中国大样本成骨不全症的基因突变谱探索及成骨不全症成人患者的临床特点和双膦酸盐疗效分析
发布时间：2018-07-29 15:09
【摘要】：第一部分中国大样本成骨不全症的基因突变谱探索目的:成骨不全症(Osteogenesis Imperfecta,OI)是一组有高度遗传和表型异质性的单基因遗传性骨病,以骨量减少、骨脆性增加和反复骨折为主要特点。目前我国O1致病基因和潜在分子机制尚不清楚,相关临床表型研究也较为缺乏。本研究采用新型分子诊断平台,深入探索中国大样本OI患者的致病基因突变谱,并分析多种遗传模式O1患者的基因型与临床表型关系。方法:本研究利用自主设计、包含19种OI致病基因的二代靶向测序平台,对2013-2016年在北京协和医院就诊的152例OI患者进行致病基因突变检测,采用Sanger测序对每例患者进行家系验证。此外,纳入本课题组既往行基因检测的O1患者,在共261例OI患者中总结全面的致病基因突变谱;分析不同基因型患者,身高、骨折率、腰椎和股骨颈骨密度(bone mineral density,BMD)、骨转换生化指标血碱性磷酸酶(alkaline phosphatase,ALP)和β胶原降解产物(cross-linked C-telopeptide of type I collagen,β-CTX)、骨骼畸形、骨骼外表现等表型差异;对常见的Ⅰ型胶原基因变异患者,进行深入的基因型-表型关联分析。结果:本研究利用二代测序联合家系Sanger测序,发现了 140例OI患者的致病基因突变,并检出50种新突变位点;新型分子诊断平台对OI的检出率为92%,准确性为100%。在本课题组261例OI患者中,Ⅰ型胶原编码基因(COLlA1/COLlA2)突变最为常见(198例,76%),其次是IFITM5基因(15例,6%),SERPINF 和WNT1(12例,4.6%)是常染色体隐性遗传性OI中检出率较高的两种致病基因。然而在轻型OI中,Ⅰ型胶原基因检出率为84%;在中重型OI中,Ⅰ型胶原基因检出率仅68%,但隐性遗传基因可达21%。相比于Ⅰ型胶原结构变异,COL1A/单倍剂量不足患者身高Z值(-0.4±1.3)和BMDZ值(腰椎-1.7±1.3、股骨颈-2.7±2.2)更高,骨骼畸形更少(11%,P均0.05)。Ⅰ型胶原αl链结构变异位点与蓝巩膜、牙本质发育不全,α2链变异位点与股骨颈BMD Z值存在一定相关性;但未发现氨基酸替换种类与表型的相关性。所有常染色体隐性遗传基因突变的患者均为中重型OI,且β-CTX(1.09±0.48ng/ml)和BMD Z值(腰椎-3.5±2.4)显著高于Ⅰ型胶原基因变异的患者;80%存在严重骨骼畸形和活动受限,但蓝巩膜(40%)和牙本质发育不全(7%)少见。结论:Ⅰ型胶原编码基因COLlA1和COLlA2是中国OI主要的致病基因,其次是常染色体显性遗传IFITM5基因,以及常染色体隐性遗传SERPINF1和WNT1基因;不同临床分型的OI患者具有显著不同的基因突变谱。Ⅰ型胶原单倍剂量不足的患者临床表型轻、骨骼畸形少;罕见常染色体隐性遗传性OI患者病情严重、普遍有骨畸形和活动受限,但缺乏典型骨骼外表现。此外,新型靶向二代测序平台显著提高了 OI分子诊断水平,为未来产前诊断和分子靶向治疗奠定了初步基础。第二部分成骨不全症成人患者的临床特点和双膦酸盐疗效分析目的:成骨不全症(Osteogenesis imperfecta,OI)是以骨骼脆性增加和反复骨折为特征的单基因遗传性骨病。OI临床异质性大,可表现骨折风险轻度增加甚至围生期死亡(Ⅰ-Ⅳ型);双膦酸盐(Bisphosphonates,BPs)是目前广泛应用的OI治疗药物,以阿仑膦酸钠和唑来膦酸较为常用。然而,成人OI患者的具体临床表现、是否仍需药物干预,尚不十分清楚。本研究探讨成人OI患者的临床特点,并评估阿仑膦酸钠和唑来膦酸治疗成人OI的有效性和安全性。方法:纳入2007-2016年于北京协和医院内分泌科首诊的102例18岁以上OI患者。回顾性分析成人OI的临床特点,包括骨密度(bone mineral density,BMD)、骨转换生化指标血碱性磷酸酶(alkaline phosphatase,ALP)和β胶原降解产物(cross-linked C-telopeptide of type Ⅰ collagen,β-CTX)、25 羟维生素 D(25-hydroxyvitaminD,250HD)、甲状旁腺激素(parathyroid hormone,PTH)、骨折率、影像学和骨骼外表现,并与102例年龄、性别和体重指数匹配的健康对照者进行比较。对2011-2015年接受治疗的60例成人OI患者,按2:1分别纳入阿仑膦酸钠组(口服70mg/周)或唑来膦酸组(静脉注射5mg/年),进行为期2年的前瞻性药物疗效观察;治疗有效性指标包括腰椎和髋部BMD变化率、骨转换指标变化率和新发骨折率。结果:102例成人OI患者中,近3/4为Ⅰ-Ⅳ型OI。与健康对照组相比,轻、中、重型(Ⅰ/Ⅲ/Ⅳ)患者的血ALP水平更高,仅重型(Ⅲ)患者β-CTX高于对照组(P=0.023)。成人OI患者250HD水平为16.2 ± 8.1 ng/ml,维生素D缺乏和不足分别占73.4%、89.0%。骨骼表型方面,成人OI的腰椎和髋部BMD明显低于对照组,且Ⅰ/Ⅲ/Ⅳ型之间有统计学差异(P均0.001);此外,69.5%患者BMDZ值在-2SD以下。所有Ⅲ型患者均表现四肢长骨畸形、脊柱侧弯和压缩性骨折,64%有牙本质发育不全。成人OI的治疗方面,共52例患者完成2年BPs治疗和随访。经2年治疗,腰椎、股骨颈和全髋BMD在阿仑膦酸钠组(分别为10.5、13.2、14.7%)和唑来膦酸组(分别为11.3、13.7、11.7%)显著升高,且两组间无显著性差异(P均＞0.05);双膦酸盐均能显著降低两组骨转换指标ALP和β-CTX水平,组间无显著性差异(P=0.12、0.48);与OI患者治疗前的骨折率相比,治疗后两组的新发骨折率下降。结论:与健康人群相比,成人OI患者维生素D营养状况差、骨转换水平高、腰椎和髋部骨密度低,仍存在高骨折风险,故OI患者进入成年期仍需要积极的药物干预。口服阿仑膦酸钠和静脉唑来膦酸均能有效提高成人OI患者的骨密度、抑制骨转换,并可能降低骨折率,且两种药物的安全性较好。
[Abstract]:The first part of the gene mutation spectrum of Chinese large sample osteogenesis imperfecta: Osteogenesis Imperfecta (OI) is a group of genetic and phenotypic heterogenetic monogenic osteopathy, which is characterized by reduced bone mass, increased bone fragility and repeated fractures. Currently, the pathogenicity and potential molecular mechanisms of O1 in China are yet to be found. This study uses a new molecular diagnostic platform to explore the pathogenetic mutation spectrum of OI patients with large samples in China and to analyze the relationship between genotype and clinical phenotype in a variety of O1 patients with genetic patterns. Methods: This study uses the independent design, including the two generation of 19 OI pathogenicity genes. Sequence platform, 152 cases of OI patients who had been diagnosed in Peking Union Medical College Hospital for 2013-2016 years were tested for mutation of pathogenic gene. Sanger sequencing was used to