Abstract
In the United States, incidence and mortality from sarcoidosis, a chronic, granulomatous disease, are increased in black women. In data from the Black Women’s Health Study, a follow-up of US black women, we assessed two SNPs (rs2076530 and rs9268480) previously identified in the BTNL2 gene (chromosome 6p21), of which rs4424066 and rs3817963 are perfect proxies, to determine if they represent independent signals of disease risk. We also assessed whether local ancestry in four genomic regions previously identified through admixture mapping was associated with sarcoidosis. Finally, we assessed the relation of global percent African ancestry to risk. We conducted a nested case–control study of 486 sarcoidosis cases and 943 age- and geography-matched controls. Both BTNL2 SNPs were associated with risk of sarcoidosis in separate models, but in a combined analysis the increased risk was due to the A-allele of the rs3817963 SNP; each copy of the A-allele was associated with a 40 % increase in risk of sarcoidosis (p = 0.02) and was confirmed by our haplotypic analysis. Local African ancestry around the rs30533 ancestry informative marker at chromosome 5q31 was associated with a 29 % risk reduction (p = 0.01). Therefore, we adjusted our analysis of global African ancestry for number of copies of African alleles in rs30533. Subjects in the highest quintile of percent African ancestry had a 54 % increased risk of sarcoidosis. The present results from a population of African-American women support the role of the BTNL2 gene and the 5q31 locus in the etiology of sarcoidosis, and also demonstrate that percent African ancestry is associated with disease risk.
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Abraham C, Cho JH (2009) Inflammatory bowel disease. N Engl J Med 361:2066–2078
ACCESS Research Group (1999) Design of a case control etiologic study of sarcoidosis (ACCESS). ACCESS Research Group. J Clin Epidemiol 52:1173–1186
Adrianto I, Lin CP, Hale JJ, Levin AM, Datta I, Parker R, Adler A, Kelly JA, Kaufman KM, Lessard CJ, Moser KL, Kimberly RP, Harley JB, Iannuzzi MC, Rybicki BA, Montgomery CG (2012) Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility. PLoS ONE 7:e43907
Awotedu AA, George AO, Oluboyo PO, Alabi GO, Onadeko BO, Ogunseyinde O, Aghadiuno PU (1987) Sarcoidosis in Africans: 12 cases with histological confirmation from Nigeria. Trans R Soc Trop Med Hyg 81:1027–1029
Benatar SR (1977) Sarcoidosis in South Africa. A comparative study in Whites, Blacks and Coloureds. S Afr Med J 52:602–606
Benatar SR (1980) A comparative study of sarcoidosis in white, black and coloured South Africans. Alpha Omega Publishing Ltd, Cardiff
Bresnitz EA, Strom BL (1983) Epidemiology of sarcoidosis. Epidemiol Rev 5:124–156
Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, Amtmann D, Bode R, Buysse D, Choi S, Cook K, Devellis R, DeWalt D, Fries JF, Gershon R, Hahn EA, Lai JS, Pilkonis P, Revicki D, Rose M, Weinfurt K, Hays R (2010) The patient-reported outcomes measurement information system (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008. J Clin Epidemiol 63:1179–1194
Coudurier M, Freymond N, Aissaoui S, Calender A, Pacheco Y, Devouassoux G (2009) Homozygous variant rs2076530 of BTNL2 and familial sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 26:162–166
Cozier YC, Palmer JR, Rosenberg L (2004) Comparison of methods for collection of DNA samples by mail in the Black Women’s Health Study. Ann Epidemiol 14:117–122
Cozier YC, Berman JS, Palmer JR, Boggs DA, Serlin DM, Rosenberg L (2011) Sarcoidosis in black women in the United States: data from the Black Women’s Health Study. Chest 139:144–150
