本文選題：孕婦 + 血漿25(OH)D�。� 參考：《浙江大學(xué)》2017年碩士論文

【摘要】：研究背景及目的維生素D缺乏是一個全球性的健康問題,全世界有超過十億人維生素D缺乏或者不足。維生素D缺乏與多種骨骼肌肉相關(guān)疾病和非骨骼肌肉疾病發(fā)生相關(guān)。由于女性戶外活動較少且常懫取防曬措施,而且孕婦在孕期維生素D的需求明顯增加,所以維生素D缺乏在妊娠期孕婦中非常普遍。孕婦在妊娠期維生素D的缺乏或不足可能與先兆子癇、妊娠期糖尿病、炎癥性疾病等妊娠期并發(fā)癥和早產(chǎn)、低出生體重等不良妊娠結(jié)局相關(guān),甚至還會影響母親和子代遠期疾病的發(fā)生,包括癌癥、糖尿病、炎癥疾病、過敏性疾病、神經(jīng)退行性疾病等。血漿25(OH)D被認為是代表體內(nèi)維生素D營養(yǎng)狀況的最佳指標。環(huán)境因素包括季節(jié)、地理緯度、維生素D攝入量等,以及遺傳因素都會影響體內(nèi)的維生素D水平。家庭研究和雙生子研究發(fā)現(xiàn)血漿25(OH)D水平變異中遺傳因素估計約占23-80%。既往研究發(fā)現(xiàn)NADSYN1、DHCR7、GC、CYP2R1和VDHR等維生素D代謝通路相關(guān)基因的單核苷酸多態(tài)性與血漿25(OH)D水平存在顯著的關(guān)聯(lián)。但是研究對象主要是普通成年人,且結(jié)論不一致。目前,在孕婦人群中尚未見對維生素D代謝通路相關(guān)基因的單核苷酸多態(tài)性與孕期血漿25(OH)D水平之間的關(guān)聯(lián)進行的系統(tǒng)性的研究。因此,本研究以浙江省舟山市婦幼保健院為研究現(xiàn)場,采用橫斷面研究的設(shè)計探討孕婦維生素D代謝通路相關(guān)基因(NADSYN1、DHCR7、GC、CYP2R1、CYP3A4、CYP27A1、CYP27B1、CYP244A1、VDHR)多態(tài)性與孕早期血漿 25(OH)D 水平之間的關(guān)聯(lián);并且對可能的基因-環(huán)境及基因-基因的交互作用與血漿25(OH)D水平之間的關(guān)聯(lián)進行分析,為孕期合理補充維生素D提供更多的科學(xué)依據(jù)。材料和方法本研究以浙江省舟山市婦幼保健院為研究現(xiàn)場,在知情同意后,通過面對面訪談獲得流行病學(xué)調(diào)查問卷資料(包括研究對象的一般社會人口學(xué)特征、生活行為方式、身高體重等基本信息),并采集孕早、中、晚期空腹血樣。從2011年8月到2014年4月期間納入隊列的孕婦中,隨機選擇759例已完成分娩的孕婦,檢測其孕早期血漿25(OH)D水平,并且利用孕早期白細胞血樣檢測相關(guān)基因多態(tài)。本研究中,懫用高效液相色譜串聯(lián)質(zhì)譜分析法測定孕早期血漿25(OH)D水平。通過文獻閱讀、數(shù)據(jù)庫檢索等方法選擇基因的SNP位點并且運用基于MALDI-TOF-MS技術(shù)的美國Sequenom公司的MassARRAY系統(tǒng)完成SNP分型。采用多元線性模型分析、叉生分析、多因子降維分析等方法,對基因多態(tài)的主效應(yīng)、基因-環(huán)境、基因-基因交互作用與血漿25(OH)D水平之間的關(guān)聯(lián)進行分析。結(jié)果本研究納入的759名孕早期孕婦的平均年齡為28.30±3.06歲,平均孕周為11.51±0.63周,在春季、夏季、秋季和冬季采血人數(shù)分別為168、192、195和204人,分別占總?cè)藬?shù)的22.13%、25.30%、25.69%和26.88%。孕婦的血漿25(OH)D水平平均為 15.64 ± 6.52 ng/mL,其中 593 人維生素 D 缺乏(25(OH)D20 ng/mL),另外 166 人的血漿 25(OH)D ≥ 20 ng/mL,.分別占 78.13%和 21.87%。采用線性回歸模型分析基因多態(tài)與血漿25(OH)D水平的關(guān)聯(lián),在檢測的.49個SNPs中,其中10個SNP與血漿25(OH)D水平顯著相關(guān)。在GC基因的多態(tài)分析中,經(jīng)年齡、孕前BMI、采血季節(jié)、體育鍛煉情況調(diào)整后,與rs16846876的AA基因型相比,AT基因型和TT基因型攜帶者的血漿25(OH)D水平分別平均降低1.22 ng/mL 和 2.72ng/mL(P=0.0121;P=0.0006);與 rs17467825 的 AA 基因型攜帶者相比,GA基因型攜帶者和GG基因型攜帶者的血漿25(OH)D水平也降低(β =-1.95,P0.0001;β=-2.88,P= 0.0003)。結(jié)果還顯示,與 rs17467825 連鎖強度很強(r20.98)的 SNPs 包括 rs2282679、rs3755967、rs2298850、rs4588 的多態(tài)均與血漿25(OH)D水平相關(guān),并且其基因型與血漿25(OH)D水平的相關(guān)趨勢與rs17467825的相似。另外,與rs7041的AA基因型相比,CA基因型攜帶者和CC基因型攜帶者的血漿25(OH)D水平平均升高1.80 ng/mL和2.30 ng/mL(P =0.0002;P=0.0123);與rs1155563的TT基因型相比,CC基因型的攜帶者血漿25(OH)D水平較低(ββ=-1.80,P=0.0104);而rs2298849的GG基因型攜帶者與AA基因型攜帶者相比,血漿25(OH)D水平相對較高(β=1.44,P=0.0423)。另外在CYP3A4基因多態(tài)分析中,與rs2242480的CC基因型相比,TT基因型的攜帶者血漿25(OH)D水平較高(ββ=2.48,P=0.0081)。單體型分析結(jié)果顯示,與GC基因單體型TTGTGTCA相比,調(diào)整可能的混雜因素后,單倍型 ATAGGCTG(β=2.17,P =0.0041)、ATATGCTG(β=1.47,P =0.0110)、ACATTCTG(β=3.08,P=0.0001)、ATATTTCA(β=1.99,P=0.0092)均顯著增加血漿25(OH)D水平。LP2基因中,經(jīng)調(diào)整后,與最常見單倍型TCCCGCA相比,TCCCCTG單倍型顯著降低血漿25(OH)D水平(β=-1.55,P=0.0462)。但未發(fā)現(xiàn)其他基因單倍型分析中與血漿25(OH)D水平存在顯著關(guān)聯(lián)�；�-環(huán)境、基因-基因交互作用的叉生分析結(jié)果顯示,采血季節(jié)與rs933994-CYP27A1、rs2246709-CYP3A4多態(tài)性的交互作用1與血漿25(OH)D水平存在關(guān)聯(lián)。此外,本研究還發(fā)現(xiàn) rs7041-GC 與 rs1562902-CYP2R1、rs10766197-CYP2R1、rs2248137-CYP24A1、rs2242480-CYP34;rs2298849-GC與 rs2246709-CYP3A4;rs2209314-CYP24A1與rs1544410-VDR之間的交互作用與血漿25(OH)D水平存在顯著的關(guān)聯(lián)。GMDR分析基因多態(tài)交互效應(yīng)發(fā)現(xiàn),由rs7041-GC、rs1155563-GC,rs1562902-CYP2R1,rs2209314-CYP2441構(gòu)成的模型是預(yù)測血漿25(OH)D水平的最佳模型。結(jié)論在孕婦人群中,維生素D代謝通路基因多態(tài)性與孕早期血漿25(OH)D水平存在關(guān)聯(lián),其中GC基因變異可能是影響孕早期血漿25(OH)D水平的主要基因變異。采血季節(jié)與維生素D代謝通路基因?qū)S生素D水平存在交互作用。研究結(jié)果仍需要進一步予以驗證。