test the families of each patient. In addition, a total of 261 cases of OI patients with previous gene detection in the group of O1 were included, and the patients with different genotypes were analyzed. Height, fracture rate, lumbar and femoral neck bone density (bone mineral density, BMD), bone conversion biochemical indicators of blood alkaline phosphatase (alkaline phosphatase, ALP) and beta collagen degradation products (cross-linked C-telopeptide of type I), bone malformation, and exoskeletal manifestations, and the common type I collagen gene variation In this study, two generation sequencing combined with family Sanger sequencing was used to detect the mutation of the pathogenic gene in 140 patients with OI, and 50 new mutation sites were detected. The detection rate of the new molecular diagnostic platform for OI was 92%, and the accuracy was 100%. in 261 cases of OI patients in this group. The gene (COLlA1/COLlA2) mutation was the most common (198 cases, 76%), followed by the IFITM5 gene (15 cases, 6%), SERPINF and WNT1 (12 cases, 4.6%) were two pathogenic genes in the autosomal recessive genetic OI. However, in the light OI, the detection rate of type I collagen gene was 84%, and in the medium heavy OI, the detection rate of type I collagen gene was only 68%, but recessive, but recessive The genetic variation of 21%. was compared with the structural variation of type I collagen. The height Z value (-0.4 + 1.3) and BMDZ value (-1.7 + 1.3, -2.7 + 2.2) of the patients with COL1A/ were higher, and the bone malformation was less (11%, P 0.05). Type I collagen alpha L chain structural variation site and blue sclera, dentin development, alpha 2 chain change point and BMD Z of femur neck There was a correlation between the values, but no correlation between the amino acid replacement type and the phenotype. All the patients with autosomal recessive gene mutations were medium heavy OI, and the values of beta -CTX (1.09 + 0.48ng/ml) and BMD Z (-3.5 + 2.4) were significantly higher than those of type I collagen gene mutation; 80% had severe skeletal deformity and limited activity, but blue was blue. Sclera (40%) and dentin dysplasia (7%) are rare. Conclusion: type I collagen encoding gene COLlA1 and COLlA2 are the main pathogenic genes of Chinese OI, followed by autosomal dominant genetic IFITM5 gene, and autosomal recessive SERPINF1 and WNT1 gene, and different genotyping of OI patients with significant different gene mutation spectrum. Patients with primary undoubled doses were mild in clinical phenotypes and less skeletal deformities; rare autosomal recessive OI patients were seriously ill, with common bone malformation and limited activity, but lack of typical exoskeletal manifestations. In addition, the new target two generation sequencing platform significantly improved the level of OI diagnosis for the future prenatal diagnosis and molecular targeting therapy. The clinical characteristics of second adult patients with osteogenesis imperfecta and analysis of the efficacy of bisphosphonates: Osteogenesis imperfecta (OI) is a single gene hereditary bone disease characterized by increased bone fragility and repeated fractures, with a large clinical heterogeneity of.OI, which may show a slight increase in the risk of fracture and even perinatal period. Death (type I - IV); Bisphosphonates (BPs) is currently a widely used OI treatment, with alendronate and zoledronic acid more commonly used. However, it is not clear whether the specific clinical manifestations of adult OI patients still need drug intervention. This study explored the clinical characteristics of adult OI patients