Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 150 No. 1516 (2020)

A review of HLA allele and SNP associations with highly prevalent infectious diseases in human populations

  • Alicia Sanchez-Mazas
Cite this as:
Swiss Med Wkly. 2020;150:w20214


Human leucocyte antigen (HLA) alleles and single nucleotide polymorphisms (SNPs) lying in the HLA region are known to be associated with several infectious diseases among which acquired immunodeficiency syndrome, hepatitis B, hepatitis C, tuberculosis, leprosy and malaria are highly prevalent in many human populations worldwide. Distinct approaches such as case-control comparisons, immunogenetic analyses, bioinformatic peptide-binding predictions, ancient DNA and genome-wide association studies (GWAS) have contributed to improving this knowledge during the last decade, although many results still need stronger statistical and/or functional support. The present review updates the information regarding the main HLA allele and SNP associations observed to date for six of the most widespread and some other infectious diseases, and provides a synthetic illustration of these findings on a schematic HLA genomic map. It then discusses these results by stressing the importance of integrating information on HLA population diversity in disease-association studies.


  1. Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA Database. Nucleic Acids Res. 2020;48(D1):D948–55. doi:.
  2. Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: expression, interaction, diversity and disease. J Hum Genet. 2009;54(1):15–39. doi:.
  3. Parham P, Janeway C. The immune system. 4th edition. New York, NY: Garland Science, Taylor & Francis Group; 2015
  4. Buhler S, Sanchez-Mazas A. HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events. PLoS One. 2011;6(2):e14643. doi:.
  5. Solberg OD, Mack SJ, Lancaster AK, Single RM, Tsai Y, Sanchez-Mazas A, et al. Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. Hum Immunol. 2008;69(7):443–64. doi:.
  6. Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet. 1975;305(7922):1406–9. doi:.
  7. Lenz TL. Computational prediction of MHC II-antigen binding supports divergent allele advantage and explains trans-species polymorphism. Evolution. 2011;65(8):2380–90. doi:.
  8. Bitarello BD, Francisco RS, Meyer D. Heterogeneity of dN/dS ratios at the classical HLA Class I genes over divergence time and across the allelic phylogeny. J Mol Evol. 2016;82(1):38–50. doi:.
  9. Wakeland EK, Boehme S, She JX, Lu CC, McIndoe RA, Cheng I, et al. Ancestral polymorphisms of MHC class II genes: divergent allele advantage. Immunol Res. 1990;9(2):115–22. doi:.
  10. Buhler S, Nunes JM, Sanchez-Mazas A. HLA class I molecular variation and peptide-binding properties suggest a model of joint divergent asymmetric selection. Immunogenetics. 2016;68(6-7):401–16. doi:.
  11. Meyer D, Thomson G. How selection shapes variation of the human major histocompatibility complex: a review. Ann Hum Genet. 2001;65(Pt 1):1–26. doi:.
  12. Lipsitch M, Bergstrom CT, Antia R. Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures. BMC Med Genet. 2003;4(1):2. doi:.
  13. de Groot NG, Otting N, Doxiadis GG, Balla-Jhagjhoorsingh SS, Heeney JL, van Rood JJ, et al. Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees. Proc Natl Acad Sci USA. 2002;99(18):11748–53. doi:.
  14. de Groot NG, Heijmans CM, de Groot N, Otting N, de Vos-Rouweller AJ, Remarque EJ, et al. Pinpointing a selective sweep to the chimpanzee MHC class I region by comparative genomics. Mol Ecol. 2008;17(8):2074–88. doi:.
  15. de Groot NG, Heijmans CMC, Helsen P, Otting N, Pereboom Z, Stevens JMG, et al. Limited MHC class I intron 2 repertoire variation in bonobos. Immunogenetics. 2017;69(10):677–88. doi:.
  16. Meyer D, C Aguiar VR, Bitarello BD, C Brandt DY, Nunes K. A genomic perspective on HLA evolution. Immunogenetics. 2018;70(1):5–27. doi:.
  17. Klebanov N. Genetic predisposition to infectious disease. Cureus. 2018;10(8):e3210. doi:.
  18. Blackwell JM, Jamieson SE, Burgner D. HLA and infectious diseases. Clin Microbiol Rev. 2009;22(2):370–85. doi:.
  19. Alper CA. Major Histocompatibility Complex: Disease Associations, in Encyclopedia of Life Sciences. Chichester, UK: John Wiley & Sons, Ltd; 2009. pp. 1−7.
