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NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans

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Abstract

Tuberculosis (TB) has substantial mortality worldwide with 5–10% of those exposed progressing to active TB disease. Studies in mice and humans indicate that the inducible nitric oxide synthase (iNOS) molecule plays an important role in immune response to TB. A mixed case–control association study of individuals with TB, relatives, or close contact controls was performed in 726 individuals (279 case and 166 control African-Americans; 198 case and 123 control Caucasians). Thirty-nine single nucleotide polymorphisms (SNPs) were selected from the NOS2A gene for single SNP, haplotype, and multilocus interaction analyses with other typed candidate genes using generalized estimating equations. In African-Americans, ten NOS2A SNPs were associated with TB. The strongest associations were observed at rs2274894 (odds ratio (OR) = 1.84, 95% confidence interval (CI) [1.23–2.77], p = 0.003) and rs7215373 (OR = 1.67, 95% CI [1.17–2.37], p = 0.004), both of which passed a false discovery rate correction for multiple comparisons (q* = 0.20). The strongest gene–gene interactions were observed between NOS2A rs2248814 and IFNGR1 rs1327474 (p = 0.0004) and NOS2A rs944722 and IFNGR1 rs1327474 (p = 0.0006). Three other SNPs in NOS2A interacted with TLR4 rs5030729 and five other NOS2A SNPs interacted with IFNGR1 rs1327474. No significant associations were observed in Caucasians. These results suggest that NOS2A variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1.

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Acknowledgments

The work in this manuscript was supported by grant number R01 HL068534 from the National Heart, Lung and Blood Institute, National Institutes of Health. Dr. Hamilton acknowledges support from NIH K24-AI001833. We thank the study participants, without whom this study would have been impossible, the North Carolina TB Control Nurse Consultants (Myra Allen, Dee Foster, Julie Luffman and Elizabeth Zeringue) and county TB nurses who referred subjects to the study. We would also like to thank Martha Fletcher, Elizabeth Levine, Earline Little, and Carol Poszik for assistance in recruiting participants in South Carolina, and Courtney Linton, Regina Carney, and Ann Mosher for recruiting participants in North Carolina.

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Authors and Affiliations

  1. Dr. John T. Macdonald Foundation Department of Human Genetics, Miami Institute of Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Ave., BRB 414 (M-860), Miami, FL, 33136, USA

    Digna Rosa Velez, William F. Hulme, Jamie L. Myers, John R. Gilbert & William K. Scott

  2. Department of Medicine, Duke University and V.A. Medical Centers, Durham, NC, USA

    J. Brice Weinberg, Marc C. Levesque & Carol D. Hamilton

  3. Division of Infectious Diseases, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Buenos Aires, Argentina

    Martin E. Stryjewski

  4. Department of Medicine, Hospital F.J. Muñiz, Buenos Aires, Argentina

    Eduardo Abbate & Rosa Estevan

  5. Duke University Medical Center, Durham, NC, USA

    Sara G. Patillo & Carol D. Hamilton

  6. Family Health International, Research Triangle Park, Durham, NC, USA

    Carol D. Hamilton

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  1. Digna Rosa Velez
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  2. William F. Hulme
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  3. Jamie L. Myers
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  4. J. Brice Weinberg
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Correspondence to William K. Scott.

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439_2009_713_MOESM1_ESM.doc

Supplemental Figure A1. NOS2A r 2 linkage disequilibrium plots for control samples. LD plots were generated in Haploview and are presented for controls. Within each triangle is presented the pairwise correlation coefficient (r 2). Standard color code was used for the Haploview LD plots, for r 2 LD plots white (r 2 = 0), shades of grey (0 < r 2 < 1), black (r 2 = 1). Black and red squares without numbers indicate complete LD (r 2 = 1.00 if square is black). Blocks were defined according the Gabriel et al. (2002) algorithm, this algorithm defines a block according to the 95% CI of the D′ value for the pairwise LD between SNPs (Gabriel et al. 2002) (DOC 171 kb)

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Velez, D.R., Hulme, W.F., Myers, J.L. et al. NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans. Hum Genet 126, 643–653 (2009). https://doi.org/10.1007/s00439-009-0713-y

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