and assessed alendronate and azole. Methylene phosphonate in the treatment of adult OI in 102 patients over 18 years old in Department of Endocrinology, Peking Union Medical College Hospital, for 2007-2016 years. The clinical characteristics of adult OI were analyzed retrospectively, including bone mineral density (bone mineral density, BMD), bone conversion biochemical markers of serum alkaline phosphatase (alkaline phosphatase, ALP), and beta collagen. Degradation products (cross-linked C-telopeptide of type I collagen, beta -CTX), 25 hydroxyvitamin D (25-hydroxyvitaminD, 250HD), parathyroid hormone (parathyroid hormone, PTH), fracture rate, imaging and exoskeletal performance, and compared with 102 healthy controls matched by age, sex and body mass index. For 2011-2015 years 60 adult OI patients were treated with 2:1 in the alendronate group (orally 70mg/ weeks) or zoledronic acid group (intravenous 5mg/ years) for a 2 year prospective drug effect. The therapeutic effectiveness index included the change rate of lumbar and hip BMD, the change rate of bone conversion index and the rate of new fracture. Results: 102 cases of adult OI patients, nearly 3/4 The level of blood ALP in light, middle, and heavy (I / III / IV) patients was higher than that in the control group of type I - IV OI.. The level of beta -CTX in severe (III) patients was higher than that of the control group (P=0.023). The level of 250HD in adult OI was 16.2 + 8.1 ng/ml, vitamin D deficiency and deficiency accounted for 73.4%, and 89.0%. skeletal phenotype in adult OI was significantly lower in the lumbar and hip than in adult OI. In the control group, there was a statistical difference between type I / III / IV (P 0.001); in addition, 69.5% patients had a BMDZ value below -2SD. All type III patients showed long bone malformation, scoliosis and compression fracture, 64% with dentin dysplasia. In adult OI treatment, a total of 52 patients completed 2 years of BPs treatment and follow-up. After 2 years of treatment, lumbar, femoral, femoral The bone neck and total hip BMD were significantly higher in the alendronate group (10.5,13.2,14.7%) and zoledronic acid group (respectively 11.3,13.7,11.7%), and there was no significant difference between the two groups (P > 0.05). The bisphosphonates could significantly reduce the level of ALP and beta -CTX in two groups of bone conversion indicators, and there was no significant difference between the groups (P=0.12,0.48); before the treatment of OI patients. Compared to the two groups, the new fracture rate in the two groups decreased. Conclusion: compared with healthy people, adult OI patients have poor vitamin D nutritional status, high bone conversion level, low bone density in the lumbar and hip and high fracture risk, so OI patients still need active drug intervention to enter adulthood. Oral alendronate and zoledronic acid are both oral. It can effectively increase bone mineral density in adult OI patients, inhibit bone turnover and reduce fracture rate, and the safety of the two drugs is better.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R681.1
本文编号：2153077
