Fig 1.
Genetic association of the PKLR SNPs with mycobacterial diseases in the studied population.
Only the homozygous genotypes for the association, considered as “risk genotypes”, for the co-dominant (cod) and recessive (rec) models were represented for visualization purposes. The complete data of the individual SNPs are detailed in S3 Table. X-axis shows the Odds Ratio (OR) given in a linear scale. Red and gray dots with 95% confidence interval (CI) represented the significant (p<0.05) and borderline (0.05≤p≤0.07) associations, respectively. Black dots with 95% CI represented no association. RIO = Rio de Janeiro (Southeast Brazil); SAL = Salvador (Northeast Brazil); ROO = Rondonópolis (Midwest Brazil); MAN = Manaus (North Brazil); BRA = all Brazilians (meta-analysis) and MOZ = Mozambique (East Africa).
Table 1.
Haplotype frequencies in the PKLR genomic region within populations and association with leprosy and TB.
Table 2.
Linkage disequilibrium between the SNPs associated with leprosy and the 25 SNPs with a suggestive selection sweep in European population by the cross-population xpEHH.
Fig 2.
Serum iron, ferritin and haptoglobin levels among genotypes of the SNP rs1052176 by gender.
Bars represent the median. Measurements in healthy subjects (Control) and leprosy patients (Case). Analysis were performed using Kruskal-Wallis test (p<0.05). F = Female; M = Male.
Fig 3.
Putative mechanism of mycobacterial infection in the presence of the PKLR risk haplotype.
The scheme illustrates the possible pathway that led to increase in ferritin levels and consequently M. leprae persistence inside macrophages. We hypothesized that the RBCs of T/G/G individuals could speed the hemolysis rate of erythrocytes with low levels of PK. Because of the hemoglobin (Hb) release, haptoglobin (Hp) is increased and the complex Hp-Hb internalizes heme inside macrophages via CD163. Heme-oxigenase 1 (HO-1) cleaves heme into iron, which is stored inside ferritin. Hemolysis is a common mechanism that occur in homeostasis to prevent oxidative stress. However, it can be enhanced in the presence of genetic determinants (PKLR T/G/G haplotype), leading to a subtle iron overload and a possible advantage for mycobacterial growth.