Type 1 diabetes (T1D) is a multifactorial disease in which the insulin producing β-cells of the pancreas are destroyed by the immune system, a process determined by the activity of major histocompatibility complex (MHC)-restricted T lymphocytes. This disease is regulated by the interaction among a number of alleles scattered throughout the genome. For Chinese population, the results of a number of case-control studies were not totally consistent. In this paper, we studied 23 case-control reports about the relavance of HLA-DQ, DR allele polymorphism and T1D in the Chinese Han population using meta-analysis and we provide evidence-based medical evidence to analyze HLA genetic susceptibility of T1D in this population.
Information retrieval and collection
Access to relative literatures about the HLA-DQ, DR allele polymorphism in the Chinese Han population was obstained through CNKI Chinese Journal Full Text Special Database and PUBMED. Key words for retrieval were: "HLA-DQ, HLA-DR, type 1 diabetes and allele polymorphism" and the period searched was from January 1980 to December 2007.
General description of the quality of the literature
The following criteria were used to select studies for inclusion in this meta-analysis: published literature which can be accessed with the full text; Research focused on the relationship between HLA-DQ, DR alleles and T1D; Case-control studies; Study subjects within the Chinese population of mainly Han nationality; Case studies including the case group and the normal control group; Diagnosis of T1D is in line with WHO standards; Cases in the control group are healthy adults from the same area which are matched for gender and nationality in order to exclude the children who may develop T1D in the future. The content of the samples were clearly defined; Containing enough case volume information to compare HLA-DQ, DR genetic distribution differences between case and control groups. HLA involves multiple alleles and the selected literature provided the ratio of cases carrying the susceptible (or protective) alleles and the total number of cases. Hard-Weinberg test was used only for the literatures including the proportion of the alleles. Literature was excluded in which the implementation and published time of the study was unclear or those contained repeated reports. We checked the PCR primer sequence in GeneBank (http://www.ncbi.nlm.nih.Gov/genebank/index.html) to confirm that the selected genes were the target genes.
Homogeneity was tested by Q test (α=0.05). If the results of the Q test had no significant heterogeneity, the Mantel-Haenszel fixed effect model (Peto method) was used for the combination of data and the combined value of the odds ratios (OR) and 95% confidence interval (CI) were calculated; If the results of the Q test had significant heterogeneity, the Dersimonian-Laird random effects model (DL method) were used for the combination of data and the total value of the OR and 95% CI were calculated. Revman 4.2 provided by the Cochrane Collaboration Internet was used to analyze the above results. We calculated effective values, variance and weight with Log (OR). We used OR and 95% CI as the effect of the combined results.
Allele frequency was compared between the control groups with software SPSS 13.0, with P <0.05 selected to indicate a significant difference.
With the OR value of the HLA-DQ, DR alleles as the horizontal axis and SE (log OR) as the vertical axis to draw a funnel map, we evaluated the publication bias through observation of symmetry of funnel and application of the Egger's test with STATA software.
Study selection and subject characteristics
The primary search generated 102 potentially relevant articles, of which 23 met the selection criteria. The flowchart of literature screening is presented in Figure. Key information on the 23 publications included in this meta-analysis is provided in Table 1. The Hard-Weinberg balance was used to test representation of allelic frequency, and the results suggested that the tested allele distribution was representative.
Meta-analysis of the relationship between HLA-DQ allele polymorphism and T1D in the Chinese population and Egger's test
DQA1*0301, DQA1*0501, DQB1*0201, DQB1*0302 were susceptible alleles for T1D (P <0.05); DQA1*0103, DQA1*0201, DQA1*0401, DQB1*0301, DQB1*0402, DQB1*0501, DQB1*0503, DQB1*0601 and DQB1*0602 were protective alleles for T1D (P <0.05). Their combined OR value, 95% CI and Egger's test are listed in Table 2.
Meta-analysis of the relationship between HLA-DR allele polymorphism and T1D in the Chinese population in serological level and Egger's test
DR3, DR4, DR9 alleles were the susceptible alleles (P <0.05). HLA-DR2, DR5, DR7 were protective alleles (P <0.05). Their combined OR value, 95% CI and Egger's test are listed in Table 3.