Donfack J, Schneider DH, Tan Z, Kurz T, Dubchak I, Frazer KA, Ober C (2005) Variation in conserved non-coding sequences on chromosome 5q and susceptibility to asthma and atopy. Respir Res 6:145
Edmondstone WM, Wilson AG (1985) Sarcoidosis in Caucasians, Blacks and Asians in London. Br J Dis Chest 79:27–36
Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 40:710–712
Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP (1992) CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356:607–609
Ho P, Bruce IN, Silman A, Symmons D, Newman B, Young H, Griffiths CE, John S, Worthington J, Barton A (2005) Evidence for common genetic control in pathways of inflammation for Crohn’s disease and psoriatic arthritis. Arthritis Rheum 52:3596–3602
Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM (2003) Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72:1492–1504
Hosoda Y, Yamaguchi M, Hiraga Y (1997) Global epidemiology of sarcoidosis. What story do prevalence and incidence tell us? Clin Chest Med 18:681–694
Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA (2003) Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med 167:1225–1231
Iannuzzi MC, Iyengar SK, Gray-McGuire C, Elston RC, Baughman RP, Donohue JF, Hirst K, Judson MA, Kavuru MS, Maliarik MJ, Moller DR, Newman LS, Rabin DL, Rose CS, Rossman MD, Teirstein AS, Rybicki BA (2005) Genome-wide search for sarcoidosis susceptibility genes in African-Americans. Genes Immun 6:509–518
Iannuzzi MC, Rybicki BA, Teirstein AS (2007) Sarcoidosis. N Engl J Med 357:2153–2165
International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796
Jacyk WK (1984) Sarcoidosis in the West African. A report of eight Nigerian patients with cutaneous lesions. Trop Geogr Med 36:231–236
James DG, Hosoda Y (1994) Epidemiology. In: James DG (ed) Sarcoidosis and other granulomatous disorders. Marcel Dekker, New York, pp 729–743
Kotler MN, Zwi S (1967) Sarcoidosis in South Africa—clinical manifestations. S Afr Med J 41:615–624
McKeigue PM, Carpenter JR, Parra EJ, Shriver MD (2000) Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations. Ann Hum Genet 64:171–186
McNicol MW, Luce PJ (1985) Sarcoidosis in a racially mixed community. J R Coll Physicians Lond 19:179–183
Milman N, Svendsen CB, Nielsen FC, van Overeem Hansen T (2011) The BTNL2 A allele variant is frequent in Danish patients with sarcoidosis. Clin Respir J 5:105–111
Nguyen T, Liu XK, Zhang Y, Dong C (2006) BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. J Immunol 176:7354–7360
Oluboyo PO, Awotedu AA, Onadeko BO, Ukoly CO (1987) Sarcoidosis presenting as tuberculosis: a case report. East Afr Med J 64:504–507
Onnie C, Fisher SA, King K, Mirza M, Roberts R, Forbes A, Sanderson J, Lewis CM, Mathew CG (2006) Sequence variation, linkage disequilibrium and association with Crohn’s disease on chromosome 5q31. Genes Immun 7:359–365
Pathan S, Gowdy RE, Cooney R, Beckly JB, Hancock L, Guo C, Barrett JC, Morris A, Jewell DP (2009) Confirmation of the novel association at the BTNL2 locus with ulcerative colitis. Tissue Antigens 74:322–329
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Reich D, Patterson N, De Jager PL, McDonald GJ, Waliszewska A, Tandon A, Lincoln RR, DeLoa C, Fruhan SA, Cabre P, Bera O, Semana G, Kelly MA, Francis DA, Ardlie K, Khan O, Cree BA, Hauser SL, Oksenberg JR, Hafler DA (2005) A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 37:1113–1118
Rhodes DA, Stammers M, Malcherek G, Beck S, Trowsdale J (2001) The cluster of BTN genes in the extended major histocompatibility complex. Genomics 71:351–362
Ruiz-Narvaez EA, Rosenberg L, Wise LA, Reich D, Palmer JR (2011) Validation of a small set of ancestral informative markers for control of population admixture in African Americans. Am J Epidemiol 173:587–592
