Date Published: May 24, 2016
Publisher: Public Library of Science
Author(s): Jean Gaschignard, Audrey Virginia Grant, Nguyen Van Thuc, Marianna Orlova, Aurélie Cobat, Nguyen Thu Huong, Nguyen Ngoc Ba, Vu Hong Thai, Laurent Abel, Erwin Schurr, Alexandre Alcaïs, Christian Johnson. http://doi.org/10.1371/journal.pntd.0004345
Abstract: After sustained exposure to Mycobacterium leprae, 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.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.
Partial Text: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, with over 200,000 new cases detected each year, often leading to severe disabilities and social stigma. After sustained exposure to M. leprae, only a subset of individuals develops clinical leprosy. From the early observations of familial aggregation of leprosy cases to the most recent genome-wide association studies identifying genetic polymorphisms associated with leprosy, there is strong evidence that the development of the disease is under tight human genetic control [1,2]. The interest in the genetics of leprosy is reflected by the continuous increase in the number of genetic publications (host and pathogen), while publications on immunology of leprosy have decreased significantly after 1980 .
No epidemiological study specifically dealing with MB or PB leprosy has been published. Therefore, we based our approach on more general epidemiological studies of leprosy per se that included information on MB and PB forms. The vast majority of recent epidemiological studies focused on the contacts of an index leprosy case to identify risk factors for the occurrence of secondary cases [17–21]. In this setting, subgroup analysis of clinical forms is not very powerful, given the low number of such secondary cases: indeed, the detection rate of new cases is often less than 1% after 4 years of follow-up, requiring 10,000 contacts to ultimately study 100 secondary leprosy cases [18,19]. Since there is minimal variability within the genome of M. leprae, [22–24], pathogen factors are unlikely to contribute to clinical variability. Therefore, we restricted our explorations to host-related risk factors: sex, age, geographical origin, and bacille Calmette-Guérin (BCG) vaccination status.
There are many methodological tools in genetic epidemiology that can be used according to the hypotheses to be tested and the nature of the data. Their main characteristics are summarized in S1 Table . A number of approaches do not require any biological material and rely only on the information and the knowledge of the familial relationships. These DNA-independent studies are of particular interest in the context of neglected tropical diseases and knowledge transfer to endemic countries: they are easier to implement and intrinsically technology-independent (i.e., their cost has remained low). The following section illustrates how such DNA-independent methods have contributed to our current understanding of the genetics of leprosy subtypes.
The number of genes for which a variant has been associated in one of leprosy’s subtypes or its polarization (39 associations in 28 genes) (Table 1) is shorter than for leprosy per se (82 associations in 50 genes). Fig 3 summarizes the distribution of the associations according to leprosy phenotypes. Several scenarios may explain the difference. First, since most studies were conducted in samples used for leprosy per se studies, by design patient numbers for subtype analysis were smaller than for leprosy per se, resulting in lower power to detect genetic variants impacting on leprosy subtype. This is consistent with the fact that most reported associations concerned the MB form, which is more common in endemic countries except India. Second, an inadequate definition of MB and PB forms can also lead to a loss of power, as illustrated by the study of IL-17F . Third, most studies analyzing leprosy polarization did not account for demographic risk factors: yet, the study of leprosy per se has revealed that the inclusion of these covariates was essential (e.g., the association of leprosy per se with PARK2 or LTA was three to five times stronger in young patients [86,87]).
Here, we summarized the accumulated evidence for susceptibility genes acting at the polarization level that do not influence the onset of leprosy disease. We