The effect of adding PTH(1–84) to conventional treatment of hypoparathyroidism: A randomized,placebo‐controlled study

In hypoparathyroidism, plasma parathyroid hormone (PTH) levels are inadequate to maintain plasma calcium concentration within the reference range. On conventional treatment with calcium supplements and active vitamin D analogues, bone turnover is abnormally low, and BMD is markedly increased. We aimed to study the effects of PTH‐replacement therapy (PTH‐RT) on calcium‐phosphate homeostasis and BMD. In a double‐blind design, we randomized 62 patients with hypoparathyroidism to daily treatment with PTH(1–84) 100 µg or similar placebo for 24 weeks as add‐on therapy to conventional treatment. Compared with placebo, patients on PTH(1–84) reduced their daily dose of calcium and active vitamin D significantly by 75% and 73%, respectively, without developing hypocalcemia. However, hypercalcemia occurred frequently during the downtitration of calcium and active vitamin D. Plasma phosphate and renal calcium and phosphate excretion did not change. Compared with placebo, PTH(1–84) treatment significantly increased plasma levels of bone‐specific alkaline phosphatase (+226% ± 36%), osteocalcin (+807% ± 186%), N‐terminal propeptide of procollagen 1 (P1NP; +1315% ± 330%), cross‐linked C‐telopeptide of type 1 collagen (CTX; +1209% ± 459%), and urinary cross‐linked N‐telopeptide of type 1 collagen (NTX; (+830% ± 165%), whereas BMD decreased at the hip (?1.59% ± 0.57%), lumbar spine (?1.76% ± 1.03%), and whole body (?1.26% ± 0.49%) but not at the forearm. In conclusion, the need for calcium and active vitamin D is reduced significantly during PTH‐RT, whereas plasma calcium and phosphate levels are maintained within the physiologic range. In contrast to the effect of PTH(1–84) treatment in patients with osteoporosis, PTH‐RT in hypoparathyroidism causes a decrease in BMD. This is most likely due to the marked increased bone turnover. Accordingly, PTH‐RT counteracts the state of overmineralized bone and, during long‐term treatment, may cause a more physiologic bone metabolism. © 2011 American Society for Bone and Mineral Research     

PTH(1‐84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization

Patients with hypoparathyroidism have low circulating parathyroid (PTH) levels and higher cancellous bone volume and trabecular thickness. Treatment with PTH(1‐84) was shown to increase abnormally low bone remodeling dynamics. In this work, we studied the effect of 1‐year or 2‐year PTH(1‐84) treatment on cancellous and cortical bone mineralization density distribution (Cn.BMDD and Ct.BMDD) based on quantitative backscattered electron imaging (qBEI) in paired transiliac bone biopsy samples. The study cohort comprised 30 adult hypoparathyroid patients (14 treated for 1 year; 16 treated for 2 years). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.Ca_Mean +3.9% and +2.7%, p < 0.001) compared to reference BMDD. After 1‐year PTH(1‐84), Cn.Ca_Mean was significantly lower than that at baseline (–6.3%, p < 0.001), whereas in the 2‐year PTH(1‐84) group Cn.Ca_Mean did not differ from baseline. Significant changes of Ct.BMDD were observed in the 1‐year treatment group only. The change in histomorphometric bone formation (mineralizing surface) was predictive for Cn.BMDD outcomes in the 1‐year PTH(1‐84) group, but not in the 2‐year PTH(1‐84) group. Our findings suggest higher baseline bone matrix mineralization consistent with the decreased bone turnover in hypoparathyroidism. PTH(1‐84) treatment caused differential effects dependent on treatment duration that were consistent with the histomorphometric bone formation outcomes. The greater increase in bone formation during the first year of treatment was associated with a decrease in bone matrix mineralization, suggesting that PTH(1‐84) exposure to the hypoparathyroid skeleton has the greatest effects on BMDD early in treatment. © 2015 American Society for Bone and Mineral Research.     

PTH(1–84) administration reverses abnormal bone‐remodeling dynamics and structure in hypoparathyroidism