Meta-analysis of the relationship between HLA-DR allele polymorphism and T1D at the genetic level and Egger's test
DRB1*04, DRB1*0301, DRB1*0404, DRB1*0405 were susceptible alleles (P <0.05). DRB1*0406, DRB1*07, DRB1*08, DRB1*12, DRB1*13, DRB1*14 and DRB1*16 were protective alleles (P <0.05). Their combined OR value, 95% CI and Egger's test are listed in Table 4.
Assessment of publication bias (Egger's test) and homogeneity of the studies
Publication bias was analyzed by meta-analysis (n ≥3) and the results are listed in Tables 2-4. For the Chinese Han population, DQA1*0101, DQA1*0102 had a publication bias of which the merger OR was less than 1 and their protective effect was overvalued, DQA1*0301 had publication bias of which the merger OR was more than 1 and their susceptible effect was overvalued. The other meta-analysis (n ≥3) had no publication bias. Through comparison of the HLA-DQ allelic frequency in the control groups in different studies we found that there was no significant difference between the control groups of the various studies for following alleles: DQA1*0101, DQA1*0102, DQA1*0103, DQA1*0401, DQA1*0601, DQB1*0301, DQB1*0402, DQB1*0502, DQB1*0503, DQB1*0603, DQB1*0604 (P >0.05). However, there was a significant difference between the different studies' control groups in the following alleles; DQA1*0201, DQA1*0301, DQA1*0501, DQB1*0201, DQB1*0302, DQB1*0303, DQB1*0401, DQB1*0501, DQB1*0601 (P <0.05). The Q test was used for homogeneity (α=0.05), and a random effect or fixed effect model was used according to the Q test results (Table 2).
Through comparison of HLA-DR alleles frequency in serum levels in control groups between different studies we found there was a significant difference between different studies (P <0.05); The results from Q tests was used for homogeneity (α=0.05). A random effect or fixed effect model was used according to the Q test results (Table 3).
Through comparison of the HLA-DR allelic frequency in control groups between different studies in the genotyping level, we found that there was no significant difference between control groups in different studies in the following alleles: DRB1*01, DRB1*07, DRB1*08, DRB1*10, DRB1*11, DRB1*12, DRB1*13, DRB1*14, DRB1*15, DRB1*16, DRB1*0401, DRB1*0402, DRB1*0403, DRB1*0404, DRB1*0406 (P >0.05), and there was a significant difference between different studies in control groups in the following alles: DRB1*04, DRB1*0301, DRB1*0405, DRB1*0901 (P <0.05). A Q test was used for homogeneity (α=0.05). A random effect or fixed effect model was used according to the Q test results (Table 4).
HLA-II type gene is located in 6q21 including DQ, DR, DP, TAP1, TAP2, LMP2 and LMP7 and other loci. A large number of studies indicate that the HLA loci related with IDDM are mainly concentrated in the HLA-II class gene area. This study systematically evaluated the relevance between HLA-DQ, DR alleles and T1D in the Chinese Han population and compared the difference of genetic susceptibility to T1D between the Chinese population and non-Chinese populations abroad.
Through the complex linkage analysis of DQ, DR done abroad researchers found that DQ sites were closely related with T1D and may be the primary susceptibility factors.23-25 DQA1*0301, DQA1*0501, DQB1*0201, DQB1*0302 were reported to be the susceptible alleles for T1D and DQA1*0201, DQB1*0301, DQB1*0402, DQB1*0501, DQB1*0601, DQB1*0602 were reported as protective alleles for T1D.26-43 DQA1*0302 was the susceptible allele of T1D in North America,37 DQB1*0303 was the susceptible allele in Japan28 but the protective allele for United Kingdom Caucasians,44 but domestic studies did not indicate this relevance. DQB1*0603 was the protective allele in the Slovak population,30 the United Kingdom Caucasian population44 and Kuwaiti Arab children;43 DQA1*0102 was a protective allele in the United Kingdom Caucasian population44 and in Zimbabwe;36 DQB1*0604 was a protective allele in the United Kingdom Caucasian population;44 DQB1*0502 was a protective allele in Kuwaiti Arab children.43 The above alleles were not associated with T1D in this study and we found DQA1*0103, DQA1*0401, and DQB1*0503 alleles were the protective alleles in the Chinese Han population but not in Caucasians. DQB1*0401 has a lower frequency in T1D patients in Caucasians, while it was reported that DQB1*0401 was the risky allele in the Chinese population.45 In this study no relevance was found for DQB1*0401 and T1D, possilby due to linkage disequilibrium between DQB1*0401 and DRB1*0405 which is a high susceptibility allele. Some domestic researchers found that DQB1*0302 had no relationship with T1D in the Chinese population,45 while this meta-analysis found that DQB1*0302 was a risk allele in the Chinese population, which is in line with overseas studies. These results indicated that susceptibility/protection of T1D was relevant with linkage disequilibrium in addition to race and geography. However, a comparison of alleles alone could not completely reflect the genetic susceptibility of T1D.
