ResultsHigher vitamin D binding protein levels were associated with elevated risk for incident ESRD (OR, 1.76; 95% CI, 1.22-2.54; P=0.003). Higher free and bioavailable 25(OH)D levels were associated with reduced risk for incident ESRD (ORs of 0.65 [95% CI, 0.46-0.92; P=0.02] and 0.63 [95% CI, 0.43-0.91; P=0.02] for free and bioavailable 25[OH]D, respectively). There was no association between ESRD and overall levels of 25(OH)D (OR, 0.83; 95% CI, 0.58-1.19; P=0.3) or 1,25(OH)2D (OR, 0.73; 95% CI, 0.48-1.13; P=0.2).LimitationsLack of direct measurement of free and bioavailable vitamin D.ConclusionsIn the general population, blood levels of vitamin D binding protein were pos
Published: 2016

35. Association of sleep apnea and sleep duration with peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis (MESA).

Author: Nagayoshi, Mako, Nagayoshi, Mako, Lutsey, Pamela L, Benkeser, David, Wassel, Christina L, Folsom, Aaron R, Shahar, Eyal, Iso, Hiroyasu, Allison, Matthew A, Criqui, Michael H, Redline, Susan, Nagayoshi, Mako, Nagayoshi, Mako, Lutsey, Pamela L, Benkeser, David, Wassel, Christina L, Folsom, Aaron R, Shahar, Eyal, Iso, Hiroyasu, Allison, Matthew A, Criqui, Michael H, and Redline, Susan
Abstract: Background and aimsNumerous biological pathways linking sleep disturbances to atherosclerosis have been identified, such as insulin resistance, inflammation, hypertension, and endothelial dysfunction. Yet, the association of sleep apnea and sleep duration with peripheral artery disease (PAD) is not well characterized.MethodsWe evaluated the cross-sectional association between objectively measured sleep and prevalent PAD in 1844 participants (mean age 68 years) who in 2010-2013 had in-home polysomnography, 7-day wrist actigraphy and ankle-brachial index (ABI) measurements. We also evaluated the relation between self-reported diagnosed sleep apnea and PAD incidence in 5365 participants followed from 2000 to 2012. PAD was defined as ABI < 0.90.ResultsIn cross-sectional analyses, severe sleep apnea [apnea-hypopnea index (AHI) ≥30 vs. AHI <5] was associated with greater prevalent PAD only among black participants [multivariate adjusted prevalence ratio (95% CI): 2.29 (1.07-4.89); p-interaction = 0.05]. Short and long sleep duration was also associated with a 2-fold higher prevalence of PAD as compared with those who slept 7 h/night, in the full sample. In longitudinal analyses, participants with self-reported diagnosed sleep apnea were at higher risk of incident PAD [multivariable adjusted hazard ratio (95% CI): 1.93 (1.05-3.53)], with no evidence of interaction by race/ethnicity.ConclusionsThese findings support a significant association between sleep apnea and prevalent and incident PAD, with evidence for stronger associations with objectively measured sleep apnea and cross sectional PAD in blacks. In addition, short and long sleep duration was associated with PAD. These results identify sleep disturbances as a potential risk factor for PAD.
Published: 2016

36. Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

Author: Joshi, Amit D, Andersson, Charlotte, Buch, Stephan, Stender, Stefan, Noordam, Raymond, Weng, Lu-Chen, Weeke, Peter E, Auer, Paul L, Boehm, Bernhard, Chen, Constance, Choi, Hyon, Curhan, Gary, Denny, Joshua C, De Vivo, Immaculata, Eicher, John D, Ellinghaus, David, Folsom, Aaron R, Fuchs, Charles, Gala, Manish, Haessler, Jeffrey, Hofman, Albert, Hu, Frank, Hunter, David J, Janssen, Harry L A, Kang, Jae H, Kooperberg, Charles, Kraft, Peter, Kratzer, Wolfgang, Lieb, Wolfgang, Lutsey, Pamela L, Darwish Murad, Sarwa, Nordestgaard, Børge G, Pasquale, Louis R, Reiner, Alex P, Ridker, Paul M, Rimm, Eric, Rose, Lynda M, Shaffer, Christian M, Schafmayer, Clemens, Tamimi, Rulla M, Uitterlinden, Andre G, Völker, Uwe, Völzke, Henry, Wakabayashi, Yoshiyuki, Wiggs, Janey L., Zhu, Jun, Roden, Dan M, Stricker, Bruno H Ch, Tang, Weihong, Teumer, Alexander, Hampe, Jochen, Tybjærg-Hansen, Anne, Chasman, Daniel I, Chan, Andrew T, Johnson, Andrew D, Joshi, Amit D, Andersson, Charlotte, Buch, Stephan, Stender, Stefan, Noordam, Raymond, Weng, Lu-Chen, Weeke, Peter E, Auer, Paul L, Boehm, Bernhard, Chen, Constance, Choi, Hyon, Curhan, Gary, Denny, Joshua C, De Vivo, Immaculata, Eicher, John D, Ellinghaus, David, Folsom, Aaron R, Fuchs, Charles, Gala, Manish, Haessler, Jeffrey, Hofman, Albert, Hu, Frank, Hunter, David J, Janssen, Harry L A, Kang, Jae H, Kooperberg, Charles, Kraft, Peter, Kratzer, Wolfgang, Lieb, Wolfgang, Lutsey, Pamela L, Darwish Murad, Sarwa, Nordestgaard, Børge G, Pasquale, Louis R, Reiner, Alex P, Ridker, Paul M, Rimm, Eric, Rose, Lynda M, Shaffer, Christian M, Schafmayer, Clemens, Tamimi, Rulla M, Uitterlinden, Andre G, Völker, Uwe, Völzke, Henry, Wakabayashi, Yoshiyuki, Wiggs, Janey L., Zhu, Jun, Roden, Dan M, Stricker, Bruno H Ch, Tang, Weihong, Teumer, Alexander, Hampe, Jochen, Tybjærg-Hansen, Anne, Chasman, Daniel I, Chan, Andrew T, and Johnson, Andrew D
Abstract: BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.CONCLUSIONS: In this large-scale GWAS of gallstone dis
Published: 2016

37. Obstructive sleep apnea and progression of coronary artery calcium: the multi-ethnic study of atherosclerosis study.

Author: Kwon, Younghoon, Kwon, Younghoon, Duprez, Daniel A, Jacobs, David R, Nagayoshi, Mako, McClelland, Robyn L, Shahar, Eyal, Budoff, Matthew, Redline, Susan, Shea, Steven, Carr, J Jeffrey, Lutsey, Pamela L, Kwon, Younghoon, Kwon, Younghoon, Duprez, Daniel A, Jacobs, David R, Nagayoshi, Mako, McClelland, Robyn L, Shahar, Eyal, Budoff, Matthew, Redline, Susan, Shea, Steven, Carr, J Jeffrey, and Lutsey, Pamela L
Abstract: BackgroundObstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self-reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association.Methods and resultsIn the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002-2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010-2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA ("normal"). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow-up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group.ConclusionsOSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.
Published: 2014

38. Obstructive sleep apnea and progression of coronary artery calcium: the multi-ethnic study of atherosclerosis study.

Author: Kwon, Younghoon, Kwon, Younghoon, Duprez, Daniel A, Jacobs, David R, Nagayoshi, Mako, McClelland, Robyn L, Shahar, Eyal, Budoff, Matthew, Redline, Susan, Shea, Steven, Carr, J Jeffrey, Lutsey, Pamela L, Kwon, Younghoon, Kwon, Younghoon, Duprez, Daniel A, Jacobs, David R, Nagayoshi, Mako, McClelland, Robyn L, Shahar, Eyal, Budoff, Matthew, Redline, Susan, Shea, Steven, Carr, J Jeffrey, and Lutsey, Pamela L
Abstract: BackgroundObstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self-reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association.Methods and resultsIn the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002-2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010-2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA ("normal"). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow-up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group.ConclusionsOSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.
Published: 2014

39. Serum and dietary magnesium and incidence of atrial fibrillation in whites and in african americans - Atherosclerosis risk in communities (ARIC) study

Author: Misialek, Jeffrey R., Lopez, Faye L., Lutsey, Pamela L., Huxley, Rachel R., Peacock, James M., Chen, Lin Y., Soliman, Elsayed Z., Agarwal, Sunil K., Alonso, Alvaro, Misialek, Jeffrey R., Lopez, Faye L., Lutsey, Pamela L., Huxley, Rachel R., Peacock, James M., Chen, Lin Y., Soliman, Elsayed Z., Agarwal, Sunil K., and Alonso, Alvaro
Published: 2013