Hypoparathyroidism is associated with abnormal structural and dynamic skeletal properties. We hypothesized that parathyroid hormone(1–84) [PTH(1–84)] treatment would restore skeletal properties toward normal in hypoparathyroidism. Sixty‐four subjects with hypoparathyroidism were treated with PTH(1–84) for 2 years. All subjects underwent histomorphometric assessment with percutaneous iliac crest bone biopsies. Biopsies were performed at baseline and at 1 or 2 years. Another group of subjects had a single biopsy at 3 months, having received tetracycline before beginning PTH(1–84) and prior to the biopsy (quadruple‐label protocol). Measurement of biochemical bone turnover markers was performed. Structural changes after PTH(1–84) included reduced trabecular width (144 ± 34 µm to 128 ± 34 µm, p = 0.03) and increases in trabecular number (1.74 ± 0.34/mm to 2.07 ± 0.50/mm, p = 0.02) at 2 years. Cortical porosity increased at 2 years (7.4% ± 3.2% to 9.2% ± 2.4%, p = 0.03). Histomorphometrically measured dynamic parameters, including mineralizing surface, increased significantly at 3 months, peaking at 1 year (0.7% ± 0.6% to 7.1% ± 6.0%, p = 0.001) and persisting at 2 years. Biochemical measurements of bone turnover increased significantly, peaking at 5 to 9 months of therapy and persisting for 24 months. It is concluded that PTH(1–84) treatment of hypoparathyroidism is associated with increases in histomorphometric and biochemical indices of skeletal dynamics. Structural changes are consistent with an increased remodeling rate in both trabecular and cortical compartments with tunneling resorption in the former. These changes suggest that PTH(1–84) improves abnormal skeletal properties in hypoparathyroidism and restores bone metabolism toward normal euparathyroid levels. © 2011 American Society for Bone and Mineral Research     

The role of quick bio-intact PTH(1-84) assay during parathyroidectomy for secondary hyperparathyroidism

OBJECTIVE: The role of the quick PTH assay in surgery for secondary HPT is unclear because of overestimation of intact PTH(1-84) values due to the cross-reactivity of currently available first-generation PTH assays with non-PTH(1-84) fragments that accumulate in renal failure. In this study, we used a second-generation quick PTH immunometric assay that are claimed to detect the biologically active PTH(1-84) molecule with no cross-reactivity with PTH fragments to investigate the potential utility of the assay during parathyroidectomy for secondary HPT. MATERIAL AND METHODS: The study was performed on 18 patients (12 women, 6 men) between October 2004 and March 2005. EDTA serum samples were drawn via a peripheral venous catheter after induction of anesthesia (basal), and at 5, 10, and 30 min after excision of diseased parathyroid glands. Serum active PTH(1-84) was measured by the quick Bio-Intact PTH(1-84) assay, which is a two-site chemiluminometric assay. RESULTS: At 30 min the quick Bio-PTH(1-84) level of 16 patients was under 45 pg/mL. Four parathyroid glands were removed macroscopically from 12 of the 16 patients, and three glands were removed from the other four patients. All patients were cured of their HPT. Four enlarged parathyroid glands were removed from a patient whose Bio-Intact PTH(1-84) at 30 min had not fallen below 45 pg/mL, and no other glands were found by further exploration. At the 6 mo follow-up examination, the first-generation intact PTH level of this patient was over 45 pg/mL, but several diagnostic imaging methods did not reveal any enlarged parathyroid glands. Three enlarged parathyroid glands from the other patient, and exploration led to the identification of an ectopic parathyroid gland at the carotid bifurcation. CONCLUSIONS: The results of this prospective study show that quick Bio-Intact PTH(1-84) monitoring is a valuable new tool for use in the surgical treatment of secondary HPT. An intraoperative, quick Bio-Intact PTH(1-84) assay will be of value for the adequate prediction of surgical cure.     

Association of increased active PTH(1–84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D

Summary As the serum calcium and glomerular filtration rate decreased, the proportion of active PTH(1–84) molecules in PTH immunoreactivity increased in serum from predialysis uremic patients, particularly those with vitamin D insufficiency. Introduction The PTH(1–84) fraction was altered in predialysis patients with chronic renal failure (CRF). Methods Serum PTH in predialysis CRF patients without any medication was measured by PTH(1–84)-specific whole PTH assay and intact PTH assay cross-reacting with N-truncated PTH. Results In CRF patients, the glomerular filtration rate (GFR) correlated positively with serum Ca and 1,25-dihydroxyvitamin D (1,25(OH)₂D), and inversely with serum Pi, log intact PTH, and log whole PTH. In multiple regression analysis, including age, gender, body mass index, GFR, Ca, and Pi and 1,25(OH)₂D as independent variables, serum Ca and GFR associated significantly with serum log whole PTH and intact PTH. Serum log whole PTH/intact PTH ratio, which increased as serum Ca and GFR decreased, retained a negative correlation in those with serum 25-hydroxyvitamin D levels below 20 ng/ml, but not in those above 20 ng/ml. The ratio also correlated positively with serum log tartrate-resistant acid-phosphatase-5b, log cross-linked N-telopeptide of type-I collagen, and log bone alkaline-phosphatase. Conclusion As GFR declined with suppression of serum Ca, the proportion of active PTH molecules increased in predialysis CRF patients, particularly those with vitamin D insufficiency.     

Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18‐month open‐labeled observational study using HR‐pQCT

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open‐label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (?2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment‐specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.     

