Vitamin D Receptor (VDR) mRNA and VDR Protein Levels in Relation to Vitamin D Status, Insulin Secretory Capacity, and VDR Genotype in Bangladeshi Asians
- Babatunji-William Ogunkolade1,
- Barbara J. Boucher1,
- Jean M. Prahl6,
- Stephen A. Bustin2,
- Jacky M. Burrin3,
- Kate Noonan4,
- Bernard V. North5,
- Nassima Mannan1,
- Michael F. McDermott1,
- Hector F. DeLuca6 and
- Graham A. Hitman1
- 1Department of Diabetes and Metabolic Medicine, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 2Department of Surgery, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 3Department of Endocrinology, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 4Department of Clinical Biochemistry, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London
- 5Department of Psychiatry, Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London, U.K.
- 6Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin
Abstract
Associations have been reported between vitamin D receptor (VDR) gene polymorphisms, type 1 diabetes, insulin secretion, and the insulin resistance syndrome. As VDR polymorphisms have no known functional significance, these findings may implicate a variant of the VDR gene or a locus in linkage disequilibrium with the VDR. We have examined VDR mRNA and VDR protein levels in relation to VDR polymorphisms (41 Bangladeshi subjects) and analyzed insulin secretory capacity (143 Bangladeshi subjects), allowing for other known determinants. Peripheral blood mononuclear cells (PBMCs) from subjects who had been genotyped for BsmI, ApaI, TaqI, and FokI VDR restriction fragment length polymorphisms were used for both total VDR mRNA quantitation (using TaqMan) and measurement of VDR protein levels (using a specific micro-immunoassay). Stepwise multiple regression analyses were used (to P < 0.05) to analyze the data. For the insulin secretion index, the best-fit model (n = 143, P < 0.0001) gave age (P = 0.002), TaqI (P < 0.0001), and BMI (P = 0.001) as independent determinants; with the inclusion of VDR mRNA and VDR protein levels, VDR mRNA was the sole independent determinant (n = 41, P = 0.024). However, the best-fit model for VDR mRNA (P = 0.004) gave FokI (P = 0.044) and TaqI (P = 0.04) genotypes and insulin secretory capacity (P = 0.042) as independent determinants. For VDR protein levels, the best-fit model (P = 0.006) gave TaqI genotype (P = 0.005) and circulating 1,25-dihydroxyvitamin-D levels (P = 0.03) as independent determinants. In conclusion, these studies confirm an association between VDR polymorphisms and insulin secretory capacity and demonstrate the VDR genotype to be a significant determinant of VDR mRNA and VDR protein levels in PBMCs, providing functional support to previously described genetic associations with the VDR gene. Furthermore, VDR expression has been shown to be a determinant of insulin secretory capacity.
Footnotes
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Address correspondence and reprint requests to Prof. G.A. Hitman, Department of Diabetes and Metabolic Medicine, Royal London Hospital, Whitechapel, London, E1 1BB U.K. E-mail: g.a.hitman{at}qmul.ac.uk.
Received for publication 18 June 2001 and accepted in revised form 10 April 2002.
25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihdroxyvitamin D; IHD, ischemic heart disease; MMP, matrix metalloproteinase; OGTT, oral glucose tolerance test; PBMC, peripheral blood mononuclear cell; RFLP, restriction fragment length polymorphism; VDR, vitamin D receptor.
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