  20. Trowsdale J. The MHC, disease and selection. Immunol Lett. 2011;137(1-2):1–8. doi:.
  21. Dendrou CA, Petersen J, Rossjohn J, Fugger L. HLA variation and disease. Nat Rev Immunol. 2018;18(5):325–39. doi:.
  22. Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet. 2013;14(1):301–23. doi:.
  23. Abel L, Alcaïs A, Schurr E. The dissection of complex susceptibility to infectious disease: bacterial, viral and parasitic infections. Curr Opin Immunol. 2014;30:72–8. doi:.
  24. Cardoso DM, Marangon AV, Sell AM, Visentainer JEL, De Souza CA. HLA and infectious diseases. In: HLA and associated important diseases. Xi Y, editor. Rijeka, Croatia: InTech; 2014. pp. 259−300.
  25. Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens. 2004;64(6):631–49. doi:.
  26. Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, et al. Positive natural selection in the human lineage. Science. 2006;312(5780):1614–20. doi:.
  27. Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 2017;18(1):76. doi:.
  28. Mozzi A, Pontremoli C, Sironi M. Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches. Infect Genet Evol. 2018;66:286–307. doi:.
  29. Tian C, Hromatka BS, Kiefer AK, Eriksson N, Noble SM, Tung JY, et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat Commun. 2017;8(1):599. doi:.
  30. McLaren PJ, Carrington M. The impact of host genetic variation on infection with HIV-1. Nat Immunol. 2015;16(6):577–83. doi:.
  31. Tang J, Costello C, Keet IP, Rivers C, Leblanc S, Karita E, et al. HLA class I homozygosity accelerates disease progression in human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 1999;15(4):317–24. doi:.
  32. Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science. 1999;283(5408):1748–52. doi:.
  33. Itescu S, Mathur-Wagh U, Skovron ML, Brancato LJ, Marmor M, Zeleniuch-Jacquotte A, et al. HLA-B35 is associated with accelerated progression to AIDS. J Acquir Immune Defic Syndr (1988). 1992;5(1):37–45.
  34. Gao X, Nelson GW, Karacki P, Martin MP, Phair J, Kaslow R, et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med. 2001;344(22):1668–75. doi:.
  35. Scherer A, Frater J, Oxenius A, Agudelo J, Price DA, Günthard HF, et al.; Swiss HIV Cohort Study. Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS. Proc Natl Acad Sci USA. 2004;101(33):12266–70. doi:.
  36. Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI, Walker BD, et al., International HIV Controllers Study. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010;330(6010):1551–7. doi:.
  37. Kulski JK. Long noncoding RNA HCP5, a hybrid HLA Class I endogenous retroviral gene: structure, expression, and disease associations. Cells. 2019;8(5):480. doi:.
  38. Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, et al.; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI). Common genetic variation and the control of HIV-1 in humans. PLoS Genet. 2009;5(12):e1000791. doi:.
  39. Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, et al. A whole-genome association study of major determinants for host control of HIV-1. Science. 2007;317(5840):944–7. doi:.
  40. Limou S, Le Clerc S, Coulonges C, Carpentier W, Dina C, Delaneau O, et al.; ANRS Genomic Group. Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). J Infect Dis. 2009;199(3):419–26. doi:.
  41. Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci USA. 2000;97(6):2709–14. doi:.
  42. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359(9312):1121–2. doi:.
  43. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727–32. doi:.
  44. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al.; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79. doi:.
  45. Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, et al.; Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation Study Team. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46(7):1111–8. doi:.
  46. Kløverpris HN, Leslie A, Goulder P. Role of HLA Adaptation in HIV Evolution. Front Immunol. 2016;6:665. doi:.
  47. Arora J, McLaren PJ, Chaturvedi N, Carrington M, Fellay J, Lenz TL. HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control. Proc Natl Acad Sci USA. 2019;116(3):944–9. doi:.
  48. Bardeskar NS, Mania-Pramanik J. HIV and host immunogenetics: unraveling the role of HLA-C. HLA. 2016;88(5):221–31. doi:.
  49. Apps R, Qi Y, Carlson JM, Chen H, Gao X, Thomas R, et al. Influence of HLA-C expression level on HIV control. Science. 2013;340(6128):87–91. doi:.
  50. Blais ME, Zhang Y, Rostron T, Griffin H, Taylor S, Xu K, et al. High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism. J Immunol. 2012;188(9):4663–70. doi:.
