Human Genetics

, 125:281 | Cite as

Association of Y chromosome haplogroup I with HIV progression, and HAART outcome

  • Efe Sezgin
  • Joanne M. Lind
  • Sadeep Shrestha
  • Sher Hendrickson
  • James J. Goedert
  • Sharyne Donfield
  • Gregory D. Kirk
  • John P. Phair
  • Jennifer L. Troyer
  • Stephen J. O’Brien
  • Michael W. Smith
Original Investigation

Abstract

The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.

Supplementary material

439_2008_620_MOESM1_ESM.tif (379 kb)
Supplementary figures (TIFF 379 kb)
439_2008_620_MOESM2_ESM.doc (475 kb)
Supplementary tables (DOC 475 kb)

References

  1. Agulnik AI, Mitchell MJ, Lerner JL, Woods DR, Bishop CE (1994) A mouse Y chromosome gene encoded by a region essential for spermatogenesis and expression of male-specific minor histocompatibility antigens. Hum Mol Genet 3:873–878PubMedCrossRefGoogle Scholar
  2. Anderson RN (2001) Deaths: leading Causes for 1999. National Vital Statistics Report, vol 49. National Centre for Health Statistics, HyattsvilleGoogle Scholar
  3. Bosch E, Calafell F, Rosser ZH, Norby S, Lynnerup N, Hurles ME, Jobling MA (2003) High level of male-biased Scandinavian admixture in Greenlandic Inuit shown by Y-chromosomal analysis. Hum Genet 112:353–363PubMedGoogle Scholar
  4. Bruisten SM, Frissen PH, Van Swieten P, Harrigan PR, Kinghorn I, Larder B, Weigel HM, De Vries E, Regez RM, Henrichs JH, Koot M, Huisman JG (1997) Prospective longitudinal analysis of viral load and surrogate markers in relation to clinical progression in HIV type 1-infected persons. AIDS Res Hum Retroviruses 13:327–335PubMedCrossRefGoogle Scholar
  5. Buchbinder SP, Katz MH, Hessol NA, Omalley PM, Holmberg SD (1994) Long-term HIV-1 infection without immunological progression. AIDS 8:1123–1128PubMedCrossRefGoogle Scholar
  6. Carvajal-Carmona LG, Soto ID, Pineda N, Ortiz-Barrientos D, Duque C, Ospina-Duque J, McCarthy M, Montoya P, Alvarez VM, Bedoya G, Ruiz-Linares A (2000) Strong Amerind/white sex bias and a possible Sephardic contribution among the founders of a population in northwest Colombia. Am J Hum Genet 67:1287–1295PubMedCrossRefGoogle Scholar
  7. Carvajal-Carmona LG, Ophoff R, Service S, Hartiala J, Molina J, Leon P, Ospina J, Bedoya G, Freimer N, Ruiz-Linares A (2003) Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica. Hum Genet 112:534–541PubMedGoogle Scholar
  8. Cavalli-Sforza LL, Hewlett B (1982) Exploration and mating range in African Pygmies. Ann Hum Genet 46:257–270PubMedCrossRefGoogle Scholar
  9. Centers for Disease Control (1986) Classification system for human T-lymphotropic virus type III/lymphadenopathy-associated virus infections. MMWR Morb Mortal Wkly Rep 35:334–339Google Scholar
  10. Centers for Disease Control (1992) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 41:1–19Google Scholar
  11. Chromosome Consortium Y (2002) A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res 12:339–348CrossRefGoogle Scholar
  12. Cinnioglu C, King R, Kivisild T, Kalfoglu E, Atasoy S, Cavalleri GL, Lillie AS, Roseman CC, Lin AA, Prince K, Oefner PJ, Shen PD, Semino O, Cavalli-Sforza LL, Underhill PA (2004) Excavating Y-chromosome haplotype strata in Anatolia. Hum Genet 114:127–148PubMedCrossRefGoogle Scholar
  13. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O’Brien SJ (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856–1862PubMedCrossRefGoogle Scholar
  14. Diamond JM (2005) Guns, germs, and steel: the fates of human societies. Norton, New YorkGoogle Scholar
  15. Ditton HJ, Zimmer J, Kamp C, Rajpert-De Meyts E, Vogt PH (2004) The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum Mol Genet 13:2333–2341PubMedCrossRefGoogle Scholar
  16. Dobson AP, Carper ER (1996) Infectious diseases and human population history—throughout history the establishment of disease has been a side effect of the growth of civilization. Bioscience 46:115–126CrossRefGoogle Scholar
