TY - JOUR T1 - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. JF - Hum Mol Genet Y1 - 2010 A1 - O'Seaghdha, Conall M A1 - Yang, Qiong A1 - Glazer, Nicole L A1 - Leak, Tennille S A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Kao, W H Linda A1 - Lohman, Kurt A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Chen, Yii-Der Ida A1 - Brown, Edward M A1 - Siscovick, David S A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Coresh, Josef A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Liu, Yong Mei A1 - Kestenbaum, Bryan R A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Calcium KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing AB -

Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

VL - 19 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20705733?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). JF - J Am Coll Cardiol Y1 - 2012 A1 - Ix, Joachim H A1 - Katz, Ronit A1 - Kestenbaum, Bryan R A1 - de Boer, Ian H A1 - Chonchol, Michel A1 - Mukamal, Kenneth J A1 - Rifkin, Dena A1 - Siscovick, David S A1 - Sarnak, Mark J A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Female KW - Fibroblast Growth Factors KW - Heart Failure KW - Humans KW - Kidney Function Tests KW - Male KW - Mortality KW - Renal Insufficiency, Chronic KW - United States AB -

OBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting.

BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown.

METHODS: Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.

RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45).

CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.

VL - 60 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22703926?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2014 A1 - Garimella, Pranav S A1 - Ix, Joachim H A1 - Katz, Ronit A1 - Chonchol, Michel B A1 - Kestenbaum, Bryan R A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Shastri, Shani A1 - Hiramoto, Jade S A1 - Shlipak, Michael G A1 - Sarnak, Mark J KW - Aged KW - Ankle Brachial Index KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Fibroblast Growth Factors KW - Humans KW - Incidence KW - Peripheral Arterial Disease KW - Risk Factors AB -

BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.

METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.

RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79-2.70).

CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.

VL - 233 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24529128?dopt=Abstract ER - TY - JOUR T1 - Vitamin D and the risk of dementia and Alzheimer disease. JF - Neurology Y1 - 2014 A1 - Littlejohns, Thomas J A1 - Henley, William E A1 - Lang, Iain A A1 - Annweiler, Cedric A1 - Beauchet, Olivier A1 - Chaves, Paulo H M A1 - Fried, Linda A1 - Kestenbaum, Bryan R A1 - Kuller, Lewis H A1 - Langa, Kenneth M A1 - Lopez, Oscar L A1 - Kos, Katarina A1 - Soni, Maya A1 - Llewellyn, David J KW - Aged KW - Alzheimer Disease KW - Dementia KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Proportional Hazards Models KW - Risk Factors KW - United States KW - Vitamin D KW - Vitamin D Deficiency AB -

OBJECTIVE: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.

METHODS: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.

RESULTS: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23-4.13) and 1.53 (95% CI: 1.06-2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02-4.83) and 1.69 (95% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

CONCLUSION: Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

VL - 83 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25098535?dopt=Abstract ER - TY - JOUR T1 - Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. JF - Kidney Int Y1 - 2015 A1 - Garimella, Pranav S A1 - Biggs, Mary L A1 - Katz, Ronit A1 - Ix, Joachim H A1 - Bennett, Michael R A1 - Devarajan, Prasad A1 - Kestenbaum, Bryan R A1 - Siscovick, David S A1 - Jensen, Majken K A1 - Shlipak, Michael G A1 - Chaves, Paulo H M A1 - Sarnak, Mark J KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Biomarkers KW - Cardiovascular Diseases KW - Case-Control Studies KW - Creatinine KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Incidence KW - Kidney Failure, Chronic KW - Male KW - Proportional Hazards Models KW - Uromodulin AB -

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

VL - 88 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26154925?dopt=Abstract ER - TY - JOUR T1 - Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2016 A1 - Beben, Tomasz A1 - Ix, Joachim H A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Hoofnagle, Andrew N A1 - Chonchol, Michel A1 - Kestenbaum, Bryan R A1 - de Boer, Ian H A1 - Rifkin, Dena E KW - Aged KW - Anthropometry KW - Biomarkers KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Enzyme-Linked Immunosorbent Assay KW - Female KW - Fibroblast Growth Factors KW - Frail Elderly KW - Glomerular Filtration Rate KW - Humans KW - Independent Living KW - Longitudinal Studies KW - Male KW - Phenotype KW - Risk Factors KW - Surveys and Questionnaires AB -

OBJECTIVES: To evaluate whether fibroblast growth factor 23 (FGF-23) is related to frailty and to characterize the nature of their joint association with mortality.

DESIGN: Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Community-dwelling individuals (N = 2,977; mean age 77.9 ± 4.7, 40% male, 83% white).

MEASUREMENTS: The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality.

RESULTS: Mean estimated glomerular filtration rate (eGFR) was 64 ± 17 mL/min per 1.73 m(2) . Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52% were prefrail, and 13% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38% (95% confidence interval (CI) = 17-62%) higher odds of frailty than of nonfrailty and 16% (95% CI = 3-30%) higher odds of prefrailty. FGF-23 (hazard ratio (HR) = 1.16, 95% CI = 1.10-1.23) and frailty (HR = 1.82, 95% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other.