Using serological testing methods, DR2 was reported to be a protective allele in the Brazilian,27 Belgian,46 Japanese47 and Filipino populations,48 which was consistent with the Chinese Han population included within this meta-analysis. In Greece, DR2 had the same frequency in the case and the control group, not providing a protective effect.49 DR7 was a protective allele in Brazilian,27 which was consistent with this study. DR5 had protective effect in this study which was different from studies abroad. DR9 was a susceptible gene in Japanese28 and Filipino populations;48 DR4 was a susceptible allele in Western Europe, North America and South Asia, and Africa;29 DR3 was a susceptible marker in Belgian46 and in Filipino populations48 which was consistent with this study. Other studies showed that DR3 was not affiliated with T1D in the Japanese population, DR9 was expressed at the low frequency in the T1D patients and controls in the Caucasian group.
Using genotyping methods, it was confirmed that DRB1*03, DRB1*04, DRB1*0901 were susceptible alleles in the study of both black and white groups,27,30-34,36-41,46,50-53 which was consistent with this study. There was no obvious correlation between DRB1*04 and T1DM in Cameroonians.40 The results of a study in Japan showed that susceptibility of DR was DRB1*0802 >*0403 >*0406.34 DRB1*1301 was a susceptible marker in the Cameroonians40 while DRB1*0802 and DRB1*1301 were not relevant with T1DM in the present study. DRB1*07, DRB1*11,30,36,38 DRB1*0406,51 DRB1*15,38,40 DRB1*0403,50,52 DRB1*12,13,14,1532,40 were identified as protective alleles in Caucasian groups. In this study DRB1*07, DRB1*12, DRB1*13, DRB1*14, DRB1*0406 were the protective alleles for T1D in the Chinese population and DRB1*0403, DRB1*15 were not relevant with T1D. DRB1*08 and DRB1*16 were confirmed as protective alleles for T1D in Chinese in this study which were not found relevant with T1D in other races.
Good symmetry was found in most of the funnel plots of HLA-DQ, DR alleles, Egger's test for assessment of publication bias showed that publication bias had little impact on the results of the meta-analysis. Because this study developed a strict inclusion and exclusion criteria for literature and to exclude unqualified studies, the effect of selection bias was small.
This analysis showed that there was a considerable difference in control groups among studies using serological methods and less difference for those using genotyping methods. This difference for serological methods may be related not only to race and geographical location but also to immunological detection technology at the time. That means serological methods might be less robust for this type of study whereas gene-level analysis could be more specific to a particular subtypes and improve study accuracy.
This study also had its own limitations. HLA-DQ, DR were mainly tested for by PCR with probe hybridization, but targets were not always verified by sequencing. Test methods were not identical between different laboratories, which may result in within-study bias. Although people in control groups were mainly healthy adults, we could not entirely rule out the possibility of the incidence of T1D in the future. However, the incidence rate of T1D in Chinese people is very low and, therefore, the selection bias from future incidence is negligible. For the analysis of the relationship between HLA and T1D, susceptibility and protection for T1D and DR-DQ linkage disequilibrium should be taken into account23,25 at the same time. However, because so little literature including DQ, DR haplotype (genotype) was available for inclusion in our meta-analysis, we only analyzed the specific alleles listed above. In fact, the main difference between races may be due to DR-DQ linkage disequilibrium.23 The systemic evaluation on the relationship between DR-DQ linkage disequilibrium and T1D may be the effective method to confirm genetic susceptibility of T1D between different ethnic or geographical populations, requiring further study.
This study evaluated the relevance of HLA-DQ, DR allele polymorphism and T1D in the Chinese population and compared the difference of T1D genetic susceptibility of T1D between Chinese population and other races abroad. The purpose of this study is to provide some evidence and enlightenment for further research on genetic susceptibility of T1D.
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