中国青年人群的乳糜泻风险性分析

发布时间：2018-05-28 22:28

本文选题：乳糜泻 + 系统评价　；参考：《南昌大学》2014年博士论文

【摘要】：乳糜泻是一种遗传易感个体因摄入含麸质蛋白的谷物（小麦、大麦和y|麦）及其制品而诱发的慢性自身免疫性肠病，影响着世界上1%人口的健康，并呈增长趋势。乳糜泻临床症状多样，且存在无明显症状的患者，易被“误诊”和“漏诊”，存在严重的“冰山”现象。在中国，乳糜泻曾被认为极为罕见。然而近几年来，接连报道了多例乳糜泻病例，提示中国也存在乳糜泻，并且远比原先预计的更为常见。但目前我国乳糜泻流行病学的基础数据缺乏，仅有少量乳糜泻高危群体发病率的数据，而有关中国人群乳糜泻易感基因特征的研究则几近空白。因此，为分析中国普通人群患乳糜泻的风险性，本论文工作首先通过国内外相关文献资料，从已报道的乳糜泻病例、易感基因频率和小麦消费量三方面系统评价了中国乳糜泻发生的可能性及其变化趋势；然后采用基于HLA基因分型和乳糜泻血清标志物抗组织转谷氨酰胺酶抗体（tTG-IgA）检测的“乳糜泻筛查技术”，对19,788名年龄为16-25岁的青年人进行乳糜泻筛查，获取中国青年人群乳糜泻血清学流行率的数据；同时分析抗tTG-IgA抗体阳性和阴性者HLA-DQA1和HLA-DQB1等位基因多态性，探讨HLA-DQA1和DQB1等位基因与乳糜泻血清抗体阳性的关联性，初步分析中国人群的乳糜泻易感基因特征；另外，对125名转氨酶升高的患者和125名健康对照者进行了抗tTG-IgA抗体检测，探讨是否有必要对转氨酶升高的个体进行常规性的乳糜泻血清学筛查。整个研究主要结果及结论如下： 1.中国人群乳糜泻易感基因频率的Meta分析结果显示：中国人群HLA-DQ2.5单倍型和HLA-DQ8单倍型频率分别为3.4%（95%可信限：1.3-5.5%）和2.1%（0.1-4.1%）；HLA-DQ2抗原频率为18.4%(15.0-21.7%)，且北方人群DQ2抗原频率高于南方人群（24.9%vs.14.8%）；HLA-DQ8抗原频率为8.0%(4.5-11.4%)。DQB1*0201等位基因频率为10.5%(9.3%-11.6%)，且更常见于北方人群，尤其是在中国西北地区的新疆维吾尔族自治区，DQB1*0201频率为22.04%，而在南方云南省则较罕见，仅为2.89%。 2.有关小麦及麸质蛋白暴露量的系统评价结果显示：除东北三省（黑龙江、吉林、辽宁）、江苏、安徽和上海外，北方居民小麦消费量高于大米；而大米是南方居民的主食。此外，随着南北饮食习惯的融合和西方饮食文化的渗入，中国人群的麸质暴露量增加，且饮食模式的快速改变、可能导致中国乳糜泻的发生率增加。 3.从对已报道的经小肠活检确诊的22例病例、中国人群易感基因携带率和小麦消费量的系统评价，，得出中国人群患乳糜泻的风险性比先前预计的高，且在北方，特别是西北地区的中国人群患乳糜泻的风险性高于南方人，这与北方人群以小麦为主食且其乳糜泻易感HLA基因频率高于南方人有关。 4.中国青年人群(16-25岁)抗tTG-IgA抗体阳性率为0.36%（95%CI：0.28%-0.46%）；血清学阳性同时HLA-DQ2.5/DQ8基因阳性的百分率为0.20%（95%CI：0.14%-0.27%），且在内蒙古、山东、陕西和浙江等地，此百分率超过0.5%，内蒙古高达2.11%，山东仅次于内蒙古，为0.75%；此外，女性比男性，北方人群比南方人群患乳糜泻风险高，但无显著性差异。 5.与健康人群相比，乳糜泻血清学检查阳性者的HLA-DQA1*0501、DQB1*0201和DQB1*0402等位基因频率显著性增加，相对风险度分别为1.74、2.22和9.33，表明中国人群中HLA-DQ2.5(DQA1*0501:DQB1*0201)可能是主要的乳糜泻易感基因，同时在中国人群中，HLA-DQB1*0402也可能与乳糜泻易感性相关；而DQA1*0601等位基因频率则明显降低，相对风险度为0.19，有可能是保护性基因。 6乳糜泻血清学检查阳性者和健康人群中HLA-DQ2.5的携带率分别为22.86%和10.83%，组间有显著性差异，相对风险度为2.44。DQ8的携带率在两组间无显著性差异，但若携带DQ8且另一条染色体存在着DQB1*0201等位基因的个体患乳糜泻风险增高，相对风险度为3.95。 7.在抗tTG-IgA抗体阳性的人群中，携带DQB1*0201等位基因的数量与抗tTG-IgA抗体水平成正相关。携带DQB1*0201纯合子的个体的抗体滴度＞携带单拷贝DQB1*0201等位基因的个体＞未携带DQB1*0201等位基因的个体，依次为61.57U、49.64U、31.95U。 8.在丙氨酸氨基转移酶/天冬氨酸氨基转移酶升高的青年人群中没有筛查到抗tTG-IgA抗体阳性者，未能证实转氨酶升高与乳糜泻血清抗体的关联。在尚未排除其它可能导致转氨酶升高的原因之前，没有必要在转氨酶升高的患者中进行常规性的乳糜泻血清学筛查。
[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 .
【学位授予单位】：南昌大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R574

【参考文献】