HLA-A, -B, -C, and -DRB1 genotyping and haplotype frequencies for a Hong Kong Chinese population of 7595 individuals

Human Immunology xxx (2016) xxx–xxx

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HLA-A, -B, -C, and -DRB1 genotyping and haplotype frequencies for a Hong Kong Chinese population of 7595 individuals Janette Kwok a,⇑, Mengbiao Guo b, Wanling Yang b, C.K. Lee c, Jenny Ho a, W.H. Tang a, Y.S. Chan a, Derek Middleton d, L.W. Lu e, Godfrey C.F. Chan b a

Division of Transplantation and Immunogenetics, Queen Mary Hospital, Hong Kong Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong Hong Kong Red Cross Blood Transfusion Services, Hong Kong d Transplant Immunology, Royal Liverpool Hospital, Liverpool, UK e Department of Pathology, The University of Hong Kong, Hong Kong b c

a r t i c l e

i n f o

Article history: Received 25 August 2016 Revised 12 October 2016 Accepted 17 October 2016 Available online xxxx Keywords: HLA gene frequency HLA haplotype frequency Hong Kong Chinese Registry

a b s t r a c t HLA-A, -B, -C and -DRB1 gene and haplotype frequencies have been calculated from 7595 southern Chinese unrelated donors in a Hong Kong Bone Marrow Donor Registry. This is the first large-scale paper to report the distribution of A-C-B-DRB1 alleles in Hong Kong Chinese. This information is important for phylogenetic, comparative studies and estimating the optimal and cost-effective donor size and likelihood of obtaining appropriately matched donors for Chinese patients awaiting haematopoietic stem cell transplantation. The allele and haplotype data are available in the Allele Frequencies Net Database under the population name ‘‘Hong Kong Chinese BMDR’’ and the identifier (AFND003357). Ó 2016 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.

This paper reports the HLA-A, -B, -C and -DRB1 gene and haplotype frequencies of a predominantly southern Chinese registry in Hong Kong operated by the Hong Kong Bone Marrow Donor Registry (HKBMDR) under the Hospital Authority in Hong Kong. Informed consent was obtained for the donation and use of genotype data for these anonymised individuals for research. Hong Kong has a predominantly Chinese population and a recent history as a British colony. Prior to the arrival of the British, Hong Kong was a small fishing community and a haven for travelers and pirates in the South China Sea. Hong Kong served as a refuge for exiles from China following the establishment of the Chinese Republic in 1912. Hong Kong’s population increased dramatically after the war, as a wave of skilled migrants from the Republic of China moved into seek refuge from the Chinese Civil War. When the Communist Party eventually took full control of mainland China in 1949, hundreds of thousands of people again fled to Hong Kong [1]. Since the 1997 Handover, an increase in immigrants from mainland China has brought a growing number of mainlanders to Hong Kong [2]. ⇑ Corresponding author at: Division of Transplantation and Immunogenetics, Department of Pathology and Clinical Biochemistry, Queen Mary Hospital, Pokfulam Road, Hong Kong. E-mail address: [email protected] (J. Kwok).

Hong Kong is located to the south of mainland China and had a population of around 7.3 million at the end of 2015 [3]. The current population of Hong Kong comprises 92% ethnic Chinese [4,5]. A major part of Hong Kong’s residents originated from the neighbouring Guangdong province in Southern China [6]. About 92% of the people of Hong Kong are of Chinese descent [7–8], the majority of whom are Taishanese, Chiu Chow, other Cantonese people, and Hakka. Hong Kong’s Han majority originate mainly from the Guangzhou and Taishan regions in Guangdong province [6]. The remaining 8% of the population is composed of non-ethnic Chinese [7]. Chinese and English are the official languages of Hong Kong. Cantonese speakers account for 89.5% of population [8–10]. English being an official language accounts 3.1% of the population as an everyday language and by 34.9% as a second language [11]. The HKBMDR consists predominantly of Chinese donors living in Hong Kong. HLA-A, -B, -C and -DRB1 genotypes were obtained using polymerase chain-reaction sequence-specific oligonucleotide probe methods using LifeCodes HLA-SSO Typing Kit (Gen-Probe, Stamford, CT) when analysed by Luminex 200TM system (Luminex Corp., Austin, TX). Typing ambiguity was resolved using sequence specific primer or sequence based typing methods utilising the

http://dx.doi.org/10.1016/j.humimm.2016.10.005 0198-8859/Ó 2016 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.