  51. Kulkarni S, Qi Y, O’hUigin C, Pereyra F, Ramsuran V, McLaren P, et al. Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease. Proc Natl Acad Sci USA. 2013;110(51):20705–10. doi:.
  52. Kulkarni S, Savan R, Qi Y, Gao X, Yuki Y, Bass SE, et al. Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature. 2011;472(7344):495–8. doi:.
  53. Kulpa DA, Collins KL. The emerging role of HLA-C in HIV-1 infection. Immunology. 2011;134(2):116–22. doi:.
  54. O’hUigin C, Kulkarni S, Xu Y, Deng Z, Kidd J, Kidd K, et al. The molecular origin and consequences of escape from miRNA regulation by HLA-C alleles. Am J Hum Genet. 2011;89(3):424–31. doi:.
  55. Zipeto D, Beretta A. HLA-C and HIV-1: friends or foes? Retrovirology. 2012;9(1):39. doi:.
  56. Pelak K, Goldstein DB, Walley NM, Fellay J, Ge D, Shianna KV, et al.; Infectious Disease Clinical Research Program HIV Working Group; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (CHAVI). Host determinants of HIV-1 control in African Americans. J Infect Dis. 2010;201(8):1141–9. doi:.
  57. Costello C, Tang J, Rivers C, Karita E, Meizen-Derr J, Allen S, et al. HLA-B*5703 independently associated with slower HIV-1 disease progression in Rwandan women. AIDS. 1999;13(14):1990–1. doi:.
  58. Adland E, Hill M, Lavandier N, Csala A, Edwards A, Chen F, et al. Differential immunodominance hierarchy of CD8+ T-Cell responses in HLA-B*27:05- and -B*27:02-mediated control of HIV-1 infection. J Virol. 2018;92(4):e01685-17. doi:.
  59. Kaslow RA, Carrington M, Apple R, Park L, Muñoz A, Saah AJ, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med. 1996;2(4):405–11. doi:.
  60. Arora J, Pierini F, McLaren PJ, Carrington M, Fellay J, Lenz TL. HLA heterozygote advantage against HIV-1 is driven by quantitative and qualitative differences in HLA allele-specific peptide presentation. Mol Biol Evol. 2020;37(3):639–50. doi:.
  61. Zuckerman AJ. Hepatitis viruses. In: Medical Microbiology. Baron S, editor. Galveston, TX: University of Texas Medical Branch at Galveston; 1996.
  62. WHO. Global hepatitis report 2017. Geneva, Switzerland: World Health Organization; 2017; p. 83.
  63. Wang L, Wu XP, Zhang W, Zhu DH, Wang Y, Li YP, et al. Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case-control studies. PLoS One. 2011;6(3):e17608. doi:.
  64. Matsuura K, Isogawa M, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis B virus infection. J Med Virol. 2016;88(3):371–9. doi:.
  65. Zhang Z, Wang C, Liu Z, Zou G, Li J, Lu M. Host genetic determinants of hepatitis B virus infection. Front Genet. 2019;10:696. doi:.
  66. Thio CL, Carrington M, Marti D, O’Brien SJ, Vlahov D, Nelson KE, et al. Class II HLA alleles and hepatitis B virus persistence in African Americans. J Infect Dis. 1999;179(4):1004–6. doi:.
  67. Thursz MR, Thomas HC, Greenwood BM, Hill AV. Heterozygote advantage for HLA class-II type in hepatitis B virus infection. Nat Genet. 1997;17(1):11–2. doi:.
  68. Zhang Y, Zhao F, Lan L, Qin Z, Jun L. Correlation of HLA-DQB1 gene polymorphism of Xinjiang Uygur with outcome of HBV infection. Int J Clin Exp Med. 2015;8(4):6067–72.
  69. Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV. Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med. 1995;332(16):1065–9. doi:.
  70. Thio CL, Thomas DL, Karacki P, Gao X, Marti D, Kaslow RA, et al. Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection. J Virol. 2003;77(22):12083–7. doi:.
  71. Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Seto WK, et al. New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. PLoS One. 2014;9(2):e86449. doi:.
  72. Höhler T, Gerken G, Notghi A, Lubjuhn R, Taheri H, Protzer U, et al. HLA-DRB1*1301 and *1302 protect against chronic hepatitis B. J Hepatol. 1997;26(3):503–7. doi:.
  73. Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet. 2009;41(5):591–5. doi:.
  74. Mbarek H, Ochi H, Urabe Y, Kumar V, Kubo M, Hosono N, et al. A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. Hum Mol Genet. 2011;20(19):3884–92. doi:.