Rybicki BA, Maliarik MJ, Major M, Popovich J Jr, Iannuzzi MC (1998) Epidemiology, demographics, and genetics of sarcoidosis. Semin Respir Infect 13:166–173
Rybicki BA, Iannuzzi MC, Frederick MM, Thompson BW, Rossman MD, Bresnitz EA, Terrin ML, Moller DR, Barnard J, Baughman RP, DePalo L, Hunninghake G, Johns C, Judson MA, Knatterud GL, McLennan G, Newman LS, Rabin DL, Rose C, Teirstein AS, Weinberger SE, Yeager H, Cherniack R (2001a) Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 164:2085–2091
Rybicki BA, Kirkey KL, Major M, Maliarik MJ, Popovich J Jr, Chase GA, Iannuzzi MC (2001b) Familial risk ratio of sarcoidosis in African-American sibs and parents. Am J Epidemiol 153:188–193
Rybicki BA, Maliarik MJ, Poisson LM, Sheffer R, Chen KM, Major M, Chase GA, Iannuzzi MC (2003) The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans. Am J Respir Crit Care Med 167:444–449
Rybicki BA, Hirst K, Iyengar SK, Barnard JG, Judson MA, Rose CS, Donohue JF, Kavuru MS, Rabin DL, Rossman MD, Baughman RP, Elston RC, Maliarik MJ, Moller DR, Newman LS, Teirstein AS, Iannuzzi MC (2005a) A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study. Sarcoidosis Vasc Diffuse Lung Dis 22:115–122
Rybicki BA, Walewski JL, Maliarik MJ, Kian H, Iannuzzi MC (2005b) The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet 77:491–499
Rybicki BA, Levin AM, McKeigue P, Datta I, Gray-McGuire C, Colombo M, Reich D, Burke RR, Iannuzzi MC (2011) A genome-wide admixture scan for ancestry-linked genes predisposing to sarcoidosis in African-Americans. Genes Immun 12:67–77
Scadding JG (1967) Sarcoidosis. Eyre & Spottiswoode, London
Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, Muller-Quernheim J, Schwinger E (2001) Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med 164:840–846
Spagnolo P, Sato H, Grutters JC, Renzoni EA, Marshall SE, Ruven HJ, Wells AU, Tzouvelekis A, van Moorsel CH, van den Bosch JM, du Bois RM, Welsh KI (2007) Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. Tissue Antigens 70:219–227
Stram DO, Leigh Pearce C, Bretsky P, Freedman M, Hirschhorn JN, Altshuler D, Kolonel LN, Henderson BE, Thomas DC (2003) Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals. Hum Hered 55:179–190
Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger D, Brown KK (2011) Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med 183:1524–1530
Valentonyte R, Hampe J, Huse K, Rosenstiel P, Albrecht M, Stenzel A, Nagy M, Gaede KI, Franke A, Haesler R, Koch A, Lengauer T, Seegert D, Reiling N, Ehlers S, Schwinger E, Platzer M, Krawczak M, Muller-Quernheim J, Schurmann M, Schreiber S (2005) Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 37:357–364
Van Lingen B (1961) Sarcoidosis in South Africa. Am Rev Respir Dis 84(5)Pt 2:162
Wijnen PA, Voorter CE, Nelemans PJ, Verschakelen JA, Bekers O, Drent M (2011) Butyrophilin-like 2 in pulmonary sarcoidosis: a factor for susceptibility and progression? Hum Immunol 72:342–347
Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53:79–91
Acknowledgments
This work was supported by Grant K01HL088709 from the National Heart, Lung, and Blood Institute, and grants CA058420 and CA098663 from the Division of Cancer Control and Population Science, National Cancer Institute (http://www.cancercontrol.cancer.gov). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health.
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Cozier, Y., Ruiz-Narvaez, E., McKinnon, C. et al. Replication of genetic loci for sarcoidosis in US black women: data from the Black Women’s Health Study. Hum Genet 132, 803–810 (2013). https://doi.org/10.1007/s00439-013-1292-5
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DOI: https://doi.org/10.1007/s00439-013-1292-5