[Abstract]:Background and objective vitamin D deficiency is a global health problem, more than one billion people worldwide are deficient in or deficient in vitamin D. Vitamin D deficiency is associated with a variety of skeletal muscle related diseases and non skeletal muscle diseases. The demand for vitamin D deficiency is very common in pregnant women. The deficiency or deficiency of vitamin D during pregnancy may be associated with pregnancy complications such as preeclampsia, gestational diabetes, inflammatory disease, premature birth, low birth weight, and even the mother and progeny disease. The occurrence of cancer, diabetes, inflammation, anaphylaxis, neurodegenerative diseases, and so on. Plasma 25 (OH) D is considered to represent the best indicator of vitamin D nutrition in the body. Environmental factors including season, geographical latitude, vitamin D intake, and genetic factors affect the level of vitamin D in the body. Family studies and double The study found that genetic factors in plasma 25 (OH) D levels were estimated to account for about 23-80%. previously found in NADSYN1, DHCR7, GC, CYP2R1 and VDHR, and there was a significant correlation between the single nucleotide polymorphisms of the vitamin D metabolic pathway related genes and plasma 25 (OH) D levels. However, the research subjects were mainly common adults, and the conclusions were inconsistent. Currently, There is no systematic study of the association between single nucleotide polymorphisms of vitamin D pathway related genes and plasma 25 (OH) D levels in pregnant women. Therefore, this study took the maternal and child health care hospital in Zhoushan, Zhejiang as a study site, and used a cross-sectional study to explore the correlation of vitamin D metabolic pathways in pregnant women The association between gene polymorphism (NADSYN1, DHCR7, GC, CYP2R1, CYP3A4, CYP27A1, CYP27B1, CYP244A1, VDHR) and plasma 25 (OH) D levels in the early pregnancy; and the association between the interaction of the possible gene environment and gene gene and the level of plasma 25 (OH), providing more scientific evidence for the rational supplement of vitamin supplements during pregnancy. Materials and methods were studied on the site of maternal and child health care hospital in Zhoushan, Zhejiang. After informed consent, through face-to-face interviews, the epidemiological survey data (including the general social demography characteristics, lifestyle, height and weight and other basic information) were obtained, and the early, middle and late fasting blood samples were collected from 2011. During the period from August to April 2014, 759 pregnant women who had been given birth were randomly selected to test the level of plasma 25 (OH) D at the early stage of pregnancy and the related gene polymorphisms in the early pregnancy. In this study, the level of plasma 25 (OH) D in early pregnancy was measured by HPLC MS analysis. Reading, database retrieval and other methods selected gene SNP loci and using the MassARRAY system of American Sequenom company based on MALDI-TOF-MS technology to complete SNP typing. Multiple linear model analysis, cross analysis, multi factor reduction analysis and other methods, the main effect of gene polymorphism, gene environment, gene gene interaction and plasma 25 ( OH) the correlation between D levels was analyzed. Results the average age of 759 pregnant women in this study was 28.30 + 3.06 years old, and the average gestational weeks were 11.51 + 0.63 weeks. The number of blood samples in