Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2012

Open Access 01-12-2012 | Research article

A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians

Authors: Eileen Png, Bachti Alisjahbana, Edhyana Sahiratmadja, Sangkot Marzuki, Ron Nelwan, Yanina Balabanova, Vladyslav Nikolayevskyy, Francis Drobniewski, Sergey Nejentsev, Iskandar Adnan, Esther van de Vosse, Martin L Hibberd, Reinout van Crevel, Tom HM Ottenhoff, Mark Seielstad

Published in: BMC Medical Genetics | Issue 1/2012

Login to get access

Abstract

Background

There is reason to expect strong genetic influences on the risk of developing active pulmonary tuberculosis (TB) among latently infected individuals. Many of the genome wide linkage and association studies (GWAS) to date have been conducted on African populations. In order to identify additional targets in genetically dissimilar populations, and to enhance our understanding of this disease, we performed a multi-stage GWAS in a Southeast Asian cohort from Indonesia.

Methods

In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian samples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In stage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals from the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB association in an independent Caucasian cohort (n = 3,760) from Russia.

Results

Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal significance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1, DYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4.

Conclusions

Mechanisms of immune defense suggested by some of the identified genes exhibit biological plausibility and may suggest novel pathways involved in the host containment of infection with TB.
Appendix
Available only for authorised users
Literature
1.
2.
Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C: The growing burden of tuberculosis: global trends and interactions with the HIV epidemics. Arch Intern Med. 2003, 163 (9): 1009-1021. 10.1001/archinte.163.9.1009.CrossRefPubMed
3.
Vynnycky E, Fine PE: Lifetime risks, incubation period, and serial interval of tuberculosis. Am J Epidemiol. 2000, 152 (3): 247-263. 10.1093/aje/152.3.247.CrossRefPubMed
4.
Kallmann FJ, Reisner D: Twin Studies on the significance of genetic factors in tuberculosis. Am Rev Tuberc. 1943, 47: 549-574.
5.
Bellamy R, Beyers N, McAdam KP, Ruwende C, Gie R, Samaai P, Bester D, Meyer M, Corrah T, Collin M, Camidge DR, Wilkinson D, Hoal-Van Helden E, Whittle HC, Amos W, van Helden P, Hill AV: Genetic Susceptibility to Tuberculosis in Africans: A Genome Wide Scan. Proc Natl Acad Sci USA. 2000, 97 (14): 8005-8009. 10.1073/pnas.140201897.CrossRefPubMedPubMedCentral
6.
Jepson A, Fowler A, Banya W, Singh M, Bennett S, Whittle H, Hill AV: Genetic Regulation of Acquired Immune Responses to Antigens of Mycobacterium Tuberculosis: A Study of Twins in West Africa. Infect Immun. 2001, 69 (6): 3989-3994. 10.1128/IAI.69.6.3989-3994.2001.CrossRefPubMedPubMedCentral
7.
Baghdadi JE, Orlova M, Alter A, Ranque B, Chentoufi M, Lazrak F, Archane MI, Casanova JL, Benslimane A, Schurr E, Abel L: An Autosomal Dominant Major Gene Confers Predisposition to Pulmonary Tuberculosis in Adults. J Exp Med. 2006, 203 (7): 1679-1684. 10.1084/jem.20060269.CrossRefPubMedPubMedCentral
8.