Please cite this article in press as: J. Kwok et al., HLA-A, -B, -C, and -DRB1 genotyping and haplotype frequencies for a Hong Kong Chinese population of 7595 individuals, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.10.005

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J. Kwok et al. / Human Immunology xxx (2016) xxx–xxx

Table 1 List of the deviations from HWEP at HLA-A, -B, -C and -DRB1 loci. Genotype

Observed

Expected

P value

HLA-A 02:01 + 02:03 02:06 + 02:03 30:01 + 02:01 31:01 + 02:06 34:01 + 24:02 74:01 + 33:03

247 16 69 19 9 11

218.45 48.21 49.55 9.52 3.23 3.66

0.0007 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

HLA-C 03:43 + 01:17 07:01 + 07:01 07:02 + 07:01

1 4 1

0.0001 0.548 23.86

<0.0001 <0.0001 <0.0001

HLA-B 40:01 + 15:12 48:03 + 27:06

29 2

18.94 0.12

<0.0001 <0.0001

HLA-DRB1 08:03 + 04:03 09:01 + 03:01 13:12 + 08:03

62 189 19

29.27 169.60 11.41

<0.0001 <0.0001 <0.0001

specific primers of SBTexcelleratorÒ HLA typing Kit (Genome Diagnostics, Utrecht, the Netherlands). All typing were performed at the Division of Transplantation and Immunogenetics, Queen Mary Hospital in Hong Kong. Alleles were determined according to IMGT/HLA Database release 3.18.0. HLA haplotype frequencies were calculated using the Markov Chain Monte Carlo algorithm PHASE [12]. The distribution of haplotypes in the Hong Kong Chinese is found to be more heterogeneous than that of Western countries [13]. Over two thousand five hundred A-C-B-DRB1 haplotypes were estimated from these donors (n = 7595). HLA-A, -B, -C and -DRB1 genotypes deviated from the expected Hardy-Weinberg equilibrium proportions (HWEP) (p < 0.001). Allele frequencies for each locus were determined via direct counting. Four-locus haplotype frequencies were estimated using the Markov Chain Monte Carlo algorithm PHASE [12]; adherence to HWEP was also assessed using PyPop 0.7.0 [14]. A few but significant deviations from HWEP were detected for all the four loci, HLAA, -B, -C and -DRB1. Deviation from HWEP detected at the HLA-A locus is derived primary from an excess of A * 02:01 + A * 02:03 genotypes (247 observed, 218.5 expected; p = 0.0007) and an undercount of A * 02:06 + A * 02:03 genotypes (16 observed, 48.2 expected; p = <0.0001). List of the deviations from HWEP at HLA-A, -B, -C and -DRB1 are in Table 1. The allele and haplotype frequencies data are available in the Allele Frequencies Net Database under the population name ‘‘Hong Kong Chinese BMDR’’ and the identifier (AFND003357) [15]. 34 HLA-A, 91 HLA-B, 37 HLA-C and 54 HLA-DRB1 alleles were found. The most common HLA-A, -B, -C and -DRB1 alleles were A * 11:01 (29.7%), B * 40:01 (15.2%), C * 01:02 (19.0%) and DRB1⁄09:01 (15.9%) respectively. A total of 2553 haplotypes were detected. Nine HLA-A-B-C-DRB1 haplotypes had frequencies of greater than 1%. The top three most common haplotypes were A * 33:03-B * 58:01-C * 03:02-DRB1 * 03:01 (4.7%); A * 02:01a-

B * 46:01-C * 01:02-DRB1 * 09:01 (4.1%) and A * 11:01-B * 15:02C * 08:01-DRB1 * 12:02 (3.1%). Our findings on HLA alleles and haplotypes frequencies were found to be very similar to those of Asian/Pacific Islander (A/PI) Race/Ethnicity of the NMDP Registry and other studies on Han Chinese population [13]. The most common haplotype A * 33:03-B * 58:01-C * 03:02-DRB1 * 03:01 ranked second in the A/PI of NMDP registry (2.3%) and top in Singapore Chinese (5.1%) [16]. The second most common haplotype A * 02:01-B * 46:01-C * 01:02-DRB1 * 09:01 was one of most frequent haplotypes among Chinese populations, especially the southern area of China and Guangdong [17,18]. The fifth common haplotype A * 02:03-B * 38:02-C * 07:02-DRB1 * 16:02, however, was less common in the A/PI of NMDP Registry (0.4%) and mainland China (0.3%) [13,18]. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.humimm.2016. 10.005. References [1] Trea Wiltshire, Old Hong Kong. Volume II: 1901-1945, 5th ed., FormAsia Books, 1997, p. 148. ISBN 962-7283-13-4. [2] Cherry Yum, Which Chinese? Dialect Choice in Philadelphia’s Chinatown (PDF), Haverford College, 2007, Retrieved 19 September 2016. [3] http://www.censtatd.gov.hk/hkstat/sub/so20.jsp. [4] http://www.gov.hk/en/about/abouthk/facts.htm. [5] http://www.indexmundi.com/hong_kong/demographics_profile.html. [6] Fan Shuh Ching, The Population of Hong Kong‘‘ (PDF). World Population Year (Committee for International Coordination of National Research in Demography), 1974, pp. 18–20 (Retrieved 1 August 2016). [7] Population Census – Summary Results (PDF) (Report), Census and Statistics Department, February 2012 (Retrieved 1 August 2016). [8] GovHK: Hong Kong – the Facts, (Retrieved 19 September 2016). [9] Hong Kong Demographics Profile 2014, (Retrieved 19 September 2016). [10] GovHK: Hong Kong – the Facts, (Retrieved 19 September 2016). [11] ICE Hong Kong. University College London (Retrieved 19 September 2016). [12] M. Stephens, N.J. Smith, P. Donnelly, A new statistical method for haplotype reconstruction from population data, Am. J. Hum. Genet. 68 (2001) 978–989. [13] Loren Gragert, Abeer Madbouly, John Freeman, Martin Maiers, Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry, Hum. Immunol. 74 (2013) 1313–1320. [14] A.K. Lancaster et al., PyPop update – a software pipeline for large-scale multilocus population genomics, Tissue Antigens 69 (2007) 192–197. [15] F.F. Gonzalez-Galarza, L.Y.C. Takeshita, E.J.M. Santos, F. Kempson, M.H.T. Maia, A.L.S. da Silva, et al., Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations, Nucleic Acids Res. 43 (2015) D784–D788, http://dx.doi.org/10.1093/nar/gku1166. [16] Ting F. Tang et al., HLA haplotypes in Singapore: a study of mothers and their cord blood units, Hum. Immunol. 68 (2007) 430–438. [17] Ke-Ming Dua, Yun Jia, Jun-Hua Xiea, et al., HLA-A, -B, -DR haplotype frequencies from DNA typing data of 26,266 Chinese bone marrow donors, Hum. Immunol. 68 (2007) 854–866. [18] X.-Y. Zhou, F.-M. Zhu, J.-P. Li, et al., High-resolution analyses of human leukocyte antigens allele and haplotype frequencies based on 169,995 volunteers from the china bone marrow donor registry program, PLoS One 10 (9) (2015) e0139485, http://dx.doi.org/10.1371/journal. pone.0139485.

Please cite this article in press as: J. Kwok et al., HLA-A, -B, -C, and -DRB1 genotyping and haplotype frequencies for a Hong Kong Chinese population of 7595 individuals, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.10.005