40. Serum and dietary magnesium and incidence of atrial fibrillation in whites and in african americans - Atherosclerosis risk in communities (ARIC) study

Author: Misialek, Jeffrey R., Lopez, Faye L., Lutsey, Pamela L., Huxley, Rachel R., Peacock, James M., Chen, Lin Y., Soliman, Elsayed Z., Agarwal, Sunil K., Alonso, Alvaro, Misialek, Jeffrey R., Lopez, Faye L., Lutsey, Pamela L., Huxley, Rachel R., Peacock, James M., Chen, Lin Y., Soliman, Elsayed Z., Agarwal, Sunil K., and Alonso, Alvaro
Published: 2013

41. Troponin T, N-terminal pro-B-type natriuretic peptide, and incidence of stroke: The atherosclerosis risk in communities study

Author: Folsom, Aaron R, Nambi, Vijay, Bell, Elizabeth J, Oluleye, Oludamilola W, Gottesman, Rebecca F, Lutsey, Pamela L, Huxley, Rachel R, Ballantyne, Christie M, Folsom, Aaron R, Nambi, Vijay, Bell, Elizabeth J, Oluleye, Oludamilola W, Gottesman, Rebecca F, Lutsey, Pamela L, Huxley, Rachel R, and Ballantyne, Christie M
Published: 2013

42. Impact of age at smoking initiation, dosage, and time since quitting on cardiovascular disease in African Americans and whites: The Atherosclerosis Risk in Communities Study

Author: Huxley, Rachel R., Yatsuya, Hiroshi, Lutsey, Pamela L., Woodward, Mark, Alonso, Alvaro, Folsom, Aaron R., Huxley, Rachel R., Yatsuya, Hiroshi, Lutsey, Pamela L., Woodward, Mark, Alonso, Alvaro, and Folsom, Aaron R.
Published: 2012

43. Physical activity attenuates the influence of FTO variants on obesity risk : a meta-analysis of 218,166 adults and 19,268 children

Author: Kilpeläinen, Tuomas O, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stančáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, Loos, Ruth J F, Kilpeläinen, Tuomas O, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stančáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, and Loos, Ruth J F
Abstract: BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Published: 2011
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44. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk:A Meta-Analysis of 218,166 Adults and 19,268 Children

Author: Oskari Kilpeläinen, Tuomas, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, Loos, Ruth J F, Oskari Kilpeläinen, Tuomas, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, and Loos, Ruth J F
Abstract: Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Published: 2011

45. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk:A Meta-Analysis of 218,166 Adults and 19,268 Children

Author: Oskari Kilpeläinen, Tuomas, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, Loos, Ruth J F, Oskari Kilpeläinen, Tuomas, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, and Loos, Ruth J F
Abstract: Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Published: 2011

46. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk:A Meta-Analysis of 218,166 Adults and 19,268 Children

Author: Oskari Kilpeläinen, Tuomas, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, Loos, Ruth J F, Oskari Kilpeläinen, Tuomas, Qi, Lu, Brage, Soren, Sharp, Stephen J, Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S, Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T, Mangino, Massimo, Timpson, Nicholas J, Song, Yiqing, Zillikens, M Carola, Jablonski, Kathleen A, Garcia, Melissa E, Johansson, Stefan, Bragg-Gresham, Jennifer L, Wu, Ying, van Vliet-Ostaptchouk, Jana V, Onland-Moret, N Charlotte, Zimmermann, Esther, Rivera, Natalia V, Tanaka, Toshiko, Stringham, Heather M, Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F, Snitker, Soren, Ruiz, Jonatan R, Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L, Nolan, John J, Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A, Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H, Rönnemaa, Tapani, Lakka, Timo A, Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B, Dedoussis, George V, Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M, Ebrahim, Shah, Lawlor, Debbie A, Gudnason, Vilmundur, Harris, Tamara B, Sørensen, Thorkild I A, Mohlke, Karen L, Hofman, Albert, Uitterlinden, André G, Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R, Florez, Jose C, Liu, Simin, Ness, Andy, Spector, Timothy D, Tai, E Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L, Illig, Thomas, Järvelin, Marjo-Riitta, Wareham, Nicholas J, Hu, Frank B, Groop, Leif C, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul W, and Loos, Ruth J F
Abstract: Background The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents. Conclusions The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Published: 2011

47. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

Author: Kilpelaeinen, Tuomas O., Qi, Lu, Brage, Soren, Sharp, Stephen J., Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S., Hyppoenen, Elina, Cauchi, Stephane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancakova, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T., Mangino, Massimo, Timpson, Nicholas J., Song, Yiqing, Zillikens, M. Carola, Jablonski, Kathleen A., Garcia, Melissa E., Johansson, Stefan, Bragg-Gresham, Jennifer L., Wu, Ying, van Vliet-Ostaptchouk, Jana V., Onland-Moret, N. Charlotte, Zimmermann, Esther, Rivera, Natalia V., Tanaka, Toshiko, Stringham, Heather M., Silbernagel, Guenther, Kanoni, Stavroula, Feitosa, Mary F., Snitker, Soren, Ruiz, Jonatan R., Metter, Jeffery, Martinez Larrad, Maria Teresa, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proenca, Christine, Grontved, Anders, Hallmans, Goran, Jansson, John-Olov, Kuusisto, Johanna, Kahonen, Mika, Lutsey, Pamela L., Nolan, John J., Palla, Luigi, Pedersen, Oluf, Perusse, Louis, Renstrom, Frida, Scott, Robert A., Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H., Ronnemaa, Tapani, Lakka, Timo A., Uusitupa, Matti, Serrano Rios, Manuel, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B., Dedoussis, George V., Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M., Ebrahim, Shah, Lawlor, Debbie A., Gudnason, Vilmundur, Harris, Tamara B., Sorensen, Thorkild I. A., Mohlke, Karen L., Hofman, Albert, Uitterlinden, Andre G., Tuomilehto, Jaakko, Lehtimaki, Terho, Raitakari, Olli, Isomaa, Bo, Njolstad, Pal R., Florez, Jose C., Liu, Simin, Ness, Andy, Spector, Timothy D., Tai, E. Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L., Illig, Thomas, Jarvelin, Marjo-Riitta, Wareham, Nicholas J., Hu, Frank B., Groop, Leif, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul, Loos, Ruth J. F., Kilpelaeinen, Tuomas O., Qi, Lu, Brage, Soren, Sharp, Stephen J., Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S., Hyppoenen, Elina, Cauchi, Stephane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancakova, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T., Mangino, Massimo, Timpson, Nicholas J., Song, Yiqing, Zillikens, M. Carola, Jablonski, Kathleen A., Garcia, Melissa E., Johansson, Stefan, Bragg-Gresham, Jennifer L., Wu, Ying, van Vliet-Ostaptchouk, Jana V., Onland-Moret, N. Charlotte, Zimmermann, Esther, Rivera, Natalia V., Tanaka, Toshiko, Stringham, Heather M., Silbernagel, Guenther, Kanoni, Stavroula, Feitosa, Mary F., Snitker, Soren, Ruiz, Jonatan R., Metter, Jeffery, Martinez Larrad, Maria Teresa, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proenca, Christine, Grontved, Anders, Hallmans, Goran, Jansson, John-Olov, Kuusisto, Johanna, Kahonen, Mika, Lutsey, Pamela L., Nolan, John J., Palla, Luigi, Pedersen, Oluf, Perusse, Louis, Renstrom, Frida, Scott, Robert A., Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H., Ronnemaa, Tapani, Lakka, Timo A., Uusitupa, Matti, Serrano Rios, Manuel, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B., Dedoussis, George V., Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M., Ebrahim, Shah, Lawlor, Debbie A., Gudnason, Vilmundur, Harris, Tamara B., Sorensen, Thorkild I. A., Mohlke, Karen L., Hofman, Albert, Uitterlinden, Andre G., Tuomilehto, Jaakko, Lehtimaki, Terho, Raitakari, Olli, Isomaa, Bo, Njolstad, Pal R., Florez, Jose C., Liu, Simin, Ness, Andy, Spector, Timothy D., Tai, E. Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L., Illig, Thomas, Jarvelin, Marjo-Riitta, Wareham, Nicholas J., Hu, Frank B., Groop, Leif, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul, and Loos, Ruth J. F.
Abstract: Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Published: 2011

48. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author: Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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49. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author: Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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50. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author: Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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