Pan H, Yan BS, Rojas M, Shebzukhov YV, Zhou H, Kobzik L, Higgins DE, Daly MJ, Bloom BR, Kramnik I: Ipr1 gene mediates innate immunity to tuberculosis. Nature. 2005, 434 (7034): 767-772. 10.1038/nature03419.CrossRefPubMedPubMedCentral
9.
Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, Cui Y, Yan XX, Yang HT, Yang RD, Chu TS, Zhang C, Zhang L, Han JW, Yu GQ, Quan C, Yu YX, Zhang Z, Shi BQ, Zhang LH, Cheng H, Wang CY, Lin Y, Zheng HF, Fu XA, Zuo XB, Wang Q, Long H, Sun YP, Cheng YL, Tian HQ, Zhou FS, Liu HX, Lu WS, He SM, Du WL, Shen M, Jin QY, Wang Y, Low HQ, Erwin T, Yang NH, Li JY, Zhao X, Jiao YL, Mao LG, Yin G, Jiang ZX, Wang XD, Yu JP, Hu ZH, Gong CH, Liu YQ, Liu RY, Wang DM, Wei D, Liu JX, Cao WK, Cao HZ, Li YP, Yan WG, Wei SY, Wang KJ, Hibberd ML, Yang S, Zhang XJ, Liu JJ: Genomewide association study of leprosy. N Engl J Med. 2009, 361 (27): 2609-2618. 10.1056/NEJMoa0903753.CrossRefPubMed
10.
Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, Sirugo G, Sisay-Joof F, Enimil A, Chinbuah MA, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, Ngwira B, Teo YY, Small K, Rockett K, Kwiatkowski D, Fine PE, Hill PC, Newport M, Lienhardt C, Adegbola RA, Corrah T, Ziegler A, African TB Genetics Consortium, Wellcome Trust Case Control Consortium, Morris AP, Meyer CG, Horstmann RD, Hill AV: Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18 q11.2. Nat Genet. 2010, 42 (9): 739-741. 10.1038/ng.639.CrossRefPubMed
11.
Matsuzaki H, Dong S, Loi H, Di X, Liu G, Hubbell E, Law J, Berntsen T, Chadha M, Hui H, Yang G, Kennedy GC, Webster TA, Cawley S, Walsh PS, Jones KW, Fodor SP, Mei R: Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nat Methods. 2004, 1 (2): 109-111. 10.1038/nmeth718.CrossRefPubMed
12.
Sahiratmadja E, Alisjahbana B, de Boer T, Adnan I, Maya A, Danusantoso H, Nelwan RH, Marzuki S, van der Meer JW, van Crevel R, van de Vosse E, Ottenhoff TH: Dynamic changes in pro- and anti-inflammatory cytokine profiles and gamma interferon receptor signaling integrity correlate with tuberculosis disease activity and response to curative treatment. Infect Immun. 2007, 75 (2): 820-829. 10.1128/IAI.00602-06.CrossRefPubMed
13.
Alisjahbana B, van Crevel R, Sahiratmadja E, den Heijer M, Maya A, Istriana E, Danusantoso H, Ottenhoff TH, Nelwan RH, van der Meer JW: Diabetes mellitus is strongly associated with tuberculosis in Indonesia. Int J Tuberc Lung Dis. 2006, 10 (6): 696-700.PubMed
14.
Sahiratmadja E, Baak-Pablo R, de Visser AW, Alisjahbana B, Adnan I, van Crevel R, Marzuki S, van Dissel JT, Ottenhoff TH, van de Vosse E: Association of polymorphisms in IL-12/IFN-γ pathway genes with susceptibility to pulmonary tuberculosis in Indonesia. Tuberculosis. 2007, 87 (4): 303-311. 10.1016/j.tube.2007.02.001.CrossRefPubMed
15.
Szeszko JS, Healy B, Stevens H, Balabanova Y, Drobniewski F, Todd JA, Nejentsev S: Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis. Hum Genet. 2007, 121 (2): 155-160. 10.1007/s00439-006-0293-z.CrossRefPubMed
16.
Rabbee N, Speed TP: A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics. 2006, 22 (1): 7-12. 10.1093/bioinformatics/bti741.CrossRefPubMed
17.
Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS: A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet. 2005, 37 (5): 549-554. 10.1038/ng1547.CrossRefPubMed
18.
