Evidence for cis-eQTL in stimulated <i>versus</i> non-stimulated cells.

<p>For each gene, we plotted the SNP with the lowest <i>P</i> value obtained under an additive model in one condition (stimulated or non-stimulated) against the <i>P</i> value obtained under the alternative condition. Red and grey dashed lines correspond to the 0.01 and to the 0.5 FDR to classify response eQTL (reQTL). Green dots are general cis-eQTL (found in both conditions). Blue dots are reQTL specific to cells stimulated with <i>M</i>. <i>leprae</i> sonicate while pink dots are reQTL specific to untreated cells. For this figure, reQTL are variants that exhibit a significant <i>P</i> value for genotype-phenotype association in one condition at an FDR of 0.01 and not in the other condition at an FDR of 0.5 (without taking the entire 200-kb tested regions per gene into account). The orange cloud corresponds to all the variants detected as being cis-eQTL at an FDR of 0.01.</p

Evidence for cis-eQTL in stimulated <i>versus</i> non-stimulated cells.

<p>For each gene, we plotted the SNP with the lowest <i>P</i> value obtained under an additive model in one condition (stimulated or non-stimulated) against the <i>P</i> value obtained under the alternative condition. Red and grey dashed lines correspond to the 0.01 and to the 0.5 FDR to classify response eQTL (reQTL). Green dots are general cis-eQTL (found in both conditions). Blue dots are reQTL specific to cells stimulated with <i>M</i>. <i>leprae</i> sonicate while pink dots are reQTL specific to untreated cells. For this figure, reQTL are variants that exhibit a significant <i>P</i> value for genotype-phenotype association in one condition at an FDR of 0.01 and not in the other condition at an FDR of 0.5 (without taking the entire 200-kb tested regions per gene into account). The orange cloud corresponds to all the variants detected as being cis-eQTL at an FDR of 0.01.</p

LRRK2 variants preferentially associated with T1R.

<p>LRRK2 variants preferentially associated with T1R.</p

Host versus pathogen control of <i>LRRK2</i> expression levels.

<p><i>LRRK2</i> expression levels for 53 unrelated subjects are indicated on the y-axis and stratified according to rs2404580 genotypes on the x-axis. The left panel represents baseline expression while the right panel indicates gene expression levels following stimulation with <i>M</i>. <i>leprae</i> antigen.</p

Family based sample and study design.

<p>Two sets of families were employed: those with T1R-affected offspring and those with leprosy but T1R-free offspring. The T1R-affected subset comprised 229 offspring belonging to 221 families while the T1R-free subset comprised 229 offspring in 209 families. Offspring were matched by clinical leprosy subtype in the two family sets. In a first analysis stage, the transmission disequilibrium test (TDT) was used to estimate significance of association of <i>LRRK2</i> variants with disease in each subset. In a second stage, a formal heterogeneity test was performed to identify <i>LRRK2</i> variants preferentially associated with T1R.</p

Haplotype analysis of independent signal of association with T1R.

<p>Haplotype analysis of independent signal of association with T1R.</p

Multivariate analysis of <i>LRRK2</i> variants with T1R

<p>Multivariate analysis of <i>LRRK2</i> variants with T1R</p

Proposed mechanism for LRRK2 in T1R.

<p>The LRRK2 M2397T amino acid substitution affects protein turnover. The methionine variant of LRRK2 displays a half-life of approximately 8 hours while the half-life of the threonine variant is 18 hours [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref034" target="_blank">34</a>]. LRRK2 arrests the NFAT transcription factor in the cytoplasm through a complex mechanism mediated by Ca²⁺ [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref036" target="_blank">36</a>]. This prevents NFAT to migrate to the nucleus and trigger the expression of pro-inflammatory cytokines [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref035" target="_blank">35</a>]. The M2397 allele is in tight linkage disequilibrium with alleles of SNPs that promote an increase in <i>LRRK2</i> expression creating a compensatory mechanism to counterbalance the shorter LRRK2-M2397 half-life. This compensatory mechanism is abrogated in the presence of <i>M</i>. <i>leprae</i> antigen. Hence, the effect of the M2397T amino acid substitution is most pronounced in the presence of <i>M</i>. <i>leprae</i> antigen.</p

Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases

<div><p>After sustained exposure to <i>Mycobacterium leprae</i>, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This “polarization” of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes.</p><p>Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy.</p></div

Studies identifying 28 genes associated with clinical forms of leprosy or its polarization.

<p>Studies identifying 28 genes associated with clinical forms of leprosy or its polarization.</p