本文關(guān)鍵詞： 遺傳因素 肥胖 代謝異常 維生素D 脂肪因子譜 代謝正常型肥胖 兒童青少年　出處：《北京協(xié)和醫(yī)學(xué)院》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：[背景]肥胖已成為全球性危機(jī),由肥胖所誘發(fā)的代謝綜合征、2型糖尿病、心血管疾病和腫瘤等多種嚴(yán)重疾病形式嚴(yán)峻。近年來(lái),兒童和青少年的肥胖也呈現(xiàn)逐年增長(zhǎng)的趨勢(shì),由于軌跡現(xiàn)象,兒童期肥胖會(huì)延續(xù)至成人期,成為成人慢性病后備軍。肥胖由遺傳和環(huán)境因素共同導(dǎo)致。目前,通過(guò)全基因組關(guān)聯(lián)分析(Genome-wide Association Study,GWAS)等研究,已發(fā)現(xiàn)了FTO等近百個(gè)肥胖易感基因或關(guān)聯(lián)位點(diǎn),然而,大多數(shù)GWAS研究都在歐洲成人中進(jìn)行,亞洲兒童青少年的相關(guān)研究相對(duì)缺乏。近期研究發(fā)現(xiàn)并不是所有的肥胖人群都會(huì)發(fā)生代謝異常,這使得代謝正常型肥胖(Metabolically healthy obesity,MHO)這一肥胖亞型備受關(guān)注,MHO較代謝異常肥胖人群(Metabolically unhealthy obesity,MUO)具有更健康的代謝指標(biāo),但目前仍無(wú)法有效的區(qū)分這兩種肥胖亞型。在兒童青少年中找到區(qū)分代謝正常和代謝異常肥胖的生物標(biāo)志物對(duì)于早期干預(yù)代謝異常的發(fā)生具有重要作用。脂肪組織不僅是能量存儲(chǔ)器而且還是功能強(qiáng)大的內(nèi)分泌器官,通過(guò)分泌數(shù)十種脂肪因子參與糖脂代謝、能量平衡、免疫、炎癥和血管穩(wěn)態(tài)等眾多生理功能的調(diào)節(jié)。而瘦素、脂聯(lián)素、抵抗素、成纖維細(xì)胞生長(zhǎng)因子21(Fibroblast growth factor 21,FGF21)和視黃醇結(jié)合蛋白4(Retinol binding protein 4,RBP4)等通過(guò)中樞神經(jīng)系統(tǒng)調(diào)節(jié)體重的脂肪因子,在代謝中更加起到了不可忽視的作用。近年來(lái),一個(gè)新的脂肪因子betatrophin,又被稱為脂蛋白酯酶抑制因子(Lipasin),是一個(gè)在肝臟豐富表達(dá)并受到營(yíng)養(yǎng)調(diào)節(jié)的脂肪因子。近年研究發(fā)現(xiàn)肥胖人群在發(fā)生代謝異常之前通常會(huì)出現(xiàn)脂肪因子譜的紊亂,因此探究能早期預(yù)測(cè)代謝異常的脂肪因子譜對(duì)于肥胖人群的針對(duì)性干預(yù)具有重要意義。本研究在北京兒童和青少年代謝綜合征(BCAMS)研究隊(duì)列的基線人群及10年后隨訪人群的基礎(chǔ)上探索兒童肥胖相關(guān)基因、脂肪因子譜和代謝表型的關(guān)系。[目的](1)探討成人肥胖相關(guān)基因位點(diǎn)對(duì)北京地區(qū)6-18歲兒童青少年肥胖和代謝相關(guān)指標(biāo)的影響。(2)脂肪因子譜在兒童青少年兩種肥胖亞型中差異及預(yù)警作用。(3)探討betatrophin和心血管風(fēng)險(xiǎn)因子的關(guān)系。[方法]本研究納入2004年北京兒童和青少年代謝綜合征研究(Beijing children and adolescents metabolic syndrome study,BCAMS)調(diào)查總樣本中3506名6-18歲兒童青少年,和BCAMS隊(duì)列10年后隨訪人群559名。肥胖和代謝綜合征(Metabolic Syndrom,MS)的定義分別采用中國(guó)兒童青少年BMI分類標(biāo)準(zhǔn)和修正后的美國(guó)國(guó)家膽固醇教育計(jì)劃成人治療小組第3次報(bào)告標(biāo)準(zhǔn)(Adult Treatment Panel Ⅲ guidelines,ATPⅢ)。采用胰島素抵抗指數(shù)(Homeostasis model of assessment-insulin resistance,HOMA-IR)對(duì)胰島素抵抗(Insulin Resistance,IR)進(jìn)行評(píng)價(jià)。MHO采用心血管代謝危險(xiǎn)因素(Cardio-metabolic risk factors,CR)和HOMA-IR兩種定義相結(jié)合進(jìn)行評(píng)價(jià)。運(yùn)動(dòng)和飲食數(shù)據(jù)采用問(wèn)卷調(diào)查方式進(jìn)行收集。采用質(zhì)譜法對(duì)單核苷酸多態(tài)性(Single nucleotide polymorphism,SNP)位點(diǎn)進(jìn)行檢測(cè)。采用酶聯(lián)免疫分析法(Enzyme-linked immunosorbent assay,ELISA)測(cè)定血清脂肪因子和胰島素水平。采用化學(xué)發(fā)光免疫分析法檢測(cè)血清25羥基維生素D(25-hydroxy-vitamin-D,25(OH)D)。組間比較采用t-檢驗(yàn),方差分析和卡方檢驗(yàn),多因素分析采用多元Logistic回歸和多元線性逐步回歸。[結(jié)果](1)成人肥胖相關(guān)基因位點(diǎn)與兒童青少年肥胖和代謝相關(guān)指標(biāo)的關(guān)系:①成人肥胖相關(guān)基因位點(diǎn)與兒童肥胖及脂肪因子的關(guān)系:校正多因素后,在兒童中重復(fù)出6個(gè)亞洲成人肥胖相關(guān)基因位點(diǎn)與兒童肥胖顯著相關(guān),分別是:MC4R-rs2331841(P= 2.8×10-7)、FTO-rs1558902(P= 5.6×10-5)、GNPDA2-rs16858082(P= 3.4×10-1),PCSK1-rs261967(P = 0.001)、SEC16B-rs516636(P = 0.004)和MAP2K5-rs4776970(P=0.004),比值比(odds ratio,OR)范圍從 1.211 到 1.421;另有2個(gè)位點(diǎn)與兒童肥胖臨界相關(guān):ITIH4-rs2535633和BDNF-rs2030323與(F0.05)。同樣地,上述8個(gè)位點(diǎn)與其他肥胖相關(guān)指標(biāo),如體質(zhì)指數(shù)(body mass index,BMI)、腰圍、FAT%和UAC也呈現(xiàn)顯著或臨界相關(guān)關(guān)系。而且我們發(fā)現(xiàn),其中6個(gè)SNP的風(fēng)險(xiǎn)位點(diǎn) FTO-rs1558902(P= 0.002)、MC4R-rs2331841(P=0.003)、MAP2K5-rs4776970(P= 0.003)、GNPDA2-rs16858082(P= 0.007)、PCSK1-rs261967(P=0.009)和BDNF-rs2030323(P=0.027)與瘦素水平正相關(guān),而且上述6個(gè)位點(diǎn)的基因風(fēng)險(xiǎn)評(píng)分(genetic predisposition score,GPS2)與瘦素水平的關(guān)系更顯著(P=6.2 ×10-11)。同時(shí)也發(fā)現(xiàn),MC4R-rs2331841和BDNF-rs2030323與脂聯(lián)素水平臨界相關(guān)(P0.05)。②成人肥胖相關(guān)基因位點(diǎn)與兒童代謝相關(guān)指標(biāo)的關(guān)系:在兒童中驗(yàn)證的上述8個(gè)成人肥胖相關(guān)基因位點(diǎn)與兒童代謝相關(guān)指標(biāo)也存在一定的相關(guān)性。校正BMI后,多數(shù)相關(guān)性消失,但KCNQ1-rs2237892仍與HDL-C負(fù)相關(guān)(P = 3.7×10-4),MC4R-rs2331841仍與空腹血糖正相關(guān)(P = 0.012)。(2)代謝正常型肥胖及代謝異常型肥胖兒童青少年的脂肪因子譜:聯(lián)合兩種最常用MHO/MUO定義方法,定義MHO和MUO人群:MUO:存在≥1項(xiàng)MS組分或HOMA-IR≥3;MHO:肥胖但不存在MS組分且HOMA-IR3。MHO在肥胖兒童中所占的比例為20.4%。MHO較MUO兒童具有更高的脂聯(lián)素(P=0.002)水平,更低的瘦素(P0.001),RBP-4(P= 0.001)和SPARC(P=0.011)水平。肥胖人群中,低水平的SPARC(OR = 0.821 per SD,95 CI = 0.695-0.971,P=0.021),RBP-4(OR=0.772,95%CI = 0.644-0.926,P=0.005),和瘦素脂聯(lián)素比值(OR = 0.576,95%CI = 0.433-0.765,P0.001)是MHO的獨(dú)立預(yù)測(cè)因子。以上述3種脂肪因子(瘦素/脂聯(lián)素比值、RBP-4和SPARC)異常為標(biāo)準(zhǔn),存在3種脂肪因子異常較無(wú)脂肪因子異常的肥胖人群發(fā)生MHO的可能性降低80%(OR = 0.201,95%CI = 0.097-0.415),而發(fā)生MS的風(fēng)險(xiǎn)升高近3倍(OR = 2.880,95%CI = 1.584-5.237)。(3)Betatrophin和心血管風(fēng)險(xiǎn)因子的關(guān)系:Betatrophin 水平和 TC(P0.001),TG0.001)及 LDL-C(P0.001)正相關(guān),和維生素D水平負(fù)相關(guān)(P = 0.003)。按維生素D水平分組,維生素D15ng/ml人群中,betatrophin和心血管風(fēng)險(xiǎn)因子,如高血壓、高血脂和高血糖正相關(guān),而在維生素D≥15ng/ml人群中,betatrophin和空腹胰島素,2小時(shí)胰島素及HOMA-IR負(fù)相關(guān)。[結(jié)論](1)GWAS獲得的亞洲成人肥胖相關(guān)位點(diǎn)部分與中國(guó)兒童青少年肥胖及代謝指標(biāo)相關(guān),這些與兒童肥胖相關(guān)的基因主要在中樞表達(dá),并與瘦素水平增加相關(guān),提示這些基因影響兒童肥胖的機(jī)制可能和中樞的瘦素抵抗有關(guān),同時(shí)也體現(xiàn)了中樞調(diào)控對(duì)兒童肥胖的重要作用。(2)采用嚴(yán)格的CR和IR兩種方式聯(lián)合定義MHO,MHO約占肥胖兒童的1/5。以RBP-4、SPARC以及瘦素脂聯(lián)素比值為代表的脂肪因子譜可作為區(qū)分MHO和MUO兩種肥胖表型的新型生物標(biāo)志物,存在上述3種脂肪因子(瘦素/脂聯(lián)素比值、RBP-4和SPARC)異常較無(wú)脂肪因子異常的肥胖人群發(fā)生MHO的可能性降低80%,而發(fā)生MS的風(fēng)險(xiǎn)升高近3倍。(3)青年人群中高水平的betatrophin和心血管風(fēng)險(xiǎn)因素相關(guān),首次揭示這種相關(guān)性依賴于維生素D水平。
[Abstract]:[background] obesity has become a global crisis induced by obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease and cancer and other serious diseases and severe forms. In recent years, child and adolescent obesity is also increasing trend year by year, the track phenomenon, childhood obesity will continue into adulthood, become chronic adult in the reserve army. Obesity caused by genetic and environmental factors. At present, the genome-wide association analysis (Genome-wide Association, Study, GWAS) and so on, have been found FTO nearly 100 obesity susceptible genes or related sites, however, most of the GWAS studies in Europe in the adult, the relative lack of relevant research on Asian children adolescents. Recent studies found that not all obese people have metabolic abnormalities, which makes the normal metabolism of obesity (Metabolically healthy, obesity, MHO) the subtypes of obesity Of concern, MHO is the abnormal metabolism of obesity (Metabolically unhealthy obesity, MUO) with metabolic index more healthy, but still can not effectively distinguish between these two subtypes of obesity. To distinguish normal and abnormal metabolism metabolism found obesity biomarkers play an important role in the occurrence of early intervention of metabolic abnormalities in children and adolescents adipose tissue is not only the energy storage. But powerful endocrine organs, by secreting dozens of fat factor involved in lipid metabolism, energy balance, immune regulation, inflammation and vascular homeostasis and many other physiological functions. While leptin, adiponectin, resistin, fibroblast growth factor 21 (Fibroblast growth 21 factor, FGF21) and retinol binding protein 4 (Retinol binding 4 protein, RBP4) and the regulation of body weight through the central nervous system in the metabolism of fat factor, more played Can be ignored. In recent years, a new fat factor betatrophin, also known as lipoprotein lipase inhibitory factor (Lipasin), is a rich expression in liver and fat by nutritional factor regulation. Recent studies have found that obese people in the occurrence of metabolic abnormalities usually occur before adipokines spectrum disorder, so to explore early predictors of fat metabolic abnormalities spectrum is of great significance for obese people for the intervention. The syndrome of children and adolescents in Beijing (BCAMS) to explore the metabolism of childhood obesity related gene based baseline population cohort and 10 year follow-up groups, adipokines and metabolic phenotypes. The relationship between the spectrum of purpose] (1) effects of adult obesity related gene loci related indicators in Beijing area 6-18 year old children and adolescents obesity and metabolism. (2) the fat factor spectrum in children and teenagers of two kinds of fertilizer The difference and warning function fat subtypes. (3) to investigate the relationship between] betatrophin and cardiovascular risk factors. Methods this study included syndrome study of children and adolescents in Beijing in 2004 (Beijing children and adolescents metabolic metabolism of syndrome study, BCAMS) in the total sample 3506 6-18 year old children and adolescents, and after 10 years of follow-up, the BCAMS queue 559 people. Obesity and metabolic syndrome (Metabolic Syndrom, MS) were used to define Chinese children BMI classification standard and the revised National Cholesterol Education Program Adult Treatment Panel third report standards (Adult Treatment Panel guidelines ATP III, III). The insulin resistance index (Homeostasis model of assessment-insulin resistance, HOMA-IR insulin resistance (Insulin) of Resistance, IR.MHO) were evaluated by cardiometabolic risk factors (Cardio-metabolic ris K factors, CR) two definitions and HOMA-IR combination of exercise and diet were evaluated. Data were collected by questionnaire survey. The SNPs using mass spectrometry (Single nucleotide polymorphism, SNP). Sites were detected by enzyme-linked immunosorbent assay (Enzyme-linked immunosorbent, assay, ELISA) for determination of serum adipocytokines and insulin levels using chemiluminescence immunoassay of serum 25 hydroxy vitamin D (25-hydroxy-vitamin-D, 25 (OH) D). Compared between groups using t- test, variance analysis and chi square test, multivariate analysis using Logistic regression and multiple linear regression. Results (1) relationship between obesity and adult obesity related metabolism loci with children and adolescents: the relationship between adult obesity related gene in children with obesity and adipokines: multivariate correction after repeated in children 6 Asian adult obesity associated gene loci significantly associated with childhood obesity, are: MC4R-rs2331841 (2.8 x 10-7 P=), FTO-rs1558902 (5.6 P= * 10-5 GNPDA2-rs16858082 (P=), 3.4 x 10-1), PCSK1-rs261967 (P = 0.001), SEC16B-rs516636 (P = 0.004) and MAP2K5-rs4776970 (P=0.004), odds ratio (odds ratio OR), ranging from 1.211 to 1.421; another 2 loci in children with obesity related critical: ITIH4-rs2535633 and BDNF-rs2030323 and (F0.05). Similarly, the 8 loci associated with other indicators of obesity, such as body mass index (body mass, index, BMI, waist circumference, FAT% and UAC) also showed significant or critical relationship. And we found that the 6 SNP risk loci FTO-rs1558902 (P= 0.002), MC4R-rs2331841 (P=0.003), MAP2K5-rs4776970 (P= 0.003), GNPDA2-rs16858082 (P= 0.007), PCSK1-rs261967 (P=0.009) and BDNF-rs2030323 (P=0.027) and leptin levels are And the related, 6 genes of the risk score (genetic predisposition score, GPS2) and leptin levels significantly (P=6.2 * 10-11). It is also found that MC4R-rs2331841 and BDNF-rs2030323 and adiponectin (P0.05). The relationship between the critical correlation of adult obesity related gene loci related to metabolism: validation in children children in the 8 adult obesity related gene loci associated with childhood metabolic indexes have certain correlation. After adjustment for BMI, most of the correlations disappear, but KCNQ1-rs2237892 is negatively correlated with HDL-C (P = 3.7 * 10-4), MC4R-rs2331841 is positively correlated with fasting blood glucose (P = 0.012). (2) the fat factor of children the normal metabolism of obesity and metabolic abnormalities in obese adolescents: spectrum type combined with two kinds of the most commonly used MHO/MUO method to define the definition of MHO, and MUO groups: 1 MS group or HOMA-IR = 3 are more than MUO: but not MHO:; obesity The presence of MS component and HOMA-IR3.MHO accounts for the proportion of obese children have higher adiponectin 20.4%.MHO than those of the children with MUO (P=0.002) level, lower leptin (P0.001), RBP-4 (P= 0.001) and SPARC (P=0.011). The level of obesity, low levels of SPARC (OR = 0.821 per SD, 95 CI = 0.695-0.971, P=0.021), RBP-4 (OR=0.772,95%CI = 0.644-0.926, P=0.005), and leptin adiponectin ratio (OR = 0.576,95%CI = 0.433-0.765, P0.001) were independent predictors of MHO. With the above 3 kinds of adipokines (leptin / Adiponectin ratio, RBP-4 and SPARC) anomaly as the standard, there are 3 kinds of adipokines is abnormal the possibility of abnormal fat factor of obesity MHO decreased 80% (OR = 0.201,95%CI = 0.097-0.415), the risk of MS increased by nearly 3 fold (OR = 2.880,95%CI = 1.584-5.237). (3) the relationship between Betatrophin and cardiovascular risk factors: the level of Betatrophin and TC (P0.001), TG0.001) and LDL-C (P0.001) positive correlation, negative correlation and vitamin D levels (P = 0.003). Grouped according to levels of vitamin D, vitamin D15ng/ml group, betatrophin and cardiovascular risk factors, such as hypertension, hyperlipemia and hyperglycemia is related in vitamin D than 15ng/ml group in betatrophin, and 2 hours of fasting insulin, insulin and HOMA-IR negative correlation. Conclusion] (1) Asian adult obesity related loci associated with Chinese part GWAS childhood obesity and metabolic indicators, these children with obesity related gene expression mainly in central, and leptin levels increased, suggesting that these genes may influence the mechanism of childhood obesity and central leptin resistance, but also reflects the central regulation of the important role of obesity in children. (2) the strict CR and IR two ways combined with the definition of MHO, MHO accounted for about 1/5. of obese children In RBP-4, SPARC and adipokines leptin adiponectin ratio as the representative of the spectrum can be used as a novel biological distinction between MHO and MUO two kinds of obese phenotype markers, the existence of these 3 kinds of adipokines (leptin / Adiponectin ratio, RBP-4 and SPARC) than those without abnormal fat factor abnormalities in obese people group MHO decreased 80% possibility, risk while MS increased nearly 3 times. (3) in the high level of betatrophin and cardiovascular risk factors in young people, revealed for the first time this correlation depends on the level of vitamin D.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R723.14
，

本文編號(hào)：1551459