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Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans

Genes & Immunity volume 14, pages 13–18 (2013)Cite this article

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Abstract

A recent genome-wide association study in a German population and two subsequent studies in European populations found that a non-synonymous single-nucleotide polymorphism (SNP), rs1049550, within the annexin A11 (ANXA11) gene was associated with susceptibility to sarcoidosis. We sought to identify additional ANXA11 variants independently associated with sarcoidosis, determine whether any sarcoidosis-associated ANXA11 variants were associated with chest radiographic phenotypes, and explore human leukocyte antigen (HLA) SNP–SNP interactions with ANXA11. A total of 209 SNPs spanning 100 kb including the 5' promoter, coding, and 3' untranslated regions of ANXA11 were genotyped for 1689 sarcoidosis cases and 1252 controls. After adjustment for rs1049550, two additional novel ANXA11 sarcoidosis associations were identified only in African Americans—rs61860052 (odds ratio (OR)=0.62; 95% confidence interval (CI)=0.40–0.97) and rs4377299 (OR=1.31; 95% CI=1.06–1.63). These associations were more pronounced in radiologically-classified Scadding stage IV sarcoidosis cases. We also identified a significant SNP–SNP interaction between rs1049550 and a sarcoidosis risk SNP (rs9268839) near the HLA–DRA locus. This further genetic dissection of ANXA11 may provide additional insight into the immune dysregulation characteristic of sarcoidosis pathophysiology.

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References

  1. Iannuzzi MC, Rybicki BA, Teirstein AS . Sarcoidosis. N Engl J Med 2007; 357: 2153–2165.

    Article  CAS  Google Scholar 

  2. Grunewald J . Review: role of genetics in susceptibility and outcome of sarcoidosis. Semin Respir Crit Care Med 2010; 31: 380–389.

    Article  Google Scholar 

  3. Brewerton DA, Cockburn C, James DC, James DG, Neville E . HLA antigens in sarcoidosis. Clin Exp Immunol 1977; 27: 227–229.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Rossman MD, Thompson B, Frederick M, Maliarik M, Iannuzzi MC, Rybicki BA et al. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet 2003; 73: 720–735.

    Article  CAS  Google Scholar 

  5. Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA . Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med 2003; 167: 1225–1231.

    Article  Google Scholar 

  6. Hofmann S, Franke A, Fischer A, Jacobs G, Nothnagel M, Gaede KI et al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet 2008; 40: 1103–1106.

    Article  CAS  Google Scholar 

  7. Li Y, Pabst S, Kubisch C, Grohe C, Wollnik B . First independent replication study confirms the strong genetic association of ANXA11 with sarcoidosis. Thorax 2010; 65: 939–940.

    Article  Google Scholar 

  8. Mrazek F, Stahelova A, Kriegova E, Fillerova R, Zurkova M, Kolek V et al. Functional variant ANXA11 R230C: true marker of protection and candidate disease modifier in sarcoidosis. Genes Immun 2011; 12: 490–494.

    Article  CAS  Google Scholar 

  9. Adrianto I, Chee PL, Hale JJ, Levin AM, Datta I, Parker R et al. Genome-wide association study of African and European Americans implicates multiple shared and thnic specific loci in sarcoidosis susceptibility. PLoS One 2012; 7: e43907.

    Article  CAS  Google Scholar 

  10. Moss SE, Morgan RO . The annexins. Genome Biol 2004; 5: 219.

    Article  Google Scholar 

  11. Fatimathas L, Moss SE . Annexins as disease modifiers. Histol Histopathol 2010; 25: 527–532.

    CAS  PubMed  Google Scholar 

  12. Tomas A, Futter C, Moss SE . Annexin 11 is required for midbody formation and completion of the terminal phase of cytokinesis. J Cell Biol 2004; 165: 813–822.

    Article  CAS  Google Scholar 

  13. Buschow SI, van Balkom BW, Aalberts M, Heck AJ, Wauben M, Stoorvogel W . MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunol Cell Biol 2010; 88: 851–856.

    Article  CAS  Google Scholar 

  14. Bianco NR, Kim SH, Morelli AE, Robbins PD . Modulation of the immune response using dendritic cell-derived exosomes. Methods Mol Biol 2007; 380: 443–455.

    Article  CAS  Google Scholar 

  15. Qazi KR, Torregrosa Paredes P, Dahlberg B, Grunewald J, Eklund A, Gabrielsson S . Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis. Thorax 2010; 65: 1016–1024.

    Article  Google Scholar 

  16. Rybicki BA, Maliarik MJ, Major M, Popovich J, Iannuzzi MC . Epidemiology, demographics, and genetics of sarcoidosis. Semin Respir Infect 1998; 13: 166–173.

    CAS  PubMed  Google Scholar 

  17. Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger D et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med 2011; 183: 1524–1530.

