The Study Of Pathogenesis And Clinical Profile Of Primary Hypertrophic Osteoarthropathy And Vitamin D Deficiency

Aims: The study of inherited monogenic diseases has contributed greatly to our mechanisticunderstanding of pathogenic mutations and gene regulation, and to the development of effectivediagnostic tools. The objective of the study was to expand this mutational spectrum to better delineatethe SLCO2A1deficiency phenotype and investigate the clinical and metabolic characteristics of acohort of subjects with PHO. The present study also included different kinds of monogenetic inheriteddiseases of bone.Methods: Affected individuals and their available healthy family members from Chinese families withPHO and different kinds of monogenetic inherited diseases of bone were clinically studied. Thecausative gene were screened and analyzed. Urinary levels of PGE2and PGE-M in PHO weremeasured using competitive enzyme immunoassays. The serum levels of total testosterone, estradiol,sex hormone-binding protein, luteinizing hormone (LH), follicle-stimulating hormone (FSH) andfasting gastrin were detected.Results: Novel mutations were identified in affected individual with kinds of monogenetic inheriteddiseases of bone. The urinary levels of PGE2and PGE-M were much higher in the SLCO2A1-defcientindividuals and decreased with age. There was no relationship between sex hormones and PGE2orPGE-M. There was no significant difference in the levels of fasting serum gastrin between PHOpatients with watery diarrhea and their relatives.Conclusions: The present findings broaden the allelic spectrum of causative mutations. The urinarylevels of PGE2and PGE-M in the SLCO2A1-defcient individuals decreased with age. Themeasurement of excreted PGE2and PGE-M may have implications in the differential diagnosis,treatment and follow-up of PHO. Aims: There is a lack of large-scale studies on vitamin D status and its relationship to parathyroidhormone (PTH) and bone turnover markers in adults living in Shanghai. The objectives were todetermine the prevalence of vitamin D insufficiency in Shanghai and to investigate therelationship of25(OH)D with parathyroid function and bone turnover markers and genetic factorsdetermining serum25-hydroxy vitamin D [25(OH)D] levels in Chinese.Methods:3108healthy adults in Shanghai were recruited. Serum concentrations of25(OH)D,PTH, albumin, and bone turnover markers were measured. We screened15key genes within thevitamin D metabolic pathway using96single-nucleotide polymorphism (SNP) markers in a groupof unrelated healthy Chinese subjects. Significant confounding factors that may influence thevariability in serum25(OH)D levels were used as covariates for association analyses. Anassociation test for quantitative traits was performed to evaluate the association between candidategenes and serum25(OH)D levels.Results: During the winter season, the prevalence of vitamin D insufficiency (<30ng/mL) was84%inmales and89%in females. The prevalence of vitamin D deficiency (<20ng/mL) was30%in males and46%in females. With increasing serum25(OH)D concentrations categorized as <10,10-20,20-30, and≥30ng/mL, the mean PTH and bone turnover markers levels gradually decreasd in both sexes(p<0.001). There was an inverse relationship between the serum25(OH)D and PTH concentrations inboth genders, but no threshold of25(OH)D at which PTH levels plateaued was observed. There weremodest but significantly inverse relationships between the levels of25(OH)D and bone turnovermarkers, but no plateau was observed for serum25(OH)D levels up to40ng/mL. Variants and/or haplotypes in GC, CYP2R1and DHCR7/NADSYN1were identified as being associated with25(OH)D levels. Participants with3or4risk alleles of the two variants (GC-rs4588andCYP2R1-rs10766197) had an increased chance of presenting with a25(OH)D concentration lower than20ng/mL (2.121,1.586–2.836, p=6.1×10-8) compared with those lacking the risk alleles. Eachadditional copy of a risk allele was significantly associated with a0.12-fold decrease in thelog-25(OH)D concentration (p=3.7×10-12). Haplotype TGA of GC rs705117-rs2282679-rs1491710,haplotype GAGTAC of GC rs842999-rs705120-rs222040-rs4588-rs7041-rs10488854, haplotype CA ofGC rs1155563-rs222029, and haplotype AAGA of CYP2R1rs7936142-rs12794714-rs2060793-rs16930609were genetic risk factors toward a lower25(OH)Dconcentration. In contrary, haplotype TGGGCCC of DHCR7/NADSYN1rs1790349-rs7122671-rs1790329-rs11606033-rs2276360-rs1629220-rs2282618were geneticprotective factors.Conclusions: Vitamin D deficiency/insufficiency is very common (30%of men and46%of womenwith vitamin D below20ng/mL;84%of men and89%of women with vitamin D below30ng/mL)among healthy adults living in Shanghai. Low serum25(OH)D levels were associated with bothsecondary hyperthyroidism and high bone turnover status.The results suggest that the GC, CYP2R1and DHCR7/NADSYN1genes might contribute to variability in the serum25(OH)D levels in a healthyChinese population in Shanghai. These markers could be used as tools in Mendelian randomizationanalyses of vitamin D, and they could potentially be drug targets in the Chinese population inShanghai.