PTH(1‐34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide (PTH_(1–34)) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH_(1–34) acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647‐labelled pamidronate (Pam) and radiolabeled ¹⁴C‐ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 μg/kg/d PTH_(1–34), and the effects on BP liberation and bone healing were examined by X‐ray, micro‐CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH_(1–34), there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for ¹⁴C‐ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus‐bound BP with PTH_(1–34), these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH_(1–34) increases bone turnover as well as BP turnover. © 2015 American Society for Bone and Mineral Research.     

PTH(1‐84) replacement therapy in hypoparathyroidism: A randomized controlled trial on pharmacokinetic and dynamic effects after 6 months of treatment

Untreated, hypoparathyroidism (hypoPT) is a state of hypocalcemia with inappropriately low plasma parathyroid hormone (PTH) levels and hyperphosphatemia. PTH administration normalizes plasma calcium and phosphate levels and reduces the doses of calcium and active vitamin D analogues needed. To develop an evidence‐based clinical algorithm to monitor hypoPT patients treated with recombinant human PTH (rhPTH[1‐84]) injected subcutaneously in the thigh, we performed a 24‐hour monitoring study of pharmacokinetic and pharmacodynamic effects in a group of 38 patients who had completed a 6‐month randomized study on effects of treatment with a fixed rhPTH(1‐84) dose of 100 µg/d or similar placebo as an add‐on to conventional treatment. PTH levels rose immediately, reaching a median peak level of 26.5 (interquartile range [IQR], 20.1–42.5) pmol/L 15 minutes following injection. Thereafter, levels gradually decreased until reaching predosing levels after 16 hours, with a plasma half‐life of 2.2 (1.7–2.5) hours. rhPTH(1‐84) changed the diurnal rhythms of ionized calcium levels and 1,25‐dihydroxyvitamin D (1,25[OH]₂D) levels, with rising levels following injection. Ionized calcium peaked after 7.0 (5.0–10.0) hours. Asymptomatic hypercalcemia was present in 71% of the rhPTH(1‐84)‐treated patients. Compared with placebo, 24‐hour urinary calcium, phosphate, and magnesium did not change, although the diurnal variation in renal excretion rates changed significantly in response to treatment. In conclusion, as a safety precaution, we recommend occasionally measuring calcium levels at approximately 7 hours after administration in order to reveal episodes of hypercalcemia. A 100‐µg daily dose of rhPTH(1‐84) appears to be too high in some patients, suggesting a need for a device allowing for individual dose adjustments. © 2013 American Society for Bone and Mineral Research.     

Delayed short‐course treatment with teriparatide (PTH1–34) improves femoral allograft healing by enhancing intramembranous bone formation at the graft–host junction

Clinical management of critical bone defects remains a major challenge. Despite preclinical work demonstrating teriparatide (PTH_1–34) effectiveness in small animals, inconclusive data from clinical trials have raised questions of dose and regimen. To address this, we completed a comprehensive study in the murine femoral allograft model, to assess the effects of dose (0.4, 4, and 40 µg/kg/day) and various treatment regimens on radiographic, histologic, and biomechanical healing at 2, 4, and 9 weeks. Only the high dose (40 µg/kg) of PTH_1–34 demonstrated significant effects when given daily over 9 weeks. Remarkably, equivalent biomechanical results were obtained with delayed, short treatment from 2 to 6 weeks that did not induce a significant increase in endochondral bone formation and callus volume. In contrast, PTH_1–34 treatment from 1 to 5 weeks postop demonstrated similar osteogenic effects as immediate daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. MicroCT and histologic analyses demonstrated that the 2‐week delay in treatment allowed for timely completion of the endochondral phase, such that the prominent effects of PTH_1–34 were enhanced intramembranous bone formation and remodeling at the graft–host junction. These findings support the potential use of PTH_1–34 as an adjuvant therapy for massive allograft healing, and suggest that there may be an ideal treatment window in which a short course is administered after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation. © 2012 American Society for Bone and Mineral Research     

Calcineurin/nuclear factor of activated T cells (NFAT) signaling in cobalt–chromium–molybdenum (CoCrMo) particles‐induced tumor necrosis factor‐α (TNFα) secretion in MLO‐Y4 osteocytes

Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor‐α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt–chromium–molybdenum (CoCrMo) particles upregulate TNFα production by MLO‐Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin‐nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle‐induced TNFα production in MLO‐Y4 osteocytes. MLO‐Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle‐induced upregulation of TNFα is reduced to control levels with calcineurin‐NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO‐Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin‐NFAT signaling is involved in TNFα production by MLO‐Y4 osteocytes after CoCrMo particle treatment. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1867–1873, 2011     

