Stroke and cognitive impairment are major causes of death and disability in the US and disproportionately impact blacks. While traditional stroke risk factors such as hypertension and diabetes contribute to racial disparities in cerebrovascular outcomes, they are not sufficient to completely explain these findings, suggesting that non-traditional risk factors play an important role. Disturbances in vitamin D and phosphorus metabolism have emerged as non-traditional risk factors for adverse cardiovascular outcomes. Low 25-hydroxyvitamin D (25D) levels are associated with heart disease and death via broad effects on inflammation, insulin resistance and blood pressure control. Disturbances in phosphorus metabolism stimulate the secretion of fibroblast growth factor 23 (FGF23), a bone-derived hormone that maintains phosphorus homeostasis in part by inhibiting the conversion of 25D to its activated metabolite, 1,25-dihydroxyvitamin D (1,25D). Our group and others showed that higher FGF23 levels were associated with adverse outcomes through direct and indirect effects promoting cardiovascular disease and 1,25D deficiency. Moreover, preliminary data from our group suggest that low vitamin D is an independent risk factor for stroke and cognitive impairment. The primary focus of the current proposal is to build upon this prior work by determining whether low plasma 25D levels and excess plasma FGF23 levels are associated with incident stroke and cognitive impairment in a large, national cohort (Aim 1). In addition, since disorders of vitamin D and phosphorus metabolism are more common and severe in blacks than whites, we will determine if they partly underlie racial disparities in stroke (Aim 2). Finally, given that inflammation, insulin resistance and hypertension are key risk factors for cerebrovascular disease, and are interconnected with disturbances in vitamin D and phosphorus metabolism, we will determine whether they partly mediate the associations of 25D and FGF23 with stroke and cognitive decline. We will test these hypotheses by measuring plasma 25D, FGF23 and other key mediators of mineral metabolism including 1,25D, parathyroid hormone, calcium and phosphate in stored blood samples from a specified case cohort of 2,085 participants of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national prospective study of black and white adults designed to identify novel risk factors for racial disparities in stroke. The case-cohort to be used for this study has available measures of inflammation and insulin resistance, making it uniquely well-suited to test our hypotheses. The results of these studies may have an important impact on the treatment and/or prevention of stroke and cognitive decline. Indeed, 25D deficiency and FGF23 excess are common in the general population, disproportionately impact blacks, and can be treated with safe and relatively inexpensive therapies. Thus, if vitamin D deficiency and excess FGF23 are risk factors for cerebrovascular disease, this would support intervention trials testing the treatment of these disorders in reducing rates of incident stroke and cognitive impairment, particularly among black individuals.

Public Health Relevance

Disorders of vitamin D and phosphorus metabolism are strongly linked to cardiovascular disease. The studies proposed herein will clarify the role of vitamin D deficiency and excess levels of fibroblast growth factor 23 in stroke, cognitive impairment, and racial disparities in these outcomes. Since vitamin D deficiency and elevated fibroblast growth factor 23 levels are common and disproportionately impact blacks, these studies may uncover novel therapeutic strategies for improving cerebrovascular outcomes in the general population, particularly among African Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080850-02
Application #
8539109
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Odenkirchen, Joanne
Project Start
2012-09-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$252,738
Indirect Cost
$37,175
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Gutiérrez, Orlando M; Limou, Sophie; Lin, Feng et al. (2018) APOL1 nephropathy risk variants do not associate with subclinical atherosclerosis or left ventricular mass in middle-aged black adults. Kidney Int 93:727-732
Rostand, Stephen G; McClure, Leslie A; Kent, Shia T et al. (2016) Associations of blood pressure, sunlight, and vitamin D in community-dwelling adults. J Hypertens 34:1704-10
Gutiérrez, Orlando M (2016) Fibroblast growth factor 23 and heart failure: the plot thickens. Nephrol Dial Transplant 31:688-90
Gutiérrez, Orlando M; Judd, Suzanne E; Irvin, Marguerite R et al. (2016) APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans. Nephrol Dial Transplant 31:602-8
Judd, Suzanne E; Morgan, Charity J; Panwar, Bhupesh et al. (2016) Vitamin D deficiency and incident stroke risk in community-living black and white adults. Int J Stroke 11:93-102
Gutiérrez, Orlando M; Parsa, Afshin; Isakova, Tamara et al. (2016) Genetic African Ancestry and Markers of Mineral Metabolism in CKD. Clin J Am Soc Nephrol 11:653-62
Panwar, Bhupesh; Gutiérrez, Orlando M (2016) Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease. Semin Nephrol 36:252-61
Panwar, Bhupesh; Judd, Suzanne E; Warnock, David G et al. (2016) Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults. Stroke 47:2017-24
Palmer, Nicholette D; Divers, Jasmin; Lu, Lingyi et al. (2016) Admixture mapping of serum vitamin D and parathyroid hormone concentrations in the African American-Diabetes Heart Study. Bone 87:71-7
Gutiérrez, Orlando M; Panwar, Bhupesh; Judd, Suzanne E (2016) Response by Gutiérrez et al to Letter Regarding Article, ""Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults"". Stroke 47:e260

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