  75. Zhu M, Dai J, Wang C, Wang Y, Qin N, Ma H, et al. Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese. Hum Mol Genet. 2016;25(6):1225–32. doi:.
  76. O’Brien TR, Kohaar I, Pfeiffer RM, Maeder D, Yeager M, Schadt EE, et al. Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver. Genes Immun. 2011;12(6):428–33. doi:.
  77. D’Antonio M, Reyna J, Jakubosky D, Donovan MK, Bonder M-J, Matsui H, et al. Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease. eLife. 2019;8:e48476. doi:.
  78. Thomas R, Thio CL, Apps R, Qi Y, Gao X, Marti D, et al. A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virus infection. J Virol. 2012;86(12):6979–85. doi:.
  79. Chang SW, Fann CS, Su WH, Wang YC, Weng CC, Yu CJ, et al. A genome-wide association study on chronic HBV infection and its clinical progression in male Han-Taiwanese. PLoS One. 2014;9(6):e99724. doi:.
  80. Nishida N, Sawai H, Matsuura K, Sugiyama M, Ahn SH, Park JY, et al. Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. PLoS One. 2012;7(6):e39175. doi:.
  81. Trinks J, Nishida N, Hulaniuk ML, Caputo M, Tsuchiura T, Marciano S, et al. Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population. Liver Int. 2017;37(10):1476–87. doi:.
  82. Al-Qahtani AA, Al-Anazi MR, Abdo AA, Sanai FM, Al-Hamoudi W, Alswat KA, et al. Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients. PLoS One. 2014;9(1):e80445. doi:.
  83. Lau KC, Lam CW, Law CY, Lai ST, Tsang TY, Siu CW, et al. Non-invasive screening of HLA-DPA1 and HLA-DPB1 alleles for persistent hepatitis B virus infection: susceptibility for vertical transmission and toward a personalized approach for vaccination and treatment. Clin Chim Acta. 2011;412(11-12):952–7. doi:.
  84. Hu L, Zhai X, Liu J, Chu M, Pan S, Jiang J, et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology. 2012;55(5):1426–31. doi:.
  85. Hu Z, Liu Y, Zhai X, Dai J, Jin G, Wang L, et al. New loci associated with chronic hepatitis B virus infection in Han Chinese. Nat Genet. 2013;45(12):1499–503. doi:.
  86. Hu Z, Yang J, Xiong G, Shi H, Yuan Y, Fan L, et al. HLA-DPB1 variant effect on hepatitis b virus clearance and liver cirrhosis development among southwest Chinese population. Hepat Mon. 2014;14(8):e19747. doi:.
  87. Kim YJ, Kim HY, Lee JH, Yu SJ, Yoon JH, Lee HS, et al. A genome-wide association study identified new variants associated with the risk of chronic hepatitis B. Hum Mol Genet. 2013;22(20):4233–8. doi:.
  88. Jiang DK, Ma XP, Yu H, Cao G, Ding DL, Chen H, et al. Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B. Hepatology. 2015;62(1):118–28. doi:.
  89. Vermehren J, Lötsch J, Susser S, Wicker S, Berger A, Zeuzem S, et al. A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. PLoS One. 2012;7(3):e32605. doi:.
  90. Tao J, Su K, Yu C, Liu X, Wu W, Xu W, et al. Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection. Amino Acids. 2015;47(12):2623–34. doi:.
  91. Yu L, Cheng YJ, Cheng ML, Yao YM, Zhang Q, Zhao XK, et al. Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development. Sci Rep. 2015;5(1):14933. doi:.
  92. Thio CL, Gao X, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, et al. HLA-Cw*04 and hepatitis C virus persistence. J Virol. 2002;76(10):4792–7. doi:.
  93. McKiernan SM, Hagan R, Curry M, McDonald GS, Kelly A, Nolan N, et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology. 2004;40(1):108–14. doi:.
  94. Amini M, Poustchi H. Hepatitis C virus spontaneous clearance: immunology and genetic variance. Viral Immunol. 2012;25(4):241–8. doi:.
  95. Kuniholm MH, Kovacs A, Gao X, Xue X, Marti D, Thio CL, et al. Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia. Hepatology. 2010;51(5):1514–22. doi:.
  96. Thio CL, Thomas DL, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, et al. Racial differences in HLA class II associations with hepatitis C virus outcomes. J Infect Dis. 2001;184(1):16–21. doi:.