CONCLUSION: In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes.

VL - 64 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26889836?dopt=Abstract ER - TY - JOUR T1 - Vitamin D and Memory Decline: Two Population-Based Prospective Studies. JF - J Alzheimers Dis Y1 - 2016 A1 - Kuźma, Elżbieta A1 - Soni, Maya A1 - Littlejohns, Thomas J A1 - Ranson, Janice M A1 - van Schoor, Natasja M A1 - Deeg, Dorly J H A1 - Comijs, Hannie A1 - Chaves, Paulo H M A1 - Kestenbaum, Bryan R A1 - Kuller, Lewis H A1 - Lopez, Oscar L A1 - Becker, James T A1 - Langa, Kenneth M A1 - Henley, William E A1 - Lang, Iain A A1 - Ukoumunne, Obioha C A1 - Llewellyn, David J AB -

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

VL - 50 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26836174?dopt=Abstract ER - TY - JOUR T1 - Vitamin D and Risk of Neuroimaging Abnormalities. JF - PLoS One Y1 - 2016 A1 - Littlejohns, Thomas J A1 - Kos, Katarina A1 - Henley, William E A1 - Lang, Iain A A1 - Annweiler, Cedric A1 - Beauchet, Olivier A1 - Chaves, Paulo H M A1 - Kestenbaum, Bryan R A1 - Kuller, Lewis H A1 - Langa, Kenneth M A1 - Lopez, Oscar L A1 - Llewellyn, David J AB -

Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer's disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged ≥65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25-50 nmol/L) were 0.76 (0.35-1.66) and 1.09 (0.76-1.55) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted odds ratios for ventricular grade in participants who were severely 25(OH)D deficient and deficient were 0.49 (0.20-1.19) and 1.12 (0.79-1.59) compared to those sufficient. The multivariate adjusted odds ratios for incident infarcts in participants who were severely 25(OH)D deficient and deficient were 1.95 (0.84-4.54) and 0.73 (0.47-1.95) compared to those sufficient. Overall, serum vitamin D concentrations could not be shown to be associated with the development of cerebrovascular or neurodegenerative neuroimaging abnormalities in Cardiovascular Health Study participants.

VL - 11 IS - 5 ER - TY - JOUR T1 - Bone Mineral Density and Risk of Heart Failure in Older Adults: The Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2017 A1 - Fohtung, Raymond B A1 - Brown, David L A1 - Koh, William J H A1 - Bartz, Traci M A1 - Carbone, Laura D A1 - Civitelli, Roberto A1 - Stein, Phyllis K A1 - Chaves, Paulo H M A1 - Kestenbaum, Bryan R A1 - Kizer, Jorge R AB -

BACKGROUND: Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density (BMD) and heart failure (HF) risk remains insufficiently studied.

METHODS AND RESULTS: We investigated whether BMD measured by dual-energy x-ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55% women) developed HF during the median follow-up of 10.5 years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF, with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95% CI, 1.01-1.26] per 0.1 g/cm(2) decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95% CI, 0.59-0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95% CI, 1.39-5.74]) compared with normal BMD.

CONCLUSIONS: Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.

VL - 6 IS - 3 ER - TY - JOUR T1 - The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. JF - Bone Y1 - 2018 A1 - Ginsberg, Charles A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Kestenbaum, Bryan R A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Hoofnagle, Andrew N A1 - Rifkin, Dena E A1 - Garimella, Pranav S A1 - Ix, Joachim H AB -

25-hydroxyvitamin D [25(OH)D] may not optimally indicate vitamin D receptor activity. Higher concentrations of its catabolic product 24,25-dihydroxyvitmin D [24,25(OH)2D] and a higher ratio of 24,25(OH)2D to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide additional information on receptor activity. We compared the strength of associations of these markers with serum PTH concentrations, hip bone mineral density (BMD), and risk of incident hip fracture in community-living older participants in the Cardiovascular Health Study. Among 890 participants, the mean age was 78years, 60% were women, and the mean 25(OH)D was 28±11ng/ml. In cross-sectional analysis, the strength of association of each vitamin D measure with PTH was similar; a 1% higher 25(OH)D, 24,25(OH)2D, and VMR were associated with 0.32%, 0.25%, and 0.26% lower PTH, respectively (p<0.05 for all). Among 358 participants with available BMD data, we found no associations of 25(OH)D or VMR with BMD, whereas higher 24,25(OH)2D was modestly associated with greater hip BMD (1% higher 24,25(OH)2D associated with 0.04% [95% CI 0.01-0.08%] higher BMD). Risk of incident hip fracture risk was evaluated using a case-cohort design. There were 289 hip fractures during a mean follow up time of 8.4years. Both higher 24,25(OH)2D and VMR were associated with lower risk of hip fracture (HR per SD higher, 0.73 [0.61, 0.87] and 0.74 [0.61, 0.88], respectively) whereas 25(OH)D was not associated with hip fracture (HR 0.93 [0.79, 1.10]). We conclude that evaluating vitamin D status by incorporating assessment of 24,25(OH)D and the VMR provides information on bone health above and beyond 25(OH)D alone.