spring, summer, autumn and winter were 168192195 and 204, respectively, which accounted for 22.13%, 25.30%, 25.69% and 26.88%. in the total number of pregnant women, respectively, and the levels of plasma 25 (OH) D in pregnant women. The mean was 15.64 + 6.52 ng/mL, of which 593 were vitamin D deficiency (25 (OH) D20 ng/mL), and 25 (OH) D > 20 ng/mL in the other 166, respectively, and 78.13% and 21.87%., respectively, using linear regression model to analyze the association between gene polymorphism and plasma 25 (OH) D level, and 10 of them and plasma 25. In the GC gene polymorphism analysis, the plasma 25 (OH) D levels of the AT genotypes and TT genotype carriers decreased by 1.22 ng/mL and 2.72ng/mL (P=0.0121; P=0.0006), compared with the AA genotype of rs16846876, after age, pre pregnancy, blood harvest season, and physical exercise, and compared with the AA genotype of the AT genotype and TT genotype carriers. The level of plasma 25 (OH) D of the carriers of the type carrier and the GG genotype also decreased (beta =-1.95, P0.0001; beta =-2.88, P= 0.0003). The results also showed that SNPs including rs2282679, rs3755967, and P= 0.0003 was strongly associated with the level of blood plasma 25. In addition, the level of plasma 25 (OH) D in CA genotype carriers and CC genotype carriers increased by 1.80 ng/mL and 2.30 ng/mL (P =0.0002, P=0.0123), compared with the AA genotype of rs7041, and the level of plasma carriers in the carriers of the genotype was lower than that of the AA genotype (Beta beta); In rs2298849 GG genotype carriers, plasma 25 (OH) D levels were relatively higher than those of AA genotype carriers (beta =1.44, P=0.0423). In CYP3A4 gene polymorphism analysis, the level of carrier plasma 25 (OH) was higher than the CC genotype of rs2242480 (beta beta). After adjusting the possible confounding factors, the haplotype ATAGGCTG (beta =2.17, P =0.0041), ATATGCTG (beta =1.47, P =0.0110), ACATTCTG (beta =3.08, P=0.0001) all significantly increased the plasma 25 (beta =3.08, P=0.0001), and, after adjustment, compared with the most common haplotype, the haplotype significantly reduced the plasma level of 2. 5 (OH) D level (beta =-1.55, P=0.0462). But there was no significant association with plasma level 25 (OH) D in other gene haplotypes. Gene environment, gene gene interaction, cross analysis showed that the interaction between the blood harvest season and rs933994-CYP27A1, rs2246709-CYP3A4 polymorphisms was associated with plasma 25 (OH) D levels. Furthermore, This study also found that the interaction between rs7041-GC and rs1562902-CYP2R1, rs10766197-CYP2R1, rs2248137-CYP24A1, rs2242480-CYP34, rs2298849-GC and rs2246709-CYP3A4, the interaction between rs2209314-CYP24A1 and rs1544410-VDR, and plasma 25 (OH) D levels have a significant correlation with the polymorphism interaction of the.GMDR analysis gene. The model of rs1562902-CYP2R1 and rs2209314-CYP2441 is the best model for predicting the level of plasma 25 (OH) D. Conclusion in pregnant women, the polymorphism of vitamin D pathway gene is associated with the level of plasma 25 (OH) D in early pregnancy, and the variation of GC gene may be the major gene variation affecting the level of plasma 25 (OH) D in early pregnancy. There is an interaction between vitamin D metabolic pathway genes and vitamin D levels. The results still need further validation.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R714.2

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本文編號：1816811