  97. Hong Z, Smart G, Dawood M, Kaita K, Wen SW, Gomes J, et al. Hepatitis C infection and survivals of liver transplant patients in Canada, 1997-2003. Transplant Proc. 2008;40(5):1466–70. doi:.
  98. Harris RA, Sugimoto K, Kaplan DE, Ikeda F, Kamoun M, Chang KM. Human leukocyte antigen class II associations with hepatitis C virus clearance and virus-specific CD4 T cell response among Caucasians and African Americans. Hepatology. 2008;48(1):70–9. doi:.
  99. Huang J, Huang K, Xu R, Wang M, Liao Q, Xiong H, et al. The Associations of HLA-A*02:01 and DRB1*11:01 with Hepatitis C Virus Spontaneous Clearance Are Independent of IL28B in the Chinese Population. Sci Rep. 2016;6(1):31485. doi:.
  100. Gauthiez E, Habfast-Robertson I, Rüeger S, Kutalik Z, Aubert V, Berg T, et al.; Swiss Hepatitis C Cohort Study. A systematic review and meta-analysis of HCV clearance. Liver Int. 2017;37(10):1431–45. doi:.
  101. Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R, et al. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med. 2013;158(4):235–45. doi:.
  102. Miki D, Ochi H, Takahashi A, Hayes CN, Urabe Y, Abe H, et al. HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study. PLoS One. 2013;8(12):e84226. doi:.
  103. Xu X, Yue M, Jiang L, Deng X, Zhang Y, Zhang Y, et al. Genetic variants in human leukocyte antigen-DP influence both hepatitis C virus persistence and hepatitis C virus F protein generation in the Chinese Han population. Int J Mol Sci. 2014;15(6):9826–43. doi:.
  104. Thoens C, Heinold A, Lindemann M, Horn PA, Chang DI, Scherbaum N, et al. A single-nucleotide polymorphism upstream of the HLA-C locus is associated with an anti-hepatitis C virus-seronegative state in a high-risk exposed cohort. J Infect Dis. 2018;218(12):2016–9. doi:.
  105. Sawai H, Nishida N, Khor SS, Honda M, Sugiyama M, Baba N, et al. Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma. Sci Rep. 2018;8(1):7958. doi:.
  106. Omae Y, Tokunaga K. Genetics of infectious diseases, in Genome-wide association studies. Tsunoda T, Tanaka T, and Nakamura Y, editors. Singapore: Springer; 2019. pp. 145−74.
  107. Spinola H. HLA loci and respiratory infectious diseases. Journal of Respiratory Research. 2016;2(3):56–66. doi:.
  108. Oliveira-Cortez A, Melo AC, Chaves VE, Condino-Neto A, Camargos P. Do HLA class II genes protect against pulmonary tuberculosis? A systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2016;35(10):1567–80. doi:.
  109. Harishankar M, Selvaraj P, Bethunaickan R. Influence of genetic polymorphism towards pulmonary tuberculosis susceptibility. Front Med (Lausanne). 2018;5:213. doi:.
  110. Yim JJ, Selvaraj P. Genetic susceptibility in tuberculosis. Respirology. 2010;15(2):241–56. doi:.
  111. Kone A, Diarra B, Cohen K, Diabate S, Kone B, Diakite MT, et al. Differential HLA allele frequency in Mycobacterium africanum vs Mycobacterium tuberculosis in Mali. HLA. 2019;93(1):24–31. doi:.
  112. Sveinbjornsson G, Gudbjartsson DF, Halldorsson BV, Kristinsson KG, Gottfredsson M, Barrett JC, et al. HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat Genet. 2016;48(3):318–22. doi:.
  113. Qi H, Zhang YB, Sun L, Chen C, Xu B, Xu F, et al. Discovery of susceptibility loci associated with tuberculosis in Han Chinese. Hum Mol Genet. 2017;26(23):4752–63. doi:.
  114. Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2006;103(8):2869–73. doi:.
  115. Toyo-Oka L, Mahasirimongkol S, Yanai H, Mushiroda T, Wattanapokayakit S, Wichukchinda N, et al. Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis. HLA. 2017;90(3):149–56. doi:.
  116. Ndzi EN, Nkenfou CN, Pefura EWY, Mekue LCM, Guiedem E, Nguefeu CN, et al. Tuberculosis diagnosis: algorithm that May discriminate latent from active tuberculosis. Heliyon. 2019;5(10):e02559. doi:.
