發(fā)布時(shí)間：2018-02-12 14:54

  本文關(guān)鍵詞： 肝炎 乙型 慢性 阿德福韋酯 多態(tài)性 單核苷酸 磷 骨密度　出處：《河北醫(yī)科大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:抗病毒治療是治療慢性乙型病毒性肝炎的根本，阿德福韋酯是常用的口服抗病毒藥物之一。近年來相繼報(bào)道了長期服用阿德福韋酯引起的不良反應(yīng)，其長期用藥的安全性亦是一值得關(guān)注的問題。阿德福韋酯的主要不良反應(yīng)為腎毒性，通常表現(xiàn)為血清肌酐的升高或血磷濃度的降低。本研究旨在探討長期應(yīng)用阿德福韋酯患者的低磷血癥的發(fā)生率及其影響因素；分析磷酸鈉協(xié)同轉(zhuǎn)運(yùn)蛋白的基因SLC34A1（rs6420094）和G蛋白信號(hào)調(diào)節(jié)因子14的基因RGS14（rs4074995）單核苷酸多態(tài)性和血磷濃度的關(guān)系；探討低磷血癥患者的骨密度異常（包括骨量減少和骨質(zhì)疏松）的發(fā)生率及其影響因素。 方法：篩選服用阿德福韋酯（10mg/d）單藥或聯(lián)合治療2年以上的慢性乙型病毒性肝炎患者198例，收集患者臨床資料，分為低磷血癥組和血磷正常組，計(jì)算低磷血癥發(fā)生率，并對(duì)臨床資料行單因素和多因素Logistic回歸分析，篩選低磷血癥的危險(xiǎn)因素，分析的變量包括：性別、年齡、體重、用藥時(shí)間、診斷、治療。從中篩選31例低磷血癥患者和60例血磷正�；颊撸杉�3ml的外周靜脈血，應(yīng)用聚合酶鏈?zhǔn)椒磻?yīng)-限制性片段長度多態(tài)性分析法，測(cè)定rs6420094和rs4074995的基因型，分析這兩個(gè)位點(diǎn)等位基因分布頻率與血磷濃度的關(guān)系。從中進(jìn)一步篩選低磷血癥患者28例，測(cè)量骨密度，分為骨密度正常組和骨密度異常組，計(jì)算骨密度異常的發(fā)生率，應(yīng)用卡方檢驗(yàn)和多因素Logistic回歸分析篩選骨密度異常的危險(xiǎn)因素，分析的變量包括：性別、年齡、體重、用藥時(shí)間、血磷濃度、診斷、治療、基因型。 應(yīng)用SPSS17.0軟件包進(jìn)行數(shù)據(jù)分析，臨床資料行單因素和多因素非條件二元Logistic回歸分析，計(jì)算相對(duì)風(fēng)險(xiǎn)度的比值比及95%可信區(qū)間，排除標(biāo)準(zhǔn)為0.1，納入標(biāo)準(zhǔn)為0.05。率的比較采用卡方檢驗(yàn)，當(dāng)出現(xiàn)P≈a或n40時(shí)用Fisher精確概率法進(jìn)行計(jì)算，全部檢驗(yàn)均為雙側(cè)檢驗(yàn)，P0.05為差異有統(tǒng)計(jì)學(xué)意義。應(yīng)用SHEsis軟件進(jìn)行Hardy-Weinberg遺傳平衡分析和遺傳連鎖關(guān)系分析，P0.05為符合遺傳平衡定律，r20.33和D’0.7為遺傳連鎖不平衡的判斷標(biāo)準(zhǔn)。 結(jié)果： 1在198例長期服用阿德福韋酯的慢性乙型病毒性肝炎患者中，55例（27.8%）發(fā)生了低磷血癥。多因素Logistic回歸分析：用藥時(shí)間和年齡的比值比和95%可信區(qū)間分別為1.316（1.000~1.730）和1.458（1.083~1.963）。 2應(yīng)用SHEsis軟件進(jìn)行Hardy-Weinberg平衡分析：rs6420094位點(diǎn)的血磷正常組和低磷血癥組的P值分別為0.167和0.572；rs4074995位點(diǎn)的血磷正常組和低磷血癥組的P值分別為0.316和0.856，說明均符合遺傳平衡定律。兩位點(diǎn)連鎖關(guān)系分析：D=0.759，，r2=0.412。說明兩位點(diǎn)遺傳連鎖不平衡。rs4074995的基因表型：低磷血癥組：A/A型2例、A/G型11例、G/G型18例，血磷正常組：A/A型1例、A/G型21例、G/G型38例。此位點(diǎn)的等位基因分布頻率在低磷血癥組和血磷正常組之間沒有差別（P=0.429）。rs6420094的基因表型：低磷血癥組：A/A型13例、G/A型13例、G/G型5例，血磷正常組：A/A型35例、G/A型24例、G/G型1例。此位點(diǎn)的等位基因A在血磷正常組出現(xiàn)頻率（78.3%）高于低磷血癥組（62.9%），P=0.026。 328例低磷血癥患者中，骨密度正常者11例，骨密度異常者17例（60.7%），其中骨量減少者10例，骨質(zhì)疏松者7例，低磷酸血癥的分度在骨密度正常組和骨密度異常組間的差別有統(tǒng)計(jì)學(xué)意義（P=0.041），其余影響因素的差異均無統(tǒng)計(jì)學(xué)意義。 結(jié)論： 1長期服用阿德福韋酯的慢性乙型肝炎患者的低磷血癥發(fā)生率為27.8%，長時(shí)間用藥和老齡是低磷血癥有統(tǒng)計(jì)學(xué)意義的危險(xiǎn)因素。 2rs4074995的等位基因分布頻率和患者的血磷濃度無關(guān)。rs6420094的等位基因分布頻率和服用阿德福韋酯的慢性乙型病毒性肝炎患者的血磷濃度存在關(guān)聯(lián)，此位點(diǎn)等位基因A在血磷濃度正常組出現(xiàn)頻率高于低磷血癥組。 3低磷血癥患者的骨密度異常發(fā)生率為60.7%，中度低磷血癥是骨密度異常的有統(tǒng)計(jì)學(xué)意義的危險(xiǎn)因素。 4聚合酶鏈?zhǔn)椒磻?yīng)-限制性片段長度多態(tài)性分析法較經(jīng)濟(jì)、準(zhǔn)確，在不存在非特異性內(nèi)切酶或內(nèi)切酶價(jià)格較高的情況下，可應(yīng)用引物引入突變位點(diǎn)的方法創(chuàng)造酶切位點(diǎn)，在擴(kuò)增效率低或存在非特異性擴(kuò)增片段時(shí)，可應(yīng)用半巢式PCR。