[Abstract]:The first part of the gene mutation spectrum of Chinese large sample osteogenesis imperfecta: Osteogenesis Imperfecta (OI) is a group of genetic and phenotypic heterogenetic monogenic osteopathy, which is characterized by reduced bone mass, increased bone fragility and repeated fractures. Currently, the pathogenicity and potential molecular mechanisms of O1 in China are yet to be found. This study uses a new molecular diagnostic platform to explore the pathogenetic mutation spectrum of OI patients with large samples in China and to analyze the relationship between genotype and clinical phenotype in a variety of O1 patients with genetic patterns. Methods: This study uses the independent design, including the two generation of 19 OI pathogenicity genes. Sequence platform, 152 cases of OI patients who had been diagnosed in Peking Union Medical College Hospital for 2013-2016 years were tested for mutation of pathogenic gene. Sanger sequencing was used to test the families of each patient. In addition, a total of 261 cases of OI patients with previous gene detection in the group of O1 were included, and the patients with different genotypes were analyzed. Height, fracture rate, lumbar and femoral neck bone density (bone mineral density, BMD), bone conversion biochemical indicators of blood alkaline phosphatase (alkaline phosphatase, ALP) and beta collagen degradation products (cross-linked C-telopeptide of type I), bone malformation, and exoskeletal manifestations, and the common type I collagen gene variation In this study, two generation sequencing combined with family Sanger sequencing was used to detect the mutation of the pathogenic gene in 140 patients with OI, and 50 new mutation sites were detected. The detection rate of the new molecular diagnostic platform for OI was 92%, and the accuracy was 100%. in 261 cases of OI patients in this group. The gene (COLlA1/COLlA2) mutation was the most common (198 cases, 76%), followed by the IFITM5 gene (15 cases, 6%), SERPINF and WNT1 (12 cases, 4.6%) were two pathogenic genes in the autosomal recessive genetic OI. However, in the light OI, the detection rate of type I collagen gene was 84%, and in the medium heavy OI, the detection rate of type I collagen gene was only 68%, but recessive, but recessive The genetic variation of 21%. was compared with the structural variation of type I collagen. The height Z value (-0.4 + 1.3) and BMDZ value (-1.7 + 1.3, -2.7 + 2.2) of the patients with COL1A/ were higher, and the bone malformation was less (11%, P 0.05). Type I collagen alpha L chain structural variation site and blue sclera, dentin development, alpha 2 chain change point and BMD Z of femur neck There was a correlation between the values, but no correlation between the amino acid replacement type and the phenotype. All the patients with autosomal recessive gene mutations were medium heavy OI, and the values of beta -CTX (1.09 + 0.48ng/ml) and BMD Z (-3.5 + 2.4) were significantly higher than those of type I collagen gene mutation; 80% had severe skeletal deformity and limited activity, but blue was blue. Sclera (40%) and dentin dysplasia (7%) are rare. Conclusion: type I collagen encoding gene COLlA1 and COLlA2 are the main pathogenic genes of Chinese OI, followed by autosomal dominant genetic IFITM5 gene, and autosomal recessive SERPINF1 and WNT1 gene, and different genotyping of OI patients with significant different gene mutation spectrum. Patients with primary undoubled doses were mild in clinical phenotypes and less skeletal deformities; rare autosomal recessive OI patients were seriously ill, with common bone malformation and limited activity, but lack of typical exoskeletal manifestations. In addition, the new target two generation sequencing platform significantly improved the level of OI diagnosis for the future prenatal diagnosis and molecular targeting therapy. The clinical characteristics of second adult patients with osteogenesis imperfecta and analysis of the efficacy of bisphosphonates: Osteogenesis imperfecta (OI) is a single gene hereditary bone disease characterized by increased bone fragility and repeated