| Inflammatory bowel disease (IBD) is a group of chronic intestinal diseases including of Crohn's disease (CD) and ulcerative colitis(UC). The pathogenesis of IBD is reported associated with genetic factors, environmental factors and abnormal immune factors. In addition, IBD patients are at higher risk of developing osteoporosis and osteopenia than the general population. The role of vitamin D in calcium, phosphorus, and bone metabolism has been recognized since many years ago. Recently, it has been discovered that vitamin D can play a role in autoimmune diseases, infectious diseases and tumor diseases. Many basic research have confirmed there is a link between vitamin D and pathogenesis of IBD. Some clinical study abroad found vitamin D insufficiency is common in IBD patients and serum25(OH) vitamin D level correlate with the activity of the disease. However, there is no similar study in China. Results from different researches about impact of vitamin D on bone metabolism in IBD were not consistent and there was only one single-center study of small samples about that in China. Vitamin D exert its effect by binding to vitamin D receptor. Vitamin D gene polymorphisms had been shown related to the susceptibility of many autoimmune diseases, including IBD. Vitamin D can directly and indirectly influence the expression of DEFB1, TLR4, and IRF5. All of these gene polymorphisms also had been proved associated with IBD in Caucasian population. There were only few reports studied whether the TLR4and VDR gene were associated with IBD in Chinese Han population and no reports about association study among these gene in IBD. Therefore, in our study we aim to:1. Comparing serum25(OH) vitamin D levels in patients with IBD and matched controls, to evaluate disease characteristics that correlate with low25(OH) vitamin D level and the consequence of low25(OH) vitamin D level on bone mineral density. Meanwhile, we analyzed risk factors for abnormal bone metabolism.2. Investigating the relationship between single nucleotide polymorphisms of vitamin D working pathway related genes VDR, DEFB1, TLR4and IRF5and IBD genetic susceptibility, as well as clinical phenotype.Part1. The Study of Correlation between Serum25(OH) Vitamin D Levels and Clinical Characteristics of IBD.Methods:135IBD patients (78UC and57CD) and122controls were collected. Serum25(OH) vitamin D levels were tested in all of participants (the unit of measurement was ng/ml). Spine and femoral neck bone mineral density were tested in IBD patients.Results:1. Serum25(OH) vitamin D level in IBD group were significantly lower than controls.(UC vs controls:10.65±4.87vs12.87±4.40, P=0.017; CD vs controls:10.79±5.14vs12.87±4.40, P=0.020).2. Serum25(OH) vitamin D level in UC group classified by disease activity:remission,14.38±4.71; mild activity,10.81±4.70; moderate activity,10.05±4.17; severe activity,6.91±3.76. The comparison of serum25(OH) vitamin D level between every two groups showed:the disparities between remission and each activity as well as between mild activity and severe activity were significantly, P<0.05.3. Serum25(OH) vitamin D level in CD group classified by Harvey Bradshaw Score:0-4score,12.28±4.60;5-8score,7.99±3.43;>8score,17.9±14.00. There were only two persons scored>8, so this group was not involved in comparison. The comparison of serum25(OH) vitamin D level between0-4score and5-8score group was significantly, P<0.01.4. Multivariate analysis for osteoporosis or osteopenia in IBD showed:The total doses of glucocorticoids (OR=2.821,95%CI1.365±5.831, P=0.005) and serum25(OH) vitamin D insufficiency (OR=0.866,95%CI0.757～0.992, P=0.038) were risk factors for osteoporosis or osteopenia in UC. The total doses of glucocorticoids (OR=3.362,95%CI1.218±9.821, P=0.019) and low BMI (OR=0.651,95%CI0.457±0.929, P=0.018) were risk factors for osteoporosis or osteopenia in CD.Conclusions:1. Serum25(OH) vitamin D level in both UC and CD group were significantly lower than controls.2. Serum25(OH) vitamin D level in UC correlated negatively with the severity of disease activity; Serum25(OH) vitamin D levels in CD were lower in those scored by5-8than0-4.3. Multivariate analysis for osteoporosis or osteopenia in IBD showed:The total doses of glucocorticoids were common risk factors for osteoporosis or osteopenia both in UC and in CD. However, serum25(OH) vitamin D insufficiency and low BMI were respectively risk factor for osteoporosis or osteopenia in UC and in CD.Part2. The Study of Vitamin D Working Pathway Related Genes:VDR, DEFB1, TLR4and IRF5with Genetic Susceptibility of IBD in Han Population of China.Methods:300UC patients,158CD patients,302healthy controls of Chinese Han population were included in our study. Fourteen tag SNPs of four genes were genotyped by Sequenom MassARRAY method.Results:1. The frequency of allele A in rs3807306site (P=0.007) of IRF5gene in UC patients was higher than in controls.2. The frequency of AA genotype both in rs3807306site (P=0.028) and rs4728142site (P=0.008) of IRF5gene were higher than in controls.3. Haplotypes GGATT (P=0.0002) in IRF5gene was related to disease susceptibility of UC.4. A significantly higher frequency of AA genotype in rs4728142site (P=0.011) of IRF5gene, AA genotype in rs7037117site (P=0.038) and in rs1927907site (P=0.046) of TLR4were observed among UC patients with mild activity.5. Haplotypes GTACC (P=0.0223) in IRF5gene is related to disease susceptibility of CD.6. A significantly higher frequency of GG genotype in rs2004640site (P=0.013) of IRF5and rs2978880site (P=0.006) of DEFB1were respectively observed among CD patients with colon involved and with surgery.Conclusions:1. rs3807306polymorphism of IRF5was associated with disease susceptibility of UC and rs4728142polymorphism of IRF5might be associated with the risk for UC. However, both these sites were not associated with CD.2. rs11574143, rs4760648,rs1544410sites of VDR,rs1799946,rs2741136,rs2978880,rs2741108sites of DEFB1, rs7037117,rs1927907sites of TLR4and rs2004640,rsl874328,rs7808907sites of IRF5were not observed associated with genetic susceptibility of both UC and CD.3. rs4728142site of IRF5, rs7037117, rs1927907sites of TLR4and rs2978880site of DEFB1were observed associated with IBD phenotype.
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