VL - 107 ER - TY - JOUR T1 - Genetic Variants Associated with Circulating Fibroblast Growth Factor 23. JF - J Am Soc Nephrol Y1 - 2018 A1 - Robinson-Cohen, Cassianne A1 - Bartz, Traci M A1 - Lai, Dongbing A1 - Ikizler, T Alp A1 - Peacock, Munro A1 - Imel, Erik A A1 - Michos, Erin D A1 - Foroud, Tatiana M A1 - Åkesson, Kristina A1 - Taylor, Kent D A1 - Malmgren, Linnea A1 - Matsushita, Kunihiro A1 - Nethander, Maria A1 - Eriksson, Joel A1 - Ohlsson, Claes A1 - Mellström, Daniel A1 - Wolf, Myles A1 - Ljunggren, Osten A1 - McGuigan, Fiona A1 - Rotter, Jerome I A1 - Karlsson, Magnus A1 - Econs, Michael J A1 - Ix, Joachim H A1 - Lutsey, Pamela L A1 - Psaty, Bruce M A1 - de Boer, Ian H A1 - Kestenbaum, Bryan R AB -

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 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 (=3.0×10), lies upstream of , 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 and upstream of (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 , 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.

ER - TY - JOUR T1 - Trans-ethnic Evaluation Identifies Novel Low Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations. JF - J Clin Endocrinol Metab Y1 - 2018 A1 - Hong, Jaeyoung A1 - Hatchell, Kathryn E A1 - Bradfield, Jonathan P A1 - Andrew, Bjonnes A1 - Alessandra, Chesi A1 - Chao-Qiang, Lai A1 - Langefeld, Carl D A1 - Lu, Lingyi A1 - Lu, Yingchang A1 - Lutsey, Pamela L A1 - Musani, Solomon K A1 - Nalls, Mike A A1 - Robinson-Cohen, Cassianne A1 - Roizen, Jeffery D A1 - Saxena, Richa A1 - Tucker, Katherine L A1 - Ziegler, Julie T A1 - Arking, Dan E A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Gilsanz, Vincente A1 - Houston, Denise K A1 - Kalkwarf, Heidi J A1 - Kelly, Andrea A1 - Lappe, Joan M A1 - Liu, Yongmei A1 - Michos, Erin D A1 - Oberfield, Sharon E A1 - Palmer, Nicholette D A1 - Rotter, Jerome I A1 - Sapkota, Bishwa A1 - Shepherd, John A A1 - Wilson, James G A1 - Basu, Saonli A1 - de Boer, Ian H A1 - Divers, Jasmin A1 - Freedman, Barry I A1 - Grant, Struan F A A1 - Hakanarson, Hakon A1 - Harris, Tamara B A1 - Kestenbaum, Bryan R A1 - Kritchevsky, Stephen B A1 - Loos, Ruth J F A1 - Norris, Jill M A1 - Norwood, Arnita F A1 - Ordovas, Jose M A1 - Pankow, James S A1 - Psaty, Bruce M A1 - Sanhgera, Dharambir K A1 - Wagenknecht, Lynne E A1 - Zemel, Babette S A1 - Meigs, James A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Wang, Thomas A1 - Liu, Ching-Ti A1 - Engelman, Corinne D A1 - Billings, Liana K AB -

Context: Vitamin D inadequacy is common in the adult population of the United States. While the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known in Hispanic or African ancestry populations.

Objective: The TRANSCEN-D (TRANS-ethniC Evaluation of vitamiN D GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D (25(OH)D) concentrations from the meta-analyses of European ancestry (SUNLIGHT) and to identify novel genetic variants related to vitamin D concentrations in African and Hispanic ancestries.

Design: Ancestry-specific (Hispanic and African) and trans-ethnic (Hispanic, African and European) meta-analyses were performed using the METAL software.

Patients or Other Participants: In total, 8,541 African-American and 3,485 Hispanic-American (from North America) participants from twelve cohorts, and 16,124 European participants from SUNLIGHT were included in the study.

Main Outcome Measure(s): Blood concentrations of 25(OH)D were measured for all participants.

Results: Ancestry-specific analyses in African and Hispanic Americans replicated SNPs in GC (2 and 4 SNPs, respectively). A potentially novel SNP (rs79666294) near the KIF4B gene was identified in the African-American cohort. Trans-ethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the trans-ethnic analyses revealed novel SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.

Conclusions: Ancestry-specific and trans-ethnic GWAS of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed novel findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism require further investigation.

ER -