    Article  Google Scholar 

  18. Thompson CL, Rybicki BA, Iannuzzi MC, Elston RC, Iyengar SK, Gray-McGuire C . Reduction of sample heterogeneity through use of population substructure: an example from a population of African American families with sarcoidosis. Am J Hum Genet 2006; 79: 606–613.

    Article  CAS  Google Scholar 

  19. Rybicki BA, Levin AM, McKeigue P, Datta I, Gray-McGuire C, Colombo M et al. A genome-wide admixture scan for ancestry-linked genes predisposing to sarcoidosis in African-Americans. Genes Immun 2011; 12: 67–77.

    Article  CAS  Google Scholar 

  20. Iannuzzi MC, Rybicki BA . Genetics of sarcoidosis: candidate genes and genome scans. Proc Am Thorac Soc 2007; 4: 108–116.

    Article  CAS  Google Scholar 

  21. Wright FA, Strug LJ, Doshi VK, Commander CW, Blackman SM, Sun L et al. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet 2011; 43: 539–546.

    Article  CAS  Google Scholar 

  22. Eleftherohorinou H, Hoggart CJ, Wright VJ, Levin M, Coin LJ . Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways. Hum Mol Genet 2011; 20: 3494–3506.

    Article  CAS  Google Scholar 

  23. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011; 43: 246–252.

    Article  CAS  Google Scholar 

  24. Franke A, Balschun T, Sina C, Ellinghaus D, Hasler R, Mayr G et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet 2010; 42: 292–294.

    Article  CAS  Google Scholar 

  25. Asano K, Matsushita T, Umeno J, Hosono N, Takahashi A, Kawaguchi T et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 2009; 41: 1325–1329.

    Article  CAS  Google Scholar 

  26. Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 2009; 41: 216–220.

    Article  CAS  Google Scholar 

  27. Rybicki BA, Amend KL, Maliarik MJ, Iannuzzi MC . Photocopier exposure and risk of sarcoidosis in African-American sibs. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 49–55.

    PubMed  Google Scholar 

  28. Newman LS, Rose CS, Bresnitz EA, Rossman MD, Barnard J, Frederick M et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med 2004; 170: 1324–1330.

    Article  Google Scholar 

  29. Kucera GP, Rybicki BA, Kirkey KL, Coon SW, Major ML, Maliarik MJ et al. Occupational risk factors for sarcoidosis in African-American siblings. Chest 2003; 123: 1527–1535.

    Article  Google Scholar 

  30. Barnard J, Rose C, Newman L, Canner M, Martyny J, McCammon C et al. Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med 2005; 47: 226–234.

    Article  Google Scholar 

  31. Ho LP . Exosomes in lungs of patients with sarcoidosis: a contributor to immune pathogenesis or just another by-product of heightened immune activity? Thorax 2010; 65: 947–948.

    Article  Google Scholar 

  32. Group AR . Design of a case control etiologic study of sarcoidosis (ACCESS). J Clin Epidemiol 1999; 52: 1173–1186.

    Article  Google Scholar 

  33. Rybicki BA, Hirst K, Iyengar SK, Barnard JG, Judson MA, Rose CS et al. A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22: 115–122.

    PubMed  Google Scholar 

  34. Edlund CK, Lee WH, Li D, Van Den Berg DJ, Conti DV . Snagger: a user-friendly program for incorporating additional information for tagSNP selection. BMC Bioinformatics 2008; 9: 174.

    Article  Google Scholar 

  35. Wigginton JE, Cutler DJ, Abecasis GR . A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  Google Scholar 

  36. Thornton T, McPeek MS . ROADTRIPS: case-control association testing with partially or completely unknown population and pedigree structure. Am J Hum Genet 2010; 86: 172–184.

    Article  CAS  Google Scholar 

  37. Willer CJ, Li Y, Abecasis GR . METAL: fast and efficient meta-analysis of genome wide association scans. Bioinformatics 2010; 26: 2190–2191.

    Article  CAS  Google Scholar 

  38. Chen MH, Yang Q . GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 2010; 26: 580–581.

    Article  Google Scholar 

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Acknowledgements

Primary support for this work was from research grants awarded to CGM (1RC2HL101499) and BAR (R56-AI072727 and R01-HL092576).

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Authors and Affiliations

  1. Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA

    A M Levin, S Trudeau, I Datta & B A Rybicki

  2. Department of Medicine, Upstate Medical University, Syracuse, NY, USA

    M C Iannuzzi

  3. Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    C G Montgomery

  4. Public Health Sciences Section, University of Edinburgh Medical School, Edinburgh, Scotland

    P McKeigue

  5. Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany

    A Fischer & A Nebel

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  1. A M Levin
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  2. M C Iannuzzi
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Correspondence to B A Rybicki.

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Levin, A., Iannuzzi, M., Montgomery, C. et al. Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans. Genes Immun 14, 13–18 (2013). https://doi.org/10.1038/gene.2012.48

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