Polymorphism of the HLA-DQA1 and -DQB1 genes of Han population in Jiangsu Province, China

The HLA genes, located on the short arm of human chromosome 6, encode peptides involved in host immune response, are important in tissue transplantation and are associated with a variety of infectious, autoimmune, and inflammatory diseases. Moreover, the HLA loci display an unprecedented degree of diversity and the distribution of HLA alleles and haplotypes among different populations is considerably variable.1 The expression of particular HLA alleles may be associated with the susceptibility or resistance to some diseases.2 In this study, the genetic polymorphism of HLA-DQA1 and -DQB1 in Jiangsu Han population was analyzed by polymerase chain reaction-sequence-based typing (PCR-SBT). METHODS Subjects One hundred and sixty unrelated healthy individuals inhabiting Jiansu Province were enrolled in the present investigation [85 men and 75 women, mean age (46.3±12.9) years, range 21—75 years]. They were all Han-ethnic, and their families have lived in Jiangsu Province for at least three generations. HLA-DQA1, -DQB1 genotyping For all subjects, genomic DNA was isolated from white cells of 5 ml peripheral blood by the phenol-chloroform method. HLA typing was performed by PCR-SBT analysis as previously described after the amplification of the second exon of DQA1 and DQB1 genes.3 The primers for amplifying and sequencing were adapted from the genomic DNA sequence of human MHC class II DQ gene from IMGT/HLA DATABASE (http://www.anthonynalan.com/HIG/data.html). Statistical analysis HLA-DQA1 and -DQB1 allele frequencies (AF) were calculated by direct counting. DQA1-DQB1 haplotype frequencies (HF), linkage disequilibrium (LD), normalized LD value (D'value) and χ2 values were analyzed by the maximum likelihood method with ARLEQUIN 2.0 software.4 A phylogenic tree was constructed by the neighbor-joining method based on AF of the DQA1 and DQB1 genes with the PHYLIP 3.6 phylogeny package.5 RESULTS Hardy-Weinberg equilibrium test For each locus, there was no significant difference between the observed heterozygosity and expected heterozygosity. The AF of HLA-DQA1, -DQB1 were in Hardy-Weinberg equilibrium. Allele distribution of the HLA-DQA1 gene Because the DQA1 alleles differ only at exons 1, 3 or 4, all the DQA1 alleles typing results can not be obtained by separate sequencing of exon 2; Thus, DQA1*0101/04/05 and DQA1*0301/02/03 were designated as the DQA1 alleles.3 Among the 8 DQA1 alleles, the most common allele was DQA1*0301/02/03 with a frequency of 28.8%, followed by DQA1*0501, DQA1*0102, and DQA1*0201 with frequencies of 16.3%, 15.3%, and 11.9%, respectively. The other DQA1 AF were higher than 5% and that of DQA1*0401 was the lowest (0.3%, Table 1).Table 1: DQA1 and DQB1 allele frequencies of Han population in Jiangsu ProvinceAllele distribution of HLA-DQB1 Only four DQB1 alleles can be defined based on the sequence information from exon 2. The four DQB1 alleles that differ only at exon 3 include DQB1*0201/02 and DQB1*0301/09.3 Among the 13 detected DQB1 alleles, DQB1*0301/09 allele (18.4%) was the most frequent allele, followed by DQB1*0201/02 (17.8%), DQB1*0303 (16.3%) and DQB1*0601 (9.7%). Alleles DQB1*0503, DQB1*0604, and DQB1*0609 were detected at low frequencies, ranging from 1.3% to 2.2% (Table 1), DQB1*0402 allele was not detected. DQA1-DQB1 haplotype frequencies and linkage disequilibrium Among the 34 HLA-DQA1-DQB1 haplotypes, the most common DQA1-DQB1 haplotype was DQA1*0301/02/03-DQB1*0303 with a frequency of 13.8%, followed by the DQA1*0201-DQB1*0201/02 (9.4%) and DQA1*0501-DQB1*0301/09 (7.8%). Strong linkage disequilibrium was detected between DQA1 and DQB1 locus. The strongest association was DQA1*0101/04/05-DQB1*0501(D'=1.0, χ2=190.45), although the HF was relatively low (Table 2).Table 2: DQA1-DQB1 haplotype frequencies of Han population in Jiangsu ProvincePhylogenetic tree Chinese populations were divided into southern and northern group. Together with northern Han, for example Shenyang