Purcell S, Cherny SS, Sham PC: Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003, 19 (1): 149-150. 10.1093/bioinformatics/19.1.149.CrossRefPubMed
19.
Devlin B, Roeder K: Genomic control for association studies. Biometrics. 1999, 55 (4): 997-1004. 10.1111/j.0006-341X.1999.00997.x.CrossRefPubMed
20.
Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, Feldman MW: Genetic Structure of Human Populations. Science. 2002, 298 (5602): 2381-2385. 10.1126/science.1078311.CrossRefPubMed
21.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006, 38 (8): 904-909. 10.1038/ng1847.CrossRefPubMed
22.
Davila S, Hibberd ML, Hari Dass R, Wong HE, Sahiratmadja E, Bonnard C, Alisjahbana B, Szeszko JS, Balabanova Y, Drobniewski F, van Crevel R, van de Vosse E, Nejentsev S, Ottenhoff TH, Seielstad M: Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet. 2008, 4 (10): e1000218-10.1371/journal.pgen.1000218.CrossRefPubMedPubMedCentral
23.
Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, Malasky MJ, Scafe C, Le E, De Jager PL, Mignault AA, Yi Z, De The G, Essex M, Sankale JL, Moore JH, Poku K, Phair JP, Goedert JJ, Vlahov D, Williams SM, Tishkoff SA, Winkler CA, De La Vega FM, Woodage T, Sninsky JJ, Hafler DA, Altshuler D, Gilbert DA, O'Brien SJ, Reich D: A High Density Admixture Map for Disease Gene Discovery in African Americans. Am J Hum Genet. 2004, 74 (5): 1001-1013. 10.1086/420856.CrossRefPubMedPubMedCentral
24.
Voight BF, Pritchard JK: Confounding from Cryptic Relatedness in Case-Control Association Studies. PLoS Genet. 2005, 1 (3): e32-10.1371/journal.pgen.0010032.CrossRefPubMedPubMedCentral
25.
26.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81 (3): 559-575. 10.1086/519795.CrossRefPubMedPubMedCentral
27.
Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G: Fringe Glycosyltransferases Differentially Modulate Notch1 Proteolysis Induced by Delta1 and Jagged1. Mol Biol Cell. 2005, 16 (2): 927-942.CrossRefPubMedPubMedCentral
28.
Narayana Y, Balaji KN: NOTCH1 Upregulation and Signaling Involved in Mycobacterium Bovis BCG Induced SOCS3 Expression in Macrophages. J Biol Chem. 2008, 283 (18): 12501-12511. 10.1074/jbc.M709960200.CrossRefPubMed
29.
Nutt SL, Kee BL: The Transcriptional Regulation of B Cell Lineage Commitment. Immunity. 2007, 26 (6): 715-725. 10.1016/j.immuni.2007.05.010.CrossRefPubMed
30.
Cobaleda C, Schebesta A, Delogu A, Busslinger M: Pax5 the Guardian of B Cell Identity and Function. Nat Immunol. 2007, 8 (5): 463-470. 10.1038/ni1454.CrossRefPubMed
31.
32.
Ali N, Knaüper V: Phorbol ester-induced shedding of the prostate cancer marker transmembrane protein with epidermal growth factor and two follistatin motifs 2 is mediated by the disintegrin and metalloproteinase-17. J Biol Chem. 2007, 282 (52): 37378-37388. 10.1074/jbc.M702170200.CrossRefPubMed
33.
Parr-Sturgess CA, Rushton DJ, Parkin ET: Ectodomain shedding of the Notch ligand Jagged1 is mediated by ADAM17, but is not a lipid-raft-associated event. Biochem J. 2010, 432 (2): 283-294. 10.1042/BJ20100321.CrossRefPubMed
34.
Baumgart A, Seidl S, Vlachou P, Michel L, Mitova N, Schatz N, Specht K, Koch I, Schuster T, Grundler R, Kremer M, Fend F, Siveke JT, Peschel C, Duyster J, Dechow T: ADAM17 regulates epidermal growth factor receptor expression through the activation of Notch1 in non-small cell lung cancer. Cancer Res. 2010, 70 (13): 5368-5378. 10.1158/0008-5472.CAN-09-3763.CrossRefPubMed