fractures, with a large clinical heterogeneity of.OI, which may show a slight increase in the risk of fracture and even perinatal period. Death (type I - IV); Bisphosphonates (BPs) is currently a widely used OI treatment, with alendronate and zoledronic acid more commonly used. However, it is not clear whether the specific clinical manifestations of adult OI patients still need drug intervention. This study explored the clinical characteristics of adult OI patients and assessed alendronate and azole. Methylene phosphonate in the treatment of adult OI in 102 patients over 18 years old in Department of Endocrinology, Peking Union Medical College Hospital, for 2007-2016 years. The clinical characteristics of adult OI were analyzed retrospectively, including bone mineral density (bone mineral density, BMD), bone conversion biochemical markers of serum alkaline phosphatase (alkaline phosphatase, ALP), and beta collagen. Degradation products (cross-linked C-telopeptide of type I collagen, beta -CTX), 25 hydroxyvitamin D (25-hydroxyvitaminD, 250HD), parathyroid hormone (parathyroid hormone, PTH), fracture rate, imaging and exoskeletal performance, and compared with 102 healthy controls matched by age, sex and body mass index. For 2011-2015 years 60 adult OI patients were treated with 2:1 in the alendronate group (orally 70mg/ weeks) or zoledronic acid group (intravenous 5mg/ years) for a 2 year prospective drug effect. The therapeutic effectiveness index included the change rate of lumbar and hip BMD, the change rate of bone conversion index and the rate of new fracture. Results: 102 cases of adult OI patients, nearly 3/4 The level of blood ALP in light, middle, and heavy (I / III / IV) patients was higher than that in the control group of type I - IV OI.. The level of beta -CTX in severe (III) patients was higher than that of the control group (P=0.023). The level of 250HD in adult OI was 16.2 + 8.1 ng/ml, vitamin D deficiency and deficiency accounted for 73.4%, and 89.0%. skeletal phenotype in adult OI was significantly lower in the lumbar and hip than in adult OI. In the control group, there was a statistical difference between type I / III / IV (P 0.001); in addition, 69.5% patients had a BMDZ value below -2SD. All type III patients showed long bone malformation, scoliosis and compression fracture, 64% with dentin dysplasia. In adult OI treatment, a total of 52 patients completed 2 years of BPs treatment and follow-up. After 2 years of treatment, lumbar, femoral, femoral The bone neck and total hip BMD were significantly higher in the alendronate group (10.5,13.2,14.7%) and zoledronic acid group (respectively 11.3,13.7,11.7%), and there was no significant difference between the two groups (P > 0.05). The bisphosphonates could significantly reduce the level of ALP and beta -CTX in two groups of bone conversion indicators, and there was no significant difference between the groups (P=0.12,0.48); before the treatment of OI patients. Compared to the two groups, the new fracture rate in the two groups decreased. Conclusion: compared with healthy people, adult OI patients have poor vitamin D nutritional status, high bone conversion level, low bone density in the lumbar and hip and high fracture risk, so OI patients still need active drug intervention to enter adulthood. Oral alendronate and zoledronic acid are both oral. It can effectively increase bone mineral density in adult OI patients, inhibit bone turnover and reduce fracture rate, and the safety of the two drugs is better.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R681.1
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