  117. Jarduli LR, Sell AM, Reis PG, Sippert EA, Ayo CM, Mazini PS, et al. Role of HLA, KIR, MICA, and cytokines genes in leprosy. BioMed Res Int. 2013;2013:989837. doi:.
  118. Wong SH, Gochhait S, Malhotra D, Pettersson FH, Teo YY, Khor CC, et al. Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog. 2010;6(7):e1000979. doi:.
  119. Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, et al. Genomewide association study of leprosy. N Engl J Med. 2009;361(27):2609–18. doi:.
  120. Liu H, Irwanto A, Fu X, Yu G, Yu Y, Sun Y, et al. Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet. 2015;47(3):267–71. doi:.
  121. Krause-Kyora B, Nutsua M, Boehme L, Pierini F, Pedersen DD, Kornell SC, et al. Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans. Nat Commun. 2018;9(1):1569. doi:.
  122. Alter A, Huong NT, Singh M, Orlova M, Van Thuc N, Katoch K, et al. Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India. J Infect Dis. 2011;203(9):1274–81. doi:.
  123. WHO. World Malaria Report 2019. Geneva, Switzerland: World Health Organization; 2019.
  124. Verra F, Mangano VD, Modiano D. Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies. Parasite Immunol. 2009;31(5):234–53. doi:.
  125. Garcia A, Milet J, Courtin D, Sabbagh A, Massaro JD, Castelli EC, et al. Association of HLA-G 3'UTR polymorphisms with response to malaria infection: a first insight. Infect Genet Evol. 2013;16:263–9. doi:.
  126. Sabbagh A, Courtin D, Milet J, Massaro JD, Castelli EC, Migot-Nabias F, et al. Association of HLA-G 3′ untranslated region polymorphisms with antibody response against Plasmodium falciparum antigens: preliminary results. Tissue Antigens. 2013;82(1):53–8. doi:.
  127. Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, et al. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991;352(6336):595–600. doi:.
  128. Hill AV, Elvin J, Willis AC, Aidoo M, Allsopp CE, Gotch FM, et al. Molecular analysis of the association of HLA-B53 and resistance to severe malaria. Nature. 1992;360(6403):434–9. doi:.
  129. Lyke KE, Fernández-Viňa MA, Cao K, Hollenbach J, Coulibaly D, Kone AK, et al. Association of HLA alleles with Plasmodium falciparum severity in Malian children. Tissue Antigens. 2011;77(6):562–71. doi:.
  130. Garamszegi LZ. Global distribution of malaria-resistant MHC-HLA alleles: the number and frequencies of alleles and malaria risk. Malar J. 2014;13(1):349. doi:.
  131. Sanchez-Mazas A, Černý V, Di D, Buhler S, Podgorná E, Chevallier E, et al. The HLA-B landscape of Africa: Signatures of pathogen-driven selection and molecular identification of candidate alleles to malaria protection. Mol Ecol. 2017;26(22):6238–52. doi:.
  132. Yamazaki A, Yasunami M, Ofori M, Horie H, Kikuchi M, Helegbe G, et al. Human leukocyte antigen class I polymorphisms influence the mild clinical manifestation of Plasmodium falciparum infection in Ghanaian children. Hum Immunol. 2011;72(10):881–8. doi:.
  133. Gilbert SC, Plebanski M, Gupta S, Morris J, Cox M, Aidoo M, et al. Association of malaria parasite population structure, HLA, and immunological antagonism. Science. 1998;279(5354):1173–7. doi:.
  134. Laval G, Peyrégne S, Zidane N, Harmant C, Renaud F, Patin E, et al. Recent adaptive acquisition by African rainforest hunter-gatherers of the late pleistocene sickle-cell mutation suggests past differences in malaria exposure. Am J Hum Genet. 2019;104(3):553–61. doi:.
  135. Schrider DR, Kern AD. Soft sweeps are the dominant mode of adaptation in the human genome. Mol Biol Evol. 2017;34(8):1863–77. doi:.
  136. Pritchard JK, Pickrell JK, Coop G. The genetics of human adaptation: hard sweeps, soft sweeps, and polygenic adaptation. Curr Biol. 2010;20(4):R208–15. doi:.
  137. Goeury T, Creary LE, Brunet L, Galan M, Pasquier M, Kervaire B, et al. Deciphering the fine nucleotide diversity of full HLA class I and class II genes in a well-documented population from sub-Saharan Africa. HLA. 2018;91(1):36–51. doi:.
  138. Norman PJ, Hollenbach JA, Nemat-Gorgani N, Guethlein LA, Hilton HG, Pando MJ, et al. Co-evolution of human leukocyte antigen (HLA) class I ligands with killer-cell immunoglobulin-like receptors (KIR) in a genetically diverse population of sub-Saharan Africans. PLoS Genet. 2013;9(10):e1003938. doi:.
  139. Lima-Junior JC, Pratt-Riccio LR. Major Histocompatibility Complex and malaria: focus on Plasmodium vivax infection. Front Immunol. 2016;7:13. doi:.
  140. Crosslin DR, Carrell DS, Burt A, Kim DS, Underwood JG, Hanna DS, et al. Genetic variation in the HLA region is associated with susceptibility to herpes zoster. Genes Immun. 2015;16(1):1–7. doi:.
  141. Stanaway IB, Hall TO, Rosenthal EA, Palmer M, Naranbhai V, Knevel R, et al.; eMERGE Network. The eMERGE genotype set of 83,717 subjects imputed to ~40 million variants genome wide and association with the herpes zoster medical record phenotype. Genet Epidemiol. 2019;43(1):63–81.
  142. Chen D, McKay JD, Clifford G, Gaborieau V, Chabrier A, Waterboer T, et al. Genome-wide association study of HPV seropositivity. Hum Mol Genet. 2011;20(23):4714–23. doi:.
  143. Dunstan SJ, Hue NT, Han B, Li Z, Tram TT, Sim KS, et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet. 2014;46(12):1333–6. doi:.
  144. DeLorenze GN, Nelson CL, Scott WK, Allen AS, Ray GT, Tsai AL, et al. Polymorphisms in HLA Class II genes are associated with susceptibility to Staphylococcus aureus infection in a white population. J Infect Dis. 2016;213(5):816–23. doi:.
  145. Fakiola M, Strange A, Cordell HJ, Miller EN, Pirinen M, Su Z, et al.; LeishGEN Consortium; Wellcome Trust Case Control Consortium 2. Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. Nat Genet. 2013;45(2):208–13. doi:.
  146. Blackwell JM, Fakiola M, Castellucci LC. Human genetics of leishmania infections. Hum Genet. 2020. doi:.
  147. Singh T, Fakiola M, Oommen J, Singh AP, Singh AK, Smith N, et al. Epitope-Binding characteristics for risk versus protective DRB1 alleles for visceral leishmaniasis. J Immunol. 2018;200(8):2727–37. doi:.
  148. Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res. 2018;46(D1):D754–61. doi:.
  149. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11. doi:.
  150. Crux NB, Elahi S. Human Leukocyte Antigen (HLA) and immune regulation: how do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections? Front Immunol. 2017;8:832. doi:.
  151. Robinson J, Guethlein LA, Cereb N, Yang SY, Norman PJ, Marsh SGE, et al. Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles. PLoS Genet. 2017;13(6):e1006862. doi:.
  152. Sanchez-Mazas A, Meyer D. The relevance of HLA sequencing in population genetics studies. J Immunol Res. 2014;2014:971818. doi:.
  153. Meyer D, Nunes K. HLA imputation, what is it good for? Hum Immunol. 2017;78(3):239–41. doi:.
  154. Cullen M, Noble J, Erlich H, Thorpe K, Beck S, Klitz W, et al. Characterization of recombination in the HLA class II region. Am J Hum Genet. 1997;60(2):397–407.
  155. Cullen M, Perfetto SP, Klitz W, Nelson G, Carrington M. High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet. 2002;71(4):759–76. doi:.
  156. Sanchez-Mazas A, Djoulah S, Busson M, Le Monnier de Gouville I, Poirier JC, Dehay C, et al. A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families. Eur J Hum Genet. 2000;8(1):33–41. doi:.
  157. Bugawan TL, Klitz W, Blair A, Erlich HA. High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci. Tissue Antigens. 2000;56(5):392–404. doi:.
  158. Achour Y, Ben Hamad M, Chaabane S, Rebai A, Marzouk S, Mahfoudh N, et al. Analysis of two susceptibility SNPs in HLA region and evidence of interaction between rs6457617 in HLA-DQB1 and HLA-DRB1*04 locus on Tunisian rheumatoid arthritis. J Genet. 2017;96(6):911–8. doi:.
  159. Lenz TL, Deutsch AJ, Han B, Hu X, Okada Y, Eyre S, et al. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat Genet. 2015;47(9):1085–90. doi:.
  160. Goudey B, Abraham G, Kikianty E, Wang Q, Rawlinson D, Shi F, et al. Interactions within the MHC contribute to the genetic architecture of celiac disease. PLoS One. 2017;12(3):e0172826. doi:.
  161. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38(10):1166–72. doi:.
  162. Gonzalez-Galarza FF, McCabe A, Santos EJMD, Jones J, Takeshita L, Ortega-Rivera ND, et al. Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res. 2019;gkz1029. doi:.
  163. Singh R, Kaul R, Kaul A, Khan K. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World J Gastroenterol. 2007;13(12):1770–87. doi:.
  164. Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al., 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68–74. doi:.
  165. Tshabalala M, Mellet J, Pepper MS. Human Leukocyte Antigen Diversity: A Southern African Perspective. J Immunol Res. 2015;2015:746151. doi:.
  166. Ndiaye Diallo R, Gadji M, Hennig BJ, Gueye MV, Gaye A, Diop JPD, et al. Strengthening human genetics research in Africa: report of the 9th meeting of the African Society of Human Genetics in Dakar in May 2016. Glob Health Epidemiol Genom. 2017. 2: p. e10.DOI:
  167. Sirugo G, Williams SM, Tishkoff SA. The missing diversity in human genetic studies. Cell. 2019;177(1):26–31. doi:.
  168. Ramsay M. Africa: continent of genome contrasts with implications for biomedical research and health. FEBS Lett. 2012;586(18):2813–9. doi:.
  169. McDougall I, Brown FH, Fleagle JG. Stratigraphic placement and age of modern humans from Kibish, Ethiopia. Nature. 2005;433(7027):733–6. doi:.
  170. Hublin J-J, Ben-Ncer A, Bailey SE, Freidline SE, Neubauer S, Skinner MM, et al. New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens. Nature. 2017;546(7657):289–92. doi:.. Correction in: Nature. 2018;70(141):986
  171. Meyer D, Single RM, Mack SJ, Erlich HA, Thomson G. Signatures of demographic history and natural selection in the human major histocompatibility complex Loci. Genetics. 2006;173(4):2121–42. doi:.
  172. Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005;77(2):171–92. doi:.
  173. Mangano VD, Modiano D. An evolutionary perspective of how infection drives human genome diversity: the case of malaria. Curr Opin Immunol. 2014;30:39–47. doi:.
  174. Marquet S. Overview of human genetic susceptibility to malaria: From parasitemia control to severe disease. Infect Genet Evol. 2018;66:399–409. doi:.
  175. Slade RW, McCallum HI. Overdominant vs. frequency-dependent selection at MHC loci. Genetics. 1992;132(3):861–4.
  176. Ansari MA, Pedergnana V, L C Ip C, Magri A, Von Delft A, Bonsall D, et al.; STOP-HCV Consortium. Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus. Nat Genet. 2017;49(5):666–73. doi:.
  177. Korber B, Muldoon M, Theiler J, Gao F, Gupta R, Lapedes A, et al. Timing the ancestor of the HIV-1 pandemic strains. Science. 2000;288(5472):1789–96. doi:.
  178. Faria NR, Rambaut A, Suchard MA, Baele G, Bedford T, Ward MJ, et al. The early spread and epidemic ignition of HIV-1 in human populations. Science. 2014;346(6205):56–61. doi:.
  179. Karlsson EK, Kwiatkowski DP, Sabeti PC. Natural selection and infectious disease in human populations. Nat Rev Genet. 2014;15(6):379–93. doi:.
  180. Andrés AM, Hubisz MJ, Indap A, Torgerson DG, Degenhardt JD, Boyko AR, et al. Targets of balancing selection in the human genome. Mol Biol Evol. 2009;26(12):2755–64. doi:.
  181. Penman BS, Gupta S. Detecting signatures of past pathogen selection on human HLA loci: are there needles in the haystack? Parasitology. 2018;145(6):731–9. doi:.
  182. Currat M, Poloni ES, Sanchez-Mazas A. Human genetic differentiation across the Strait of Gibraltar. BMC Evol Biol. 2010;10(1):237. doi:.
  183. Di D, Sanchez-Mazas A, Currat M. Computer simulation of human leukocyte antigen genes supports two main routes of colonization by human populations in East Asia. BMC Evol Biol. 2015;15(1):240. doi:.
  184. Dos Santos Francisco R, Buhler S, Nunes JM, Bitarello BD, França GS, Meyer D, et al. HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms. Immunogenetics. 2015;67(11-12):651–63. doi:.