Table 2.
Genes, selected mutations and ethambutol MICs in clinical M. tuberculosis isolates
| Gene | Encoded alteration | Fold increase in ethambutol MIC (µg/ml)a (95% CI) |
P valueb |
|---|---|---|---|
| embB nonsynonymous mutations | |||
| All wild type/phylogeneticc | 1.4 (1.2–1.8) | ||
| embB codon 306 | p.Met306Ile | 7.8 (5.7–10.9) | <0.001 |
| p.Met306Val | 12.4 (9.5–16.3) | <0.001 | |
| embB codon 354 | p.Asp354Ala | 3.9 (1.9–8.1) | <0.001 |
| embB codon 406 | p.Gly406Asp | 5.0 (3.3–7.6) | <0.001 |
| p.Gly406Cys | 7.8 (3.8–16.2) | <0.001 | |
| p.Gly406Ser | 7.8 (3.8–16.2) | <0.001 | |
| embB codon 497 | p.Gln497Arg | 7.8 (5.7–10.9) | <0.001 |
| Rv3806c nonsynonymous mutations | |||
| All wild type/phylogenetic | 4.2 (3.0–5.8) | ||
| Rv3806c codon 237 | p.Arg237Cys | 5.4 (1.4–20.9) | 0.014 |
| Rv3806c codon 240 | p.Arg240Cys | 5.4 (1.1–27.8) | 0.042 |
| Rv3806c any nonsynonymous mutations | |||
| All wild type/phylogenetic | 4.1 (2.8–5.9) | ||
| Rv3806c | Any nonsynonymous change |
3.6 (1.6–8.1) | 0.001 |
| Rv3792 synonymous or nonsynonymous mutations | |||
| All wild type/phylogenetic | 5.3 (3.6–7.8) | ||
| Rv3792 | Any synonymous or nonsynonymous change |
0.7 (0.3–2.1) | 0.55 |
| embC nonsynonymous mutations | |||
| All wild type/phylogenetic | 5.0 (3.5–7.2) | ||
| embC codon 779 | p.Ala779Val | 2.3 (0.3–15.6) | 0.40 |
| nuoD nonsynonymous mutations | |||
| All wild type/phylogenetic | 5.3 (3.7–7.6) | ||
| nuoD codon 428 | p.Val428Ile | –d | >0.999 |
| Select embB mutations and any nonsynonymous Rv3806c mutation | |||
| All wild type/phylogenetic | 1.4 (1.2–1.8) | ||
| embB codon 306 | p.Met306Ile | 7.9 (5.8–10.6) | <0.001 |
| p.Met306Val | 11.1 (8.7–14.2) | <0.001 | |
| embB codon 354 | p.Asp354Ala | 3.9 (1.9–7.9) | <0.001 |
| embB codon 406 | p.Gly406Asp | 4.6 (3.1–6.6) | <0.001 |
| p.Gly406Cys | 7.9 (3.9–15.9) | <0.001 | |
| p.Gly406Ser | 5.8 (2.8–12.1) | <0.001 | |
| embB codon 497 | p.Gln497Arg | 7.4 (5.4–10.1) | <0.001 |
| embB codon 1082 | p.Thr1082Ala | 2.0 (1.2–3.3) | 0.011 |
| Rv3806c | Any nonsynonymous change |
1.4e (1.1–1.7) | 0.009 |
Fold increase in the geometric mean ethambutol MIC compared to the MIC for the group comprising wild-type strains and those with SNPs representing phylogenetic markers (wild type/phylogenetic). For example, the geometric mean ethambutol MIC for the EmbB p.Met306Ile alteration is 1.4 × 7.8 = 10.92 µg/ml, whereas, for the Rv3806c p.Arg237Cys alteration, the geometric mean ethambutol MIC is 4.2 × 5.4 = 22.68 µg/ml.
Pairwise P values unadjusted for multiple comparisons comparing strains with mutations to the wild-type/phylogenetic strains.
Reverse-transformed intercept. This provides the MIC for those without mutations at any of the codons included in the model; for example, in the first model, the estimated mean MIC for an individual without embB mutations at codons 306, 354, 406, 497, 853, 1073 and 1082 is 1.4 µg/ml.
When CIs were broad, parameter estimates were omitted but P values are provided.
Additional fold increase in ethambutol MIC in a model with select embB and Rv3806c mutations. For example, the geometric mean MIC for an M. tuberculosis isolate containing both an EmbB p.Met306Val alteration and an Rv3806c alteration (any nonsynonymous change) would be 1.4 × 11.1 × 1.4 = 21.76 µg/ml.