A rare haplotype of the vitamin D receptor gene is protective against diabetic nephropathy.
BACKGROUND
Vitamin D and its analogues are reported to have renoprotective effects in chronic kidney disease including diabetic nephropathy (DN). Vitamin D(3) is converted to 1,25(OH)D(3) by CYP2R1 and CYP27B1. The biological action of 1,25(OH)D(3) is mediated via its receptor. VDR, CYP27B1 or CYP2R1 gene variants could modify the biological activity of vitamin D(3). We have conducted the first case-control association study to determine the relationship between polymorphisms in VDR, CYP27B1 and CYP2R1 genes, and the risk of DN in individuals with type 1 diabetes.


METHODS
Eight VDR single-nucleotide polymorphisms (SNPs) rs10735810 FokI C>T, rs1544410 BsmI G>A, rs7975232 ApaI G>T, rs731236 TaqI T>C, rs4303288 G>T, rs11168275 C>T, rs12721366 G>A and rs2544043 G>C were investigated with CYP27B1 rs4646536 T>C and CYP2R1 rs10741657 G>A. Genotyping was performed using pyrosequencing, Taqman, Sequenom or direct sequencing technologies in 1329 type 1 diabetics (655 nephropaths, 674 non-nephropaths).


RESULTS
No significant differences were observed in genotype or allele frequencies between case and control groups for VDR, CYP27B1 or CYP2R1 SNPs, either before or after stratification by recruitment centre or when restricted to patients with end-stage renal disease. A previously identified haplotype block from rs1544410 to rs731236 was confirmed at the 3'-end of VDR. Comparison of haplotype frequencies identified the rare AGT haplotype as significantly protective against DN, 3.1% cases versus 5.8% controls; chi(2) = 11.05, Pc = 0.009 by the permutation test.


CONCLUSIONS
Our study has identified a rare VDR haplotype that is protective against DN in patients with type 1 diabetes. Replication in a large, independent cohort is required to confirm this finding.
Martin
Rosalind J L
RJ
Nephrology Research Group, Queen's University of Belfast, Northern Ireland. nephres@qub.ac.uk
McKnight
Amy J
AJ
Patterson
Christopher C
CC
Sadlier
Denise M
DM
Maxwell
Alexander P
AP
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000293:Adolescent; D016022:Case-Control Studies; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors
D018167:Receptors, Calcitriol; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase