發(fā)布時間：2018-05-28 22:28

  本文選題：乳糜瀉 + 系統(tǒng)評價��； 參考：《南昌大學(xué)》2014年博士論文

【摘要】：乳糜瀉是一種遺傳易感個體因攝入含麩質(zhì)蛋白的谷物（小麥、大麥和y|麥）及其制品而誘發(fā)的慢性自身免疫性腸病，影響著世界上1%人口的健康，并呈增長趨勢。乳糜瀉臨床癥狀多樣，且存在無明顯癥狀的患者，易被“誤診”和“漏診”，存在嚴(yán)重的“冰山”現(xiàn)象。在中國，乳糜瀉曾被認(rèn)為極為罕見。然而近幾年來，接連報道了多例乳糜瀉病例，提示中國也存在乳糜瀉，并且遠(yuǎn)比原先預(yù)計的更為常見。但目前我國乳糜瀉流行病學(xué)的基礎(chǔ)數(shù)據(jù)缺乏，僅有少量乳糜瀉高危群體發(fā)病率的數(shù)據(jù)，而有關(guān)中國人群乳糜瀉易感基因特征的研究則幾近空白。因此，為分析中國普通人群患乳糜瀉的風(fēng)險性，本論文工作首先通過國內(nèi)外相關(guān)文獻(xiàn)資料，從已報道的乳糜瀉病例、易感基因頻率和小麥消費量三方面系統(tǒng)評價了中國乳糜瀉發(fā)生的可能性及其變化趨勢；然后采用基于HLA基因分型和乳糜瀉血清標(biāo)志物抗組織轉(zhuǎn)谷氨酰胺酶抗體（tTG-IgA）檢測的“乳糜瀉篩查技術(shù)”，對19,788名年齡為16-25歲的青年人進(jìn)行乳糜瀉篩查，獲取中國青年人群乳糜瀉血清學(xué)流行率的數(shù)據(jù)；同時分析抗tTG-IgA抗體陽性和陰性者HLA-DQA1和HLA-DQB1等位基因多態(tài)性，探討HLA-DQA1和DQB1等位基因與乳糜瀉血清抗體陽性的關(guān)聯(lián)性，初步分析中國人群的乳糜瀉易感基因特征；另外，對125名轉(zhuǎn)氨酶升高的患者和125名健康對照者進(jìn)行了抗tTG-IgA抗體檢測，探討是否有必要對轉(zhuǎn)氨酶升高的個體進(jìn)行常規(guī)性的乳糜瀉血清學(xué)篩查。整個研究主要結(jié)果及結(jié)論如下： 1.中國人群乳糜瀉易感基因頻率的Meta分析結(jié)果顯示：中國人群HLA-DQ2.5單倍型和HLA-DQ8單倍型頻率分別為3.4%（95%可信限：1.3-5.5%）和2.1%（0.1-4.1%）；HLA-DQ2抗原頻率為18.4%(15.0-21.7%)，且北方人群DQ2抗原頻率高于南方人群（24.9%vs.14.8%）；HLA-DQ8抗原頻率為8.0%(4.5-11.4%)。DQB1*0201等位基因頻率為10.5%(9.3%-11.6%)，且更常見于北方人群，尤其是在中國西北地區(qū)的新疆維吾爾族自治區(qū)，DQB1*0201頻率為22.04%，而在南方云南省則較罕見，僅為2.89%。 2.有關(guān)小麥及麩質(zhì)蛋白暴露量的系統(tǒng)評價結(jié)果顯示：除東北三省（黑龍江、吉林、遼寧）、江蘇、安徽和上海外，北方居民小麥消費量高于大米；而大米是南方居民的主食。此外，隨著南北飲食習(xí)慣的融合和西方飲食文化的滲入，中國人群的麩質(zhì)暴露量增加，且飲食模式的快速改變、可能導(dǎo)致中國乳糜瀉的發(fā)生率增加。 3.從對已報道的經(jīng)小腸活檢確診的22例病例、中國人群易感基因攜帶率和小麥消費量的系統(tǒng)評價，，得出中國人群患乳糜瀉的風(fēng)險性比先前預(yù)計的高，且在北方，特別是西北地區(qū)的中國人群患乳糜瀉的風(fēng)險性高于南方人，這與北方人群以小麥為主食且其乳糜瀉易感HLA基因頻率高于南方人有關(guān)。 4.中國青年人群(16-25歲)抗tTG-IgA抗體陽性率為0.36%（95%CI：0.28%-0.46%）；血清學(xué)陽性同時HLA-DQ2.5/DQ8基因陽性的百分率為0.20%（95%CI：0.14%-0.27%），且在內(nèi)蒙古、山東、陜西和浙江等地，此百分率超過0.5%，內(nèi)蒙古高達(dá)2.11%，山東僅次于內(nèi)蒙古，為0.75%；此外，女性比男性，北方人群比南方人群患乳糜瀉風(fēng)險高，但無顯著性差異。 5.與健康人群相比，乳糜瀉血清學(xué)檢查陽性者的HLA-DQA1*0501、DQB1*0201和DQB1*0402等位基因頻率顯著性增加，相對風(fēng)險度分別為1.74、2.22和9.33，表明中國人群中HLA-DQ2.5(DQA1*0501:DQB1*0201)可能是主要的乳糜瀉易感基因，同時在中國人群中，HLA-DQB1*0402也可能與乳糜瀉易感性相關(guān)；而DQA1*0601等位基因頻率則明顯降低，相對風(fēng)險度為0.19，有可能是保護(hù)性基因。 6乳糜瀉血清學(xué)檢查陽性者和健康人群中HLA-DQ2.5的攜帶率分別為22.86%和10.83%，組間有顯著性差異，相對風(fēng)險度為2.44。DQ8的攜帶率在兩組間無顯著性差異，但若攜帶DQ8且另一條染色體存在著DQB1*0201等位基因的個體患乳糜瀉風(fēng)險增高，相對風(fēng)險度為3.95。 7.在抗tTG-IgA抗體陽性的人群中，攜帶DQB1*0201等位基因的數(shù)量與抗tTG-IgA抗體水平成正相關(guān)。攜帶DQB1*0201純合子的個體的抗體滴度＞攜帶單拷貝DQB1*0201等位基因的個體＞未攜帶DQB1*0201等位基因的個體，依次為61.57U、49.64U、31.95U。 8.在丙氨酸氨基轉(zhuǎn)移酶/天冬氨酸氨基轉(zhuǎn)移酶升高的青年人群中沒有篩查到抗tTG-IgA抗體陽性者，未能證實轉(zhuǎn)氨酶升高與乳糜瀉血清抗體的關(guān)聯(lián)。在尚未排除其它可能導(dǎo)致轉(zhuǎn)氨酶升高的原因之前，沒有必要在轉(zhuǎn)氨酶升高的患者中進(jìn)行常規(guī)性的乳糜瀉血清學(xué)篩查。
[Abstract]:chylous diarrhea is a kind of chronic autoimmune intestinal disease induced by the ingestion of gluten - containing grains ( wheat , barley and y wheat ) and its products , which affects the health of 1 % of the population in the world .
Then , based on the detection of serum marker anti - tissue transglutaminase antibody ( tTG - IgA ) based on HLA gene typing and chyldiarrhea serum markers , 19,788 young people aged 16 - 25 years were screened for celiac disease , and data of serologic prevalence of celiac disease in Chinese youth population was obtained .
The HLA - DQA1 and HLA - DQB1 alleles polymorphism of anti - tTG - IgA antibody positive and negative were analyzed , and the association of HLA - DQA1 and DQB1 alleles with serum antibody positive of celiac disease was investigated .
In addition , the anti - tTG - IgA antibody test was performed on 125 patients with elevated transaminase and 125 healthy controls to determine whether it was necessary to carry out routine serologic screening for individuals with elevated transaminases . The results and conclusions of the study were as follows :

1 . Meta - analysis of susceptibility gene frequencies in Chinese population showed that HLA - D2.5 haplotype and HLA - DQ8 haplotype frequencies in Chinese population were 3.4 % ( 95 % CI : 1.3 - 5.5 % ) and 2.1 % ( 0.1 - 4.1 % ) , respectively ;
The frequency of HLA - DQ2 antigen was 18.4 % ( 15.0 - 21.7 % ) , and the frequency of DQ2 antigen in the northern population was higher than that in the southern population ( 24.9 % vs . 14.8 % ) ;
The frequency of HLA - DQ8 antigen was 8.0 % ( 4.5 - 11.4 % ) . DQB1 * 201 allele frequency was 10.5 % ( 9.3 % - 11.6 % ) , and was more common in the northern population , especially in the Xinjiang Uygur Autonomous Region in the northwest of China , DQB1 * 020frequency was 22.04 % , while in the southern Yunnan Province , it was only 2.89 % .

2 . The results of systematic evaluation on the exposure of wheat and gluten protein showed that the consumption of wheat in North China was higher than that of rice in the three provinces of Northeast China ( Heilongjiang , Jilin , Liaoning ) , Jiangsu , Anhui and overseas .
In addition , with the integration of the North - South eating habits and the infiltration of Western diet culture , the level of gluten exposure in Chinese population increases , and the rapid change of dietary pattern may lead to an increase in the incidence of celiac disease in China .

3 . Based on 22 cases of confirmed diagnosis of small intestine biopsy , the systematic evaluation of susceptibility gene carrying rate and consumption of wheat in Chinese population , it was concluded that the risk of celiac disease was higher in Chinese population than in the previous prediction , and that the risk of celiac disease was higher in the north , especially in the northwest of China .

4 . The positive rate of anti - tTG - IgA antibody in Chinese youth population ( 16 - 25 years ) was 0.36 % ( 95 % CI : 0.28 % - 0.46 % ) ;
The positive rate of HLA - DQ2 . 5 / DQ8 gene was 0.20 % ( 95 % CI : 0.14 % - 0.27 % ) , and in Inner Mongolia , Shandong , Shaanxi and Zhejiang provinces , this percentage was over 0.5 % , Inner Mongolia was 2.11 % , Shandong is second only to Inner Mongolia , 0.75 % ;
In addition , there were no significant differences in the risk of celiac disease among women than men and those in the North compared to those in the South .

5 . Compared with the healthy population , the frequency of HLA - DQA1 * 0501 , DQB1 * and DQB1 * 0402 in the serologic examination of celiac disease increased significantly , and the relative risk was 1.74 , 2.22 and 9.33 respectively , indicating that HLA - D2.5 ( DQA1 * 0501 : DQB1 * ) in Chinese population could be the main susceptible gene of celiac disease , while in Chinese population , HLA - DQB1 * 0402 could also be associated with susceptibility to celiac disease ;
The frequency of DQA1 * 0601 allele was significantly lower , and the relative risk was 0.19 , which could be a protective gene .

The carrier rate of HLA - D2.5 was 22.86 % and 10.83 % in the positive and healthy subjects , and the relative risk was 2.44 . DQ8 had no significant difference between the two groups .

7 . In the anti - tTG - IgA antibody - positive population , the number of alleles carrying the DQB1 * 201 allele was positively correlated with the level of anti - tTG - IgA antibody . The number of antibody titers of individuals carrying the DQB1 * 201 homozygous individuals was > that of individuals carrying single - copy DQB1 * 201 alleles > the individuals who did not carry the DQB1 * 201 allele , in turn , 61.57U , 49.64U , 31.95U .

8 . There was no screening of anti - tTG - IgA antibody positive in young people with elevated alanine aminotransferase / aspartate aminotransferase , failing to demonstrate the association of transaminase elevation with chyldiarrhea serum antibodies . No routine serologic screening should be performed in patients with elevated transaminase before other reasons that could result in increased transaminase .
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R574

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本文編號：1948422