Limits...
Tuberculin skin test negativity is under tight genetic control of chromosomal region 11p14-15 in settings with different tuberculosis endemicities.

Cobat A, Poirier C, Hoal E, Boland-Auge A, de La Rocque F, Corrard F, Grange G, Migaud M, Bustamante J, Boisson-Dupuis S, Casanova JL, Schurr E, Alcaïs A, Delacourt C, Abel L - J. Infect. Dis. (2014)

Bottom Line: A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 × 10(-5)) in close vicinity of TST1.Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15.This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.

View Article: PubMed Central - PubMed

Affiliation: McGill International TB Centre Department of Human Genetics Department of Medicine, McGill University, Montreal, Canada.

Show MeSH

Related in: MedlinePlus

Genome-wide model-free linkage analysis of tuberculin skin test negativity (TST induration diameter, 0 mm vs >0 mm) in the French (A) and the combined French and South-African samples (B). Multipoint evidence of linkage expressed as a classical LOD score (black line; left y-axis) and the information content (red line; right y-axis) are plotted along the 22 autosomes. The 2 dotted horizontal lines indicate the formal cutoffs for genome-wide suggestive or significant linkage. C, Expanded view of the region with the highest LOD score in the combined analysis (y-axis) along chromosome 11 from 0 to 40 Mb (x-axis). The multipoint evidence of linkage (black line) and information content at marker positions (red line) are given. Left and right y-axes indicate the LOD score and information content, respectively. A blue diamond indicates the TNF1 locus position. D, Multipoint evidence of linkage in the combined sample restricted to 114 families contributing to the linkage peak on 11p14-15. A family was considered as contributing positively to the linkage peak when the maximal positive LOD score contribution was greater than the absolute value of the maximal negative LOD score contribution within the 10–33-Mb interval on chromosome 11. A blue diamond indicates the TNF1 locus position. Abbreviation: TNF, tumor necrosis factor.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4279780&req=5

JIU446F1: Genome-wide model-free linkage analysis of tuberculin skin test negativity (TST induration diameter, 0 mm vs >0 mm) in the French (A) and the combined French and South-African samples (B). Multipoint evidence of linkage expressed as a classical LOD score (black line; left y-axis) and the information content (red line; right y-axis) are plotted along the 22 autosomes. The 2 dotted horizontal lines indicate the formal cutoffs for genome-wide suggestive or significant linkage. C, Expanded view of the region with the highest LOD score in the combined analysis (y-axis) along chromosome 11 from 0 to 40 Mb (x-axis). The multipoint evidence of linkage (black line) and information content at marker positions (red line) are given. Left and right y-axes indicate the LOD score and information content, respectively. A blue diamond indicates the TNF1 locus position. D, Multipoint evidence of linkage in the combined sample restricted to 114 families contributing to the linkage peak on 11p14-15. A family was considered as contributing positively to the linkage peak when the maximal positive LOD score contribution was greater than the absolute value of the maximal negative LOD score contribution within the 10–33-Mb interval on chromosome 11. A blue diamond indicates the TNF1 locus position. Abbreviation: TNF, tumor necrosis factor.

Mentions: Second, from the French sample, 97 nuclear families, including 237 offspring, were informative for linkage analysis (ie, composed of at least 2 genotyped sibs with a TST value). Characteristics of the 237 offspring are shown in Supplementary Table 1. Among them, only 4 had not received BCG vaccine, eliminating BCG vaccination as a potential confounding factor in our study. Results of the GWLA of TST-bin adjusted on the covariates are presented in Figure 1A. Information content was high across all autosomes, with mean genome-wide information of approximately 90%. We identified 1 major locus, at position 14.3 Mb on chromosomal region 11p15, that reached the threshold commonly used to claim genome-wide significance (LOD score, 3.65; P = 2.08 × 10−5; Figure 1A). In addition, we identified 18 weaker linkage peaks with a P value of <.01 (Supplementary Table 2).Figure 1.