35.
Pruessmeyer J, Martin C, Hess FM, Schwarz N, Schmidt S, Kogel T, Hoettecke N, Schmidt B, Sechi A, Uhlig S, Ludwig A: A disintegrin and metalloproteinase 17 (ADAM17) mediates inflammation-induced shedding of syndecan-1 and -4 by lung epithelial cells. J Biol Chem. 2010, 285 (1): 555-564. 10.1074/jbc.M109.059394.CrossRefPubMed
36.
Chiu BC, Freeman CM, Stolberg VR, Komuniecki E, Lincoln PM, Kunkel SL, Chensue SW: Cytokine-Chemokine Networks in Experimental Mycobacterial and Schistosomal Pulmonary Granuloma Formation. Am J Respir Cell Mol Biol. 2003, 29 (1): 106-116. 10.1165/rcmb.2002-0241OC.CrossRefPubMedPubMedCentral
37.
Li X, Yang Y, Zhou F, Zhang Y, Lu H, Jin Q, Gao L: SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. PLoS One. 2011, 6 (1): e15831-10.1371/journal.pone.0015831.CrossRefPubMedPubMedCentral
38.
Teixeira MA, Silva NL, Ramos Ade L, Hatagima A, Magalhães V: NRAMP1 gene polymorphisms in individuals with leprosy reactions attended at two reference centers in Recife, northeastern Brazil. Rev Soc Bras Med Trop. 2010, 43 (3): 281-286.PubMed
39.
Barrett JC, Cardon LR: Evaluating coverage of genome-wide association studies. Nat Genet. 2006, 38 (6): 659-662. 10.1038/ng1801.CrossRefPubMed
40.
Nicolae DL, Wen X, Voight BF, Cox NJ: Coverage and characteristics of the Affymetrix GeneChip Human Mapping 100 K SNP set. PLoS Genet. 2006, 2 (5): e67-10.1371/journal.pgen.0020067.CrossRefPubMedPubMedCentral
41.
Casanova JL, Abel L: Genetic Dissection of Immunity to Mycobacteria: The Human Model. Annu Rev Immunol. 2002, 20: 581-620. 10.1146/annurev.immunol.20.081501.125851.CrossRefPubMed
42.
Ottenhoff TH, Verreck FA, Lichtenauer-Kaligis EG, Hoeve MA, Sanal O, van Dissel JT: Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet. 2002, 32 (1): 97-105. 10.1038/ng0902-97.CrossRefPubMed
Metadata
Title
A genome wide association study of pulmonary tuberculosis susceptibility in Indonesians
Authors
Eileen Png
Bachti Alisjahbana
Edhyana Sahiratmadja
Sangkot Marzuki
Ron Nelwan
Yanina Balabanova
Vladyslav Nikolayevskyy
Francis Drobniewski
Sergey Nejentsev
Iskandar Adnan
Esther van de Vosse
Martin L Hibberd
Reinout van Crevel
Tom HM Ottenhoff
Mark Seielstad
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2012
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-13-5

Other articles of this Issue 1/2012

BMC Medical Genetics 1/2012 Go to the issue

Research article

The combined effect of the T2DM susceptibility genes is an important risk factor for T2DM in non-obese Japanese: a population based case-control study

Research article

Influence of IL17A polymorphisms on the aberrant methylation of DAPK and CDH1 in non-cancerous gastric mucosa

Research article

A novel SYBR-based duplex qPCR for the detection of gene dosage: detection of an APC large deletion in a familial adenomatous polyposis patient with an unusual phenotype

Research article

Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

Research article

Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome"

Research article

The C allele of JAK2 rs4495487 is an additional candidate locus that contributes to myeloproliferative neoplasm predisposition in the Japanese population