Relationship between polymorphisms in vitamin D metabolism-related genes and the risk of rickets in Han Chinese children

BMC Medical Genetics

Lihong Ren²  Ye Liu¹  Shufen Yang²  Yuling Zhang² 

[1] Department of Immunology, Harbin Medical University, Harbin, Heilongjiang Province, China;Department of Pediatrics, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

关键词: Polymorphism;    Rickets;    DHCR7/NADSYN1;    CYP2R1;    GC;   

Others  :  1122617
DOI  :  10.1186/1471-2350-14-101

 received in 2012-12-09, accepted in 2013-09-25,  发布年份 2013

【 摘 要 】

Background

Vitamin D deficiency rickets is common in China. Genetic factors may play an important role in the susceptibility to rickets. Our study aimed to identify the relationship between three vitamin D-related genes (group specific component [GC], cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and rickets in Han Chinese children from northeastern China.

Methods

A total of 506 Han children from northeastern China were enrolled in the current study. Twelve SNPs in three candidate genes were genotyped using the SNaPshot assay. Linear regression was used to examine the effect of 12 single-nucleotide polymorphisms (SNPs) on the risk of rickets.

Results

In our case–control cohort, six alleles of the 12 SNPs conferred a significantly increased risk of rickets in GC (rs4588 C, P = 0.003, OR: 0.583, 95% CI: 0.412-0.836; rs222020 C, P = 0.009, OR: 1.526, 95% CI: 1.117-2.0985; rs2282679 A, P = 0.010, OR: 0.636, 95% CI: 0.449-0.900; and rs2298849 C, P = 0.001, OR: 1.709, 95% CI: 1.250-2.338) and in CYP2R1 (rs10741657 G, P = 0.019, OR: 1.467, 95% CI: 1.070-2.011; and rs2060793 G, P = 0.023, OR: 0.689, 95% CI: 0.502-0.944). The results remained significant after adjustment for sex and body mass index. We further analyzed the effect of genotypes under three different genetic models. After using Bonferroni’s method for multiple corrections, rs4588, rs2282679, and rs2298849 of the GC gene were significantly associated with rickets under the dominant (P =0.003 for rs4588, P =0.024 for rs2282679, and P =0.005 for rs2298849) and additive models (P = 0.006 for rs4588, P = 0.024 for rs2282679, and P = 0.005 for rs2298849). Haplotype analysis showed that the CAT haplotype of the GC gene (P = 0.005) and the GAA haplotype of the CYP2R1 gene (P = 0.026) were associated with susceptibility to rickets.

Conclusions

This case–control study confirmed the strong effect of GC and CYP2R1 loci on rickets in Han children from northeastern China.