Tuberculin skin test negativity is under tight genetic control of chromosomal region 11p14-15 in settings with different tuberculosis endemicities.

Cobat A, Poirier C, Hoal E, Boland-Auge A, de La Rocque F, Corrard F, Grange G, Migaud M, Bustamante J, Boisson-Dupuis S, Casanova JL, Schurr E, Alcaïs A, Delacourt C, Abel L - J. Infect. Dis. (2014)

Genome-wide model-free linkage analysis of tuberculin skin test negativity (TST induration diameter, 0 mm vs >0 mm) in the French (A) and the combined French and South-African samples (B). Multipoint evidence of linkage expressed as a classical LOD score (black line; left y-axis) and the information content (red line; right y-axis) are plotted along the 22 autosomes. The 2 dotted horizontal lines indicate the formal cutoffs for genome-wide suggestive or significant linkage. C, Expanded view of the region with the highest LOD score in the combined analysis (y-axis) along chromosome 11 from 0 to 40 Mb (x-axis). The multipoint evidence of linkage (black line) and information content at marker positions (red line) are given. Left and right y-axes indicate the LOD score and information content, respectively. A blue diamond indicates the TNF1 locus position. D, Multipoint evidence of linkage in the combined sample restricted to 114 families contributing to the linkage peak on 11p14-15. A family was considered as contributing positively to the linkage peak when the maximal positive LOD score contribution was greater than the absolute value of the maximal negative LOD score contribution within the 10–33-Mb interval on chromosome 11. A blue diamond indicates the TNF1 locus position. Abbreviation: TNF, tumor necrosis factor.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4279780&req=5

JIU446F1: Genome-wide model-free linkage analysis of tuberculin skin test negativity (TST induration diameter, 0 mm vs >0 mm) in the French (A) and the combined French and South-African samples (B). Multipoint evidence of linkage expressed as a classical LOD score (black line; left y-axis) and the information content (red line; right y-axis) are plotted along the 22 autosomes. The 2 dotted horizontal lines indicate the formal cutoffs for genome-wide suggestive or significant linkage. C, Expanded view of the region with the highest LOD score in the combined analysis (y-axis) along chromosome 11 from 0 to 40 Mb (x-axis). The multipoint evidence of linkage (black line) and information content at marker positions (red line) are given. Left and right y-axes indicate the LOD score and information content, respectively. A blue diamond indicates the TNF1 locus position. D, Multipoint evidence of linkage in the combined sample restricted to 114 families contributing to the linkage peak on 11p14-15. A family was considered as contributing positively to the linkage peak when the maximal positive LOD score contribution was greater than the absolute value of the maximal negative LOD score contribution within the 10–33-Mb interval on chromosome 11. A blue diamond indicates the TNF1 locus position. Abbreviation: TNF, tumor necrosis factor.
Mentions: Second, from the French sample, 97 nuclear families, including 237 offspring, were informative for linkage analysis (ie, composed of at least 2 genotyped sibs with a TST value). Characteristics of the 237 offspring are shown in Supplementary Table 1. Among them, only 4 had not received BCG vaccine, eliminating BCG vaccination as a potential confounding factor in our study. Results of the GWLA of TST-bin adjusted on the covariates are presented in Figure 1A. Information content was high across all autosomes, with mean genome-wide information of approximately 90%. We identified 1 major locus, at position 14.3 Mb on chromosomal region 11p15, that reached the threshold commonly used to claim genome-wide significance (LOD score, 3.65; P = 2.08 × 10−5; Figure 1A). In addition, we identified 18 weaker linkage peaks with a P value of <.01 (Supplementary Table 2).Figure 1.

Bottom Line: A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 × 10(-5)) in close vicinity of TST1.Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15.This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.

View Article: PubMed Central - PubMed

Affiliation: McGill International TB Centre Department of Human Genetics Department of Medicine, McGill University, Montreal, Canada.

Show MeSH
Related in: MedlinePlus