Han, Shandong Han, Kazak and Uygur, Jiangsu Han population was clustered into the northern Chinese group. Based on the analysis of the allelic frequencies and the phylogenetic tree, the Jiangsu Han group belongs to the northern group of Chinese people. DISCUSSION In the present study, the distribution of HLA-DQA1, DQB1 alleles, and DQA1-DQB1 haplotypes in Jiangsu Han population was analyzed by highresolution SBT to study their genetic background. This approach shows more efficiently than traditional genetic methods, which are based on sequence-specific oligonucleotide probe (SSOP) and sequence-specific primers (SSP).3 The distribution of HLA-DQA1 and -DQB1 alleles in Jiangsu Han population was similar to that of the previous population studies. By comparing to other populations, it was found that DQA1*0301/02/03 and DQA1*0401 are the characteristic alleles among DQA1 locus in Chinese population. DQA1*0301/02/03, the most frequent allele, is very commonly observed in many Chinese ethnic groups.6–9 DQA1*0401 was the rarest or absent allele in different populations. The most common DQB1 allele is DQB1*0301/09 in Jiangsu Han population, which is also the highest allele in many other groups in the world, for example, Southern Han,8 Yi nationality,6 Naxi nationality,7 Northern Han,10 and Canadian.11 However, gene frequencies of HLA vary in different populations. For DQA1 locus, DQA1*0201 allele, with the frequency of 11.9 % in Jiangsu, is similar to Northern Chinese group and Euro-American population. However, it appears a low frequency or absent in southern Chinese group and Japanese population.12 The frequency of DQA1*0601 is 11.6% in Jiangsu, which is also commonly observed in Northern Han,10 Thai,13 but is relatively less in Uygur,14 Kazak,9 and Canadian.11 DQB1*0201/02, with a frequency of 17.8%, is the second most frequent allele. It is the most common allele in many other northern Chinese groups, such as Uygur,14 Kazak,9 and Northern Han.10 However, the allele frequency was significantly lower in southern group of China. Besides, this allele frequency is also lower in Korean15 and Japanese populations.12 In contrast, DQB1*0502 allele is commonly observed in southern group, but less in northern group. In our study, DQB1*0502 allele is also infrequent. The results show a close relationship between Jiangsu Han population and Chinese Northern group. Obviously, Jiangsu Han population has its own characteristics. The common allele of DQB1 locus in the population is DQB1*0603, and its high frequency has not been seen in any other populations. In addition, the phylogenetic tree based on the allele frequencies of DQA1 and DQB1 among 13 Chinese populations shows that Jiangsu Han population clusters into the northern group, and belongs to the northern group of China. In spite of the high polymorphism of DQA1 and DQB1 genes, the identification of 34 DQA1-DQB1 haplotypes in our study suggests a strong association between those two loci. Furthermore, the patterns of linkage disequilibrium of the HLA genes are unique in each ethnic group. Most of the DQB1 alleles are exclusively associated with a specific DQA1 allele and show the similar frequencies of the allele and its haplotype. For example, the allele frequency of DQB1*0501 and DQA1*0101/04/05-DQB1*0501 haplotype frequency are the same. The majority of common haplotypes in Jiangsu are Asian. Among the common haplotypes with HF more than 5%, DQA1*0101/04/05-DQB1*0501, DQA1* 0201-DQB1*0201/02 and DQA1*0501-DQB1*0301/09 show pan-ethnic distribution, whereas DQA1* 0103-DQB1*0601, DQA1*0301/02/03-DQB1*0303 and DQA1*0601-DQB1*0301/09 haplotypes are observed at high frequencies only in Asian ethnic groups. In conclusion, the distribution of HLA-DQ alleles and haplotypes in Jiangsu Han population shares some genetic characteristics with other population in north China, but has its own characteristics. These data provide useful information for anthropology, organ transplantation, and disease association studies.

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