【 授权许可】

   
2013 Zhang et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Al-Atawi MS, Al-Alwan IA, Al-Mutair AN, Tamim HM, Al-Jurayyan NA: Epidemiology of nutritional rickets in children. Saudi J Kidney Dis Transpl 2009, 20(2):260-265.
• [2]Pettifor JM: Nutritional rickets in developing countries. Forum Nutr 2003, 56:176-178.
• [3]Strand MA, Perry J, Jin M, Tracer DP, Fischer PR, Zhang P, Xi W, Li S: Diagnosis of rickets and reassessment of prevalence among rural children in northern China. Pediatr Int 2007, 49(2):202-209.
• [4]Baroncelli GI, Bereket A, El Kholy M, Audi L, Cesur Y, Ozkan B, Rashad M, Fernandez-Cancio M, Weisman Y, Saggese G, et al.: Rickets in the Middle East: role of environment and genetic predisposition. J Clin Endocrinol Metab 2008, 93(5):1743-1750.
• [5]Bora G, Ozkan B, Dayangac-Erden D, Erdem-Yurter H, Coskun T: Vitamin D receptor gene polymorphisms in Turkish children with vitamin D deficient rickets. Turk J Pediatr 2008, 50(1):30-33.
• [6]Fischer PR, Thacher TD, Pettifor JM, Jorde LB, Eccleshall TR, Feldman D: Vitamin D receptor polymorphisms and nutritional rickets in Nigerian children. J Bone Miner Res 2000, 15(11):2206-2210.
• [7]Kaneko A, Urnaa V, Nakamura K, Kizuki M, Seino K, Inose T, Takano T: Vitamin D receptor polymorphism among rickets children in Mongolia. J Epidemiol 2007, 17(1):25-29.
• [8]Gong YG, Li YN, Zhang WH, Liu LJ, Kang XG: Correlation between vitamin D receptor genetic polymorphism and 25-hydroxyvitamin D3 in vitamin D deficiency rickets. Zhongguo Dang Dai Er Ke Za Zhi 2010, 12(7):544-546.
• [9]Lu HJ, Li HL, Hao P, Li JM, Zhou LF: Association of the vitamin D receptor gene start codon polymorphism with vitamin D deficiency rickets. Zhonghua Er Ke Za Zhi 2003, 41(7):493-496.
• [10]Lu JJ, Li YN, Jin Y, Li L: Association of the vitamin D receptor gene start codon polymorphism with delayed rickets. Zhonghua Er Ke Za Zhi 2007, 45(1):46-49.
• [11]Wu SH, Yan CH, Shen XM: Vitamin D receptor gene polymorphisms and vitamin D deficiency rickets. Zhongguo Dang Dai Er Ke Za Zhi 2006, 8(1):83. inside back cover
• [12]Wu SH, Yu XD, Yan CH, Shen LX, Yu XG, Zhang YP, Zhang JS, Jin XM, Shen XM: Association between vitamin D receptor gene polymorphism and vitamin D deficiency rickets. Zhongguo Dang Dai Er Ke Za Zhi 2006, 8(2):121-124.
• [13]Xi WP, Yang JP, Li LQ, Zhu QY, Zhou XH: Association of vitamin D receptor gene Apa I polymorphism with vitamin D deficiency rickets. Zhonghua Er Ke Za Zhi 2005, 43(7):514-516.
• [14]Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW: De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 2003, 278(39):38084-38093.
• [15]Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C, Greissl C, Ramos-Lopez E, Hypponen E, Dunger DB, et al.: Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 2011, 60(5):1624-1631.
• [16]White P, Cooke N: The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 2000, 11(8):320-327.
• [17]Kurylowicz A, Ramos-Lopez E, Bednarczuk T, Badenhoop K: Vitamin D-binding protein (DBP) gene polymorphism is associated with Graves’ disease and the vitamin D status in a Polish population study. Exp Clin Endocrinol Diabetes 2006, 114(6):329-335.
• [18]Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K: CYP2R1 (Vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev 2007, 23(8):631-636.
• [19]Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, et al.: Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010, 376(9736):180-188.
• [20]Bu FX, Armas L, Lappe J, Zhou Y, Gao G, Wang HW, Recker R, Zhao LJ: Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Hum Genet 2010, 128(5):549-556.
• [21]Purcell SCS, Sham PC: Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003, 19:149-150.
• [22]Baroncelli GI, Bereket A, El Kholy M, Audì L, Cesur Y, Ozkan B, Rashad M, Fernández-Cancio M, Weisman Y, Saggese G, Hochberg Z: Rickets in the Middle East: role of environment and genetic predisposition. J Clin Endocrinol Metab 2008, 93(5):1743-1750.
• [23]Speeckaert M, Huang G, Delanghe JR, Taes YE: Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta 2006, 372(1–2):33-42.
• [24]Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, Abnet CC, Huang WY, Kibel AS, Crawford ED, et al.: Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis 2009, 30(5):769-776.
• [25]Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, Flesch-Janys D, Chang-Claude J: The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status. Cancer Epidemiol Biomarkers Prev 2008, 17(6):1339-1343.
• [26]Sinotte M, Diorio C, Berube S, Pollak M, Brisson J: Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women. Am J Clin Nutr 2009, 89(2):634-640.
• [27]Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE: Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem 2009, 42(10–11):1174-1177.
• [28]Fang Y, van Meurs JB, Arp P, van Leeuwen JP, Hofman A, Pols HA, Uitterlinden AG: Vitamin D binding protein genotype and osteoporosis. Calcif Tissue Int 2009, 85(2):85-93.
• [29]Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K: Metabolism of vitamin D by human microsomal CYP2R1. Biochem Biophys Res Commun 2004, 324(1):451-457.
• [30]Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A 2004, 101(20):7711-7715.
• [31]Wjst M, Altmuller J, Faus-Kessler T, Braig C, Bahnweg M, Andre E: Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res 2006, 7:60. BioMed Central Full Text
• [32]Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K: CYP2R1 (Vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev 2007, 23(8):631-636.