A G‐protein Subunit‐α11 Loss‐of‐Function Mutation,Thr54Met,Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα₁₁) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα₁₁, encoded by GNA11, and to date only two FHH2‐associated Gα₁₁ missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα₁₁ variant was assessed by homology modeling of the related Gα_q protein and by measuring the CaSR‐mediated intracellular calcium (Ca²⁺_i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca²⁺_o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα₁₁ helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα₁₁ in HEK293 cells stably expressing CaSR demonstrate that the Ca²⁺_i responses after stimulation with Ca²⁺_o of the mutant Met54 Gα₁₁ led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC₅₀) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC₅₀ of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα₁₁ mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα₁₁ interdomain interface in CaSR signaling and Ca²⁺_o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Mass mortality in Korean bay scallop (Argopecten irradians) associated with Ostreid Herpesvirus‐1 μVar

Since November 2017, mass mortalities of larvae of bay scallop (Argopecten irradians) were reported in hatcheries located at the southern area of Republic of Korea. Over 90% of larvae aged 5–10 days sank to the bottom of the tank and died. The hatcheries could not produce spat, and thus artificial seed production industry incurred huge losses. We identified Ostreid Herpesvirus‐1 μVar (OsHV‐1 μVar) associated with mass mortality by PCR, sequencing and transmission electron microscopy (TEM). All the samples were positive for OsHV‐1 μVar with 99% sequence identity to previously reported OsHV‐1 μVar sequences. Partial sequence of ORF‐4 of OsHV‐1 detected in this study was more closely related to sequences isolated from Europe. This is the first report to confirm the mortality caused by an OsHV‐1 infection in the bay scallop.     

Sequestosome 1 Mutations in Paget's Disease of Bone in Australia: Prevalence,Genotype/Phenotype Correlation,and a Novel Non‐UBA Domain Mutation (P364S) Associated With Increased NF‐κB Signaling Without Loss of Ubiquitin Binding

Previously reported Sequestosome 1(SQSTM1)/p62 gene mutations associated with Paget's disease of bone (PDB) cluster in, or cause deletion of, the ubiquitin‐associated (UBA) domain. The aims of this study were to examine the prevalence of SQSTM1 mutations in Australian patients, genotype/phenotype correlations and the functional consequences of a novel point mutation (P364S) located upstream of the UBA. Mutation screening of the SQSTM1 gene was conducted on 49 kindreds with PDB. In addition, 194 subjects with apparently sporadic PDB were screened for the common P392L mutation by restriction enzyme digestion. HEK293 cells stably expressing RANK were co‐transfected with expression plasmids for SQSTM1 (wildtype or mutant) or empty vector and a NF‐κB luciferase reporter gene. GST‐SQSTM1 (wildtype and mutant) proteins were used in pull‐down assays to compare monoubiquitin‐binding ability. We identified SQSTM1 mutations in 12 of 49 families screened (24.5%), comprising 9 families with the P392L mutation and 1 family each with the following mutations: K378X, 390X, and a novel P364S mutation in exon 7, upstream of the UBA. The P392L mutation was found in 9 of 194 (4.6%) patients with sporadic disease. Subjects with SQSTM1 mutations had more extensive disease, but not earlier onset, compared with subjects without mutations. In functional studies, the P364S mutation increased NF‐κB activation compared with wildtype SQSTM1 but did not reduce ubiquitin binding. This suggests that increased NF‐κB signaling, but not the impairment of ubiquitin binding, may be essential in the pathogenesis of PDB associated with SQSTM1 mutations.     

Association of tumour necrosis factor‐α gene (T‐1031C,C‐863A,and C‐857T) polymorphisms with bladder cancer susceptibility and outcome after bacille Calmette‐Guérin immunotherapy

OBJECTIVE

To investigate the association of tumour necrosis factor‐α gene (TNF‐α) polymorphisms T‐1031C, C‐863A, and C‐857T with bladder cancer risk and recurrence after bacille Calmette‐Guérin (BCG) immunotherapy, as TNF‐α regulates inflammatory process influencing bladder cancer susceptibility and outcome of BCG immunotherapy.

PATIENTS AND METHODS

In all, 220 patients with bladder cancer and 206 controls were recruited. Genotyping was done using allele specific‐polymerase chain reaction.

RESULTS

A T‐1031C, CC genotype and haplotype ?1031C/?863C/?857T showed enhanced susceptibility to bladder cancer, with an odds ratio (OR) of 2.23 and 95% confidence interval (CI) of 1.17–4.26; and an OR of 6.05 and 95%CI of 2.46–14.90, respectively. A T‐1031C, CC genotype had a reduced risk of recurrence after BCG treatment (hazard ratio 0.38, 95%CI 0.14–0.98).

CONCLUSION

The present data suggests that T‐1031C (CC) genotype and C/C/T haplotype may confer risk for bladder cancer, moreover T‐1031C (CC) decreased the risk of recurrence after BCG immunotherapy.