Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?
BACKGROUND
Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are risk factors for several disorders with inflammatory components, including coronary heart disease (CHD) and diabetes, though the mechanisms involved are unclear.


OBJECTIVE
To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase (MMP) system in a population with a high prevalence of vitamin D deficiency, a situation affecting susceptibility to CHD and diabetes.


METHODS
Prospective cross-sectional, interventional and embedded studies.


METHODS
Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults, free of known diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1, folate and homocysteine were measured. Vitamin-D-deficient subjects were re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up. Independent determinants of circulating concentrations of MMP9, TIMP-1 and CRP were assessed by multiple regression analysis.


RESULTS
Vitamin D status was the sole determinant of circulating MMP9 (inversely) and an independent determinant of CRP (inversely). Determinants of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype (TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%) concentrations followed vitamin-D supplementation.


CONCLUSIONS
Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.
Timms
P M
PM
Department of Clinical Biochemistry, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
Mannan
N
N
Hitman
G A
GA
Noonan
K
K
Mills
P G
PG
Syndercombe-Court
D
D
Aganna
E
E
Price
C P
CP
Boucher
B J
BJ
D000328:Adult; D000368:Aged; D001459:Bangladesh / Q000208:ethnology; D002097:C-Reactive Protein / Q000378:metabolism*; D002908:Chronic Disease; D003327:Coronary Disease / Q000097:blood / Q000209:etiology; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D011446:Prospective Studies; D018167:Receptors, Calcitriol / Q000235:genetics*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D014808:Vitamin D Deficiency / Q000097:blood*
D018167:Receptors, Calcitriol; D019715:Tissue Inhibitor of Metalloproteinase-1; D002097:C-Reactive Protein; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9