  17. Gleicher N, Barad DH (2007) Gender as risk factor for autoimmune diseases. J Autoimmun 28:1–6PubMedCrossRefGoogle Scholar
  18. Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC, Drummond JE, Vaidya K, Mann DL, Eyster ME, Ragni MV, Lederman MM, Cohen AR, Bray GL, Rosenberg PS, Friedman RM, Hilgartner MW, Blattner WA, Kroner B, Gail MH (1989) A prospective-study of human immunodeficiency virus type-1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 321:1141–1148PubMedGoogle Scholar
  19. Hamilton G, Stoneking M, Excoffier L (2005) Molecular analysis reveals tighter social regulation of immigration in patrilocal populations than in matrilocal populations. Proc Natl Acad Sci USA 102:7476–7480PubMedCrossRefGoogle Scholar
  20. Henrard DR, Phillips JF, Muenz LR, Blattner WA, Wiesner D, Eyster ME, Goedert JJ (1995) Natural history of HIV-1 cell-free viremia. JAMA 274:554–558PubMedCrossRefGoogle Scholar
  21. Hilgartner MW, Donfield SM, Willoughby A, Contant CF, Evatt BL, Gomperts ED, Hoots WK, Jason J, Loveland KA, Mckinlay SM, Stehbens JA (1993) Hemophilia growth and development study—design, methods, and entry data. Am J Pediatr Hematol Oncol 15:208–218PubMedCrossRefGoogle Scholar
  22. Ivanov R, Hol S, Aarts T, Hagenbeek A, Slager EH, Ebeling S (2005) UTY-specific TCR-transfer generates potential graft-versus-leukaemia effector T cells. Br J Haematol 129:392–402PubMedCrossRefGoogle Scholar
  23. Jobling MA, Tyler-Smith C (2003) The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet 4:598–612PubMedCrossRefGoogle Scholar
  24. Jobling MA, Williams GA, Schiebel GA, Pandya GA, McElreavey GA, Salas GA, Rappold GA, Affara NA, Tyler-Smith C (1998) A selective difference between human Y-chromosomal DNA haplotypes. Curr Biol 8:1391–1394PubMedCrossRefGoogle Scholar
  25. Karafet TM, Mendez FL, Meilerman MB, Underhill PA, Zegura SL, Hammer MF (2008) New binary polymorphisms reshape and increase resolution of the human Y chromosomal haplogroup tree. Genome Res 18:830–838PubMedCrossRefGoogle Scholar
  26. Katzenstein TL, Pedersen C, Nielsen C, Lundgren JD, Jakobsen PH, Gerstoft J (1996) Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome. AIDS 10:167–173PubMedCrossRefGoogle Scholar
  27. Krausz C, Quintana-Murci L, Forti G (2004) Y chromosome polymorphisms in medicine. Ann Med 36:573–583PubMedCrossRefGoogle Scholar
  28. Lahn BT, Page DC (1997) Functional coherence of the human Y chromosome. Science 278:675–680PubMedCrossRefGoogle Scholar
  29. Laurin D, Spierings E, van der Veken LT, Hamrouni A, Falkenburg JH, Souillet G, Vermeulen C, Farre A, Galambrun C, Rigal D, Bertrand Y, Goulmy E, Eljaafari A (2006) Minor histocompatibility antigen DDX3Y induces HLA-DQ5-restricted T cell responses with limited TCR-Vbeta usage both in vivo and in vitro. Biol Blood Marrow Transplant 12:1114–1124PubMedCrossRefGoogle Scholar
  30. Libert F, Cochaux P, Beckman G, Samson M, Aksenova M, Cao A, Czeizel A, Claustres M, de la Rua C, Ferrari M, Ferrec C, Glover G, Grinde B, Guran S, Kucinskas V, Lavinha J, Mercier B, Ogur G, Peltonen L, Rosatelli C, Schwartz M, Spitsyn V, Timar L, Beckman L, Parmentier M, Vassart G (1998) The deltaccr5 mutation conferring protection against HIV–1 in Caucasian populations has a single and recent origin in Northeastern Europe. Hum Mol Genet 7:399–406PubMedCrossRefGoogle Scholar
  31. Lind JM, Hutcheson-Dilks HB, Williams SM, Moore JH, Essex M, Ruiz-Pesini E, Wallace DC, Tishkoff SA, O’Brien SJ, Smith MW (2007) Elevated male European and female African contributions to the genomes of African American individuals. Hum Genet 120:713–722PubMedCrossRefGoogle Scholar
  32. Lyles RH, Munoz A, Yamashita TE, Bazmi H, Detels R, Rinaldo CR, Margolick JB, Phair JP, Mellors JW (2000) Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis 181:872–880PubMedCrossRefGoogle Scholar
  33. Marriott I, Huet-Hudson YM (2006) Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res 34:177–192PubMedCrossRefGoogle Scholar
  34. Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, Michael NL, Lee B, Doms RW, Margolick J, Buchbinder S, Goedert JJ, O’Brien TR, Hilgartner MW, Vlahov D, O’Brien SJ, Carrington M (1998) Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 282:1907–1911PubMedCrossRefGoogle Scholar
  35. McCarthy M (2000) The “gender gap” in autoimmune disease. Lancet 356:1088PubMedCrossRefGoogle Scholar
  36. Mesa NR, Mondragon MC, Soto ID, Parra MV, Duque C, Ortiz-Barrientos D, Garcia LF, Velez ID, Bravo ML, Munera JG, Bedoya G, Bortolini MC, Ruiz-Linares A (2000) Autosomal, mtDNA, and Y-chromosome diversity in Amerinds: pre- and post-Columbian patterns of gene flow in South America. Am J Hum Genet 67:1277–1286PubMedGoogle Scholar
  37. O’Brien SJ, Nelson GW (2004) Human genes that limit AIDS. Nat Genet 36:565–574PubMedCrossRefGoogle Scholar
  38. Office of AIDS Research Advisory Council (2006) Guidelines for the use of antiretroviral agents in HIV–1-infected adults and adolescents. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL05042006050.pdf
  39. Pezzotti P, Phillips AN, Dorrucci M, Lepri AC, Galai N, Vlahov D, Rezza G (1996) Category of exposure to HIV and age in the progression to AIDS: longitudinal study of 1199 people with known dates of seroconversion. HIV Italian Seroconversion Study Group. Br Med J 313:583–586Google Scholar
  40. Phair J, Jacobson L, Detels R, Rinaldo C, Saah A, Schrager L, Munoz A (1992) Acquired immune deficiency syndrome occurring within 5 years of infection with human immunodeficiency virus type-1: the Multicenter Aids Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol 5:490–496Google Scholar
  41. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRefGoogle Scholar
  42. Price AL, Butler J, Patterson N, Capelli C, Pascali VL, Scarnicci F, Ruiz-Linares A, Groop L, Saetta AA, Korkolopoulou P, Seligsohn U, Waliszewska A, Schirmer C, Ardlie K, Ramos A, Nemesh J, Arbeitman L, Goldstein DB, Reich D, Hirschhorn JN (2008) Discerning the ancestry of European Americans in genetic association studies. PLoS Genet 4:e236PubMedCrossRefGoogle Scholar
  43. Repping S, Skaletsky H, Brown L, van Daalen SK, Korver CM, Pyntikova T, Kuroda-Kawaguchi T, de Vries JW, Oates RD, Silber S, van der Veen F, Page DC, Rozen S (2003) Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet 35:247–251PubMedCrossRefGoogle Scholar
  44. Repping S, van Daalen SK, Brown LG, Korver CM, Lange J, Marszalek JD, Pyntikova T, van der Veen F, Skaletsky H, Page DC, Rozen S (2006) High mutation rates have driven extensive structural polymorphism among human Y chromosomes. Nat Genet 38:463–467PubMedCrossRefGoogle Scholar
  45. Rootsi S, Magri C, Kivisild T, Benuzzi G, Help H, Bermisheva M, Kutuev I, Barac L, Pericic M, Balanovsky O, Pshenichnov A, Dion D, Grobei M, Zhivotovsky LA, Battaglia V, Achilli A, Al-Zahery N, Parik J, King R, Cinnioglu C, Khusnutdinova E, Rudan P, Balanovska E, Scheffrahn W, Simonescu M, Brehm A, Goncalves R, Rosa A, Moisan JP, Chaventre A, Ferak V, Furedi S, Oefner PJ, Shen PD, Beckman L, Mikerezi I, Terzic R, Primorac D, Cambon-Thomsen A, Krumina A, Torroni A, Underhill PA, Santachiara-Benerecetti AS, Villems R, Semino O (2004) Phylogeography of Y-chromosome haplogroup I reveals distinct domains of prehistoric gene flow in Europe. Am J Hum Genet 75:128–137PubMedCrossRefGoogle Scholar
  46. Seielstad MT, Minch E, Cavalli-Sforza LL (1998) Genetic evidence for a higher female migration rate in humans. Nat Genet 20:278–280PubMedCrossRefGoogle Scholar
  47. Shin HD, Winkler C, Stephens JC, Bream J, Young H, Goedert JJ, O’Brien TR, Vlahov D, Buchbinder S, Giorgi J, Rinaldo C, Donfield S, Willoughby A, O’Brien SJ, Smith MW (2000) Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci USA 97:14467–14472PubMedCrossRefGoogle Scholar
  48. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G, Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S, Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen C, Ozersky P, Pepin K, Rock S, Rohlfing T, Scott K, Schultz B, Strong C, Tin-Wollam A, Yang SP, Waterston RH, Wilson RK, Rozen S, Page DC (2003) The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423:825–837PubMedCrossRefGoogle Scholar
  49. Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, Goedert JJ, O’Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O’Brien SJ (1997) Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science 277:959–965PubMedCrossRefGoogle Scholar
  50. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100:9440–9445PubMedCrossRefGoogle Scholar
  51. Teuschert C, Noubade R, Spach K, McElvany B, Bunn JY, Fillmore PD, Zachary JF, Blankenhorn EP (2006) Evidence that the Y chromosome influences autoimmune disease in male and female mice. Proc Natl Acad Sci USA 103:8024–8029CrossRefGoogle Scholar
  52. Torikai H, Akatsuka Y, Miyazaki M, Warren EH 3rd, Oba T, Tsujimura K, Motoyoshi K, Morishima Y, Kodera Y, Kuzushima K, Takahashi T (2004) A novel HLA-A*3303-restricted minor histocompatibility antigen encoded by an unconventional open reading frame of human TMSB4Y gene. J Immunol 173:7046–7054PubMedGoogle Scholar
  53. Underhill PA, Passarino G, Lin AA, Shen P, Lahr MM, Foley RA, Oefner PJ, Cavalli-Sforza LL (2001) The phylogeography of Y chromosome binary haplotypes and the origins of modern human populations. Ann Hum Genet 65:43–62PubMedCrossRefGoogle Scholar
  54. Vlahov D, Graham N, Hoover D, Flynn C, Bartlett JG, Margolick JB, Lyles CM, Nelson KE, Smith D, Holmberg S, Farzadegan H (1998) Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4(+) cell count. JAMA 279:35–40PubMedCrossRefGoogle Scholar
  55. Vogt MH, de Paus RA, Voogt PJ, Willemze R, Falkenburg JH (2000) DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood 95:1100–1105PubMedGoogle Scholar
  56. Warren EH, Gavin MA, Simpson E, Chandler P, Page DC, Disteche C, Stankey KA, Greenberg PD, Riddell SR (2000) The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen. J Immunol 164:2807–2814PubMedGoogle Scholar
  57. Wesley JD, Tessmer MS, Paget C, Trottein F, Brossay L (2007) A Y chromosome-linked factor impairs NK T development. J Immunol 179:3480–3487PubMedGoogle Scholar
  58. Whitacre CC (2001) Sex differences in autoimmune disease. Nat Immunol 2:777–780PubMedCrossRefGoogle Scholar
  59. Whitacre CC, Reingold SC, O’Looney PA (1999) A gender gap in autoimmunity. Science 283:1277–1278PubMedCrossRefGoogle Scholar
  60. Wilder JA, Kingan SB, Mobasher Z, Pilkington MM, Hammer MF (2004) Global patterns of human mitochondrial DNA and Y-chromosome structure are not influenced by higher migration rates of females versus males. Nat Genet 36:1122–1125PubMedCrossRefGoogle Scholar
  61. Wilkins JF (2006) Unraveling male and female histories from human genetic data. Curr Opin Genet Dev 16:611–617PubMedCrossRefGoogle Scholar
  62. Wilkins JF, Marlowe FW (2006) Sex-biased migration in humans: what should we expect from genetic data? Bioessays 28:290–300PubMedCrossRefGoogle Scholar
  63. Wolfe ND, Dunavan CP, Diamond J (2007) Origins of major human infectious diseases. Nature 447:279–283PubMedCrossRefGoogle Scholar
  64. Wood ET, Stover DA, Ehret C, Destro-Bisol G, Spedini G, McLeod H, Louie L, Bamshad M, Strassmann BI, Soodyall H, Hammer MF (2005) Contrasting patterns of Y chromosome and mtDNA variation in Africa: evidence for sex-biased demographic processes. Eur J Hum Genet 13:867–876PubMedCrossRefGoogle Scholar

Copyright information

© US Government 2009

Authors and Affiliations

  • Efe Sezgin
    • 1
  • Joanne M. Lind
    • 1
    • 7
  • Sadeep Shrestha
    • 1
    • 2
    • 9
  • Sher Hendrickson
    • 1
  • James J. Goedert
    • 3
  • Sharyne Donfield
    • 4
  • Gregory D. Kirk
    • 5
  • John P. Phair
    • 6
  • Jennifer L. Troyer
    • 1
    • 2
  • Stephen J. O’Brien
    • 1
  • Michael W. Smith
    • 1
    • 2
    • 8
  1. 1.Laboratory of Genomic DiversityFrederickUSA
  2. 2.Basic Research Program, SAIC-Frederick, Inc.FrederickUSA
  3. 3.Viral Epidemiology BranchNational Cancer InstituteRockvilleUSA
  4. 4.Rho, IncorporatedChapel HillUSA
  5. 5.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  6. 6.Northwestern University Medical School, Comprehensive AIDS CenterChicagoUSA
  7. 7.School of MedicineUniversity of Western SydneySydneyAustralia
  8. 8.Genetics and Genomics, Advanced Technology ProgramSAIC-Frederick, Inc., National Cancer InstituteFrederickUSA
  9. 9.Department of Epidemiology and International Health, School of Public HealthUniversity of AlabamaBirminghamUSA

Personalised recommendations