[Abstract]:Objective: antiviral treatment is essential in the treatment of chronic hepatitis B, adefovir dipivoxil is one of the commonly used oral antiviral drugs. In recent years have reported adverse reactions caused by long-term use of adefovir dipivoxil, the long-term medication safety is also a concern. The main adverse reactions of adefovir dipivoxil for renal toxicity, usually in order to reduce the serum creatinine or elevated serum phosphate concentration. The incidence and influential factors of this study is to investigate the application of hypophosphatemia in patients with long-term adefovir dipivoxil; gene SLC34A1 analysis of sodium phosphate cotransporter (rs6420094) and G signal regulated protein gene RGS14 factor 14 (rs4074995) the relationship between single nucleotide polymorphism and serum phosphorus to investigate the concentration of abnormal bone density; hypophosphatemia (including patients with osteopenia and osteoporosis) the incidence and influencing factors.
Methods: screening of adefovir dipivoxil (10mg/d) monotherapy or combination therapy for more than 2 years in patients with chronic hepatitis B in 198 cases, clinical data were collected and divided into hypophosphatemia group and normal group P, calculate the incidence of hypophosphatemia, and the clinical data for univariate and multivariate Logistic regression analysis the risk factors, screening of hypophosphatemia, analysis of variables including gender, age, weight, duration, diagnosis, treatment of 31 cases of normal patients. Screening of hypophosphatemia in patients and 60 cases of blood phosphorus from peripheral venous blood collection, 3ml, restriction fragment length polymorphism analysis using polymerase chain reaction restriction -, rs6420094 and rs4074995 genotypes were determined by the analysis of the relationship between the two allele frequency distribution and serum phosphorus concentration. The further screening of 28 cases of patients with hypophosphatemia, measurement of bone density, bone density is divided into normal group and abnormal bone density In the normal group, the incidence of bone mineral density abnormality was calculated. Chi square test and multivariate Logistic regression analysis were used to screen the risk factors of bone mineral density. The variables included: sex, age, weight, medication time, blood phosphorus concentration, diagnosis, treatment and genotype.
The data were analysed by SPSS17.0 software, the clinical data for univariate and multivariate regression analysis of two yuan Logistic, calculate the odds ratio and 95% confidence interval relative risk, 0.1 exclusion criteria for inclusion criteria were compared with 0.05., the rate of chi square test, when the P is a or N40 with Fisher exact probability method all tests were two-sided test P0.05, the difference was statistically significant. SHEsis software was used for Hardy-Weinberg analysis of genetic equilibrium analysis and genetic linkage between P0.05, to comply with the law of genetic equilibrium, r20.33 and D 0.7 as the standard for judging genetic linkage disequilibrium.
Result錛

本文編號(hào)：1505892