Genes and Immunity (2003) 4, 500–505 & 2003 Nature Publishing Group All rights reserved 1466-4879/03 $25.00 www.nature.com/gene MICA, HLA-B haplotypic variation in five population groups of sub-Saharan African ancestry W Tian1, DA Boggs2, G Uko1, A Essiet3, M Inyama4, B Banjoko5, T Adewole6, W-Z Ding1, M Mohseni1, R Fritz7, D-F Chen1, LJ Palmer8 and PA Fraser1 1Center for Blood Research, Harvard Medical School, Boston, MA, USA; 2Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; 3Department of Surgery, University of Calabar Teaching Hospital, Calabar, Nigeria; 4Blue Cross Hospital, Lagos, Nigeria; 5Department of Pathology, University College Hospital, Ibadan, Nigeria; 6Nigerian Institute of Medical Research, Yaba, Nigeria; 7National Marrow Donor Program, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 8Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA The human major histocompatibility complex (MHC) class I chain-related gene A (MICA), located 46 kb centromeric to HLA-B, encodes a stress-inducible protein, which is a ligand for the NKG2D receptor. In addition to its primary role in immune surveillance, data suggest that MICA is involved in the immune response to transplants and in susceptibility to some diseases. In this study, 152 subjects from the Yoruba (n¼74), Efik (n¼32), and Igbo (n¼46) tribes of southern Nigeria, 39 nationwide African-American stem cell donors, and 60 African-American individuals residing in the metropolitan Boston area were studied for MICA, HLA-B allelic variation, haplotypic diversity, and linkage disequilibrium (LD). MICA and HLA-B exhibited a high degree of genetic diversity among the populations studied. In particular, MICA allele and HLA-B–MICA haplotype frequencies and LD in the Efik and Igbo tribes were significantly different from the other study groups. HLA-B and MICA loci demonstrated significant global LD in all five populations (P-values o0.00001). LD also varied in a haplotype-specific manner. A novel MICA allele was detected in the Boston population. These findings are important from an anthropologic perspective, and will inform future HLA-linked disease association studies in related ethnic groups of African-derived ancestry. Genes and Immunity (2003) 4, 500–505. doi:10.1038/sj.gene.6364017 Keywords: MICA; HLA; SSOP; linkage disequilibrium; sub-Saharan Africans Introduction NKG2D.10 Recent studies11,12 suggest that MICA might be an additional histocompatibility locus. The human major histocompatibility complex (MHC) Sub-Saharan African populations studied to date encompasses a 4 Mb genomic segment on chromosome exhibit a high degree of HLA gene diversity.13,14 6p21.3. From telomere to centromere, the MHC is Although several HLA gene frequency studies and two divided into class I, III, and II regions. On the 2 Mb class MICA reports include data on African-American sub- I segment, multiple MHC class I chain-related (MIC) loci jects,15–20 there is little information available regarding have been identified.1–3 The genes at these loci represent their ancestral population groups. Presently, the informa- a second lineage of mammalian MHC class I genes. tion on MICA allelic frequencies in sub-Saharan Africans MICA (MHC class I chain-related gene A; MIM 600169) is limited to a single cell line of South African origin maps about 46 kb centromeric to the HLA-B locus and (9021-RSH) in the International Histocompatibility Work- encodes a cell-surface glycoprotein that is expressed in shop collection.21 In the current study, we investigated keratinocytes and gastrointestinal epithelium,1,4 and in MICA and HLA-B allelic variation and haplotypic several other cell types.5 MICA functions as one of the diversity in three Nigerian tribal populations and two ligands for NKG2D/DAP10,6 an activating immunor- African-American populations. eceptor complex expressed on natural killer (NK) cells, gd T cells, and CD8 þ ab T cells.7 MICA triggers the cytolysis mediated by NKG2D-bearing cells7 and also costimulates CD8 þ ab T cells in pathogen-specific Results immune response.8 MICA and HLA-B allelic distributions MICA displays a high degree of allelic polymorphism In accordance with our previous report,19 MICA allele within the nonclassical HLA gene loci.9 Some of these assignment was based on the integrated information of polymorphisms modulate binding affinities with exons 2–5. A total of 9–15 MICA alleles were observed in the five study groups. MICA*00201, *004, and *00801 were commonly observed in all groups, with combined Correspondence: Dr W Tian, Center for Blood Research, Harvard Medical School, Boston, MA, USA. E-mail: [email protected] gene frequencies ranging from 71.6 to 80.4% (Table 1). Received 09 February 2003; revised 06 June 2003; accepted 09 June Pairwise comparisons of MICA allele frequencies re- 2003 vealed significant overall differences between the three MICA, HLA-B haplotypic variation W Tian et al 501 Nigerian tribes. MICA allele frequencies in the Efik and Accuracy of imputed HLA-B–MICA haplotypes Igbo tribes were also significantly different from each of To assess the reliability of the deduced HLA-B–MICA the African-American populations (data not shown). haplotypes reported here, 33 African-American families In all, 21–33 HLA-B alleles were observed in the five were typed for HLA-B, MICA at high resolution in populations, indicating a more heterogeneous allelic this study. A total of 57 parental samples were distribution at the HLA-B locus (Table 1). HLA-B*5301 determined for HLA-B–MICA haplotype by a maximum was the most common allele in all populations except the likelihood method and by family segregation. All Efik tribe, in which HLA-B*1503 predominated. Overall families were informative and produced unambiguous HLA-B allele frequencies in the Efik tribe were signifi- phase. Concordance between the haplotypes imputed cantly different from each of the other populations. In using the maximum likelihood method and by addition, HLA-B allele frequencies in the Yoruba and family segregation was found in 107/114 (93.9%) Igbo tribes were significantly different from the nation- haplotypes. Each of the remaining seven haplotypes wide African-American study population (data not involved a distinct HLA-B allele and had a frequency shown). less than 5% in the study populations (data not shown). MICA and HLA-B Hardy–Weinberg equilibrium and HLA-B–MICA haplotype frequencies and linkage Ewens–Watterson homozygosity tests disequilibrium The MICA and HLA-B allelic distributions in each study In all, 12 haplotypes had a frequency Z5% in at least one population were consistent with Hardy–Weinberg pro- population (Table 2) and were chosen for linkage portions, with the exception of HLA-B in the Igbo tribe disequilibrium (LD) analysis. HLA-B*5301–MICA*00201 (P¼0.01). Observed values of the Ewens–Watterson was the most common haplotype in the Boston African- homozygosity statistic at the MICA locus were consistent American, Yoruba, and Igbo groups. In the nationwide with neutral expectations for all populations. The African-American and Efik populations, HLA-B*4201– observed Ewens–Watterson homozygosity statistics at MICA*004 and HLA-B*1503–MICA*00801 predomi- the HLA-B locus in the Efik and Igbo tribes were nated, respectively. Pairwise comparisons revealed that significantly higher than neutrality expectations overall HLA-B–MICA haplotype frequencies in the Efik (P¼0.04 and 0.03, respectively), whereas the Yoruba tribe and Igbo tribes were significantly different from each showed a marginal value (P¼0.06). other and from both African-American groups (data not Table 1 MICA and HLA-B allele frequencies Allele frequency Nationwide African-Americans Boston African-Americans Yoruba Efik Igbo Allele a (N¼39) (N¼60) (N¼74) (N¼32) (N¼46) MICA *00201 0.256 0.300 0.331 0.172 0.424 *004 0.295 0.233 0.270 0.219 0.130 *00801 0.231 0.183 0.142 0.328 0.250 *00802 0.051 0.075 0.068 0.031 0.011 *00902 — 0.033 0.007 0.078 — *041 0.013 0.017 0.020 0.031 0.098 Otherb 0.154 0.158 0.162 0.141 0.087 HLA-B *0702 0.077 0.042 0.068 0.063 0.033 *1503 0.038 0.050 0.047 0.141 0.098 *1510 0.077 0.075 0.074 0.031 0.011 *3501 0.051 0.075 0.088 0.063 0.065 *3910 — 0.017 0.027 — 0.054 *4201 0.179 0.067 0.041 0.031 0.044 *4403 0.051 0.083 0.047 0.031 0.054 *4501 0.026 0.025 0.034 0.094 0.022 *4901 0.026 0.017 0.027 0.109 0.011 *5101 — 0.050 0.027 0.031 0.022 *5301 0.205 0.150 0.155 0.078 0.239 *5801 0.013 0.050 0.088 0.016 0.065 *5802 0.026 0.025 0.034 0.078 0.044 Otherc 0.231 0.275 0.243 0.234 0.239 aAlleles with a frequency Z5% in at least one population. bOther MICA alleles with a frequency o5% include MICA*001, *00701, *00901, *010, *011, *01201, *015, *016, *017, *018, *019, *021, *030, *045, *046, MICA*CHAH. cOther HLA-B alleles with a frequency o5% include HLA-B*0706, *0801, *1302, *1401, *1402, *1403, *1501, *1516, *1517, *1525, *1801, *1803, *2703, *2705, *3502, *3701, *3801, *3906, *4001, *4102, *4202, *4402, *4410, *5001, *5201, *5501, *5601, *5701, *5702, *5703, *5704, *7801, *8101. Genes and Immunity MICA, HLA-B haplotypic variation W Tian et al 502 Table 2 HLA-B–MICA haplotype frequencies and haplotype-specific LD estimates Nationwide African-Americans Boston African-Americans Yoruba Efik Igbo (N¼39) (N¼60) (N¼74) (N¼32) (N¼46) Haplotype (HLA-B–MICA) Frequency D (s.e.) Frequency D (s.e.) Frequency D (s.e.) Frequency D (s.e.) Frequency D (s.e.) 0702–00801 0.077 0.054 (0.020) 0.042 0.035 (0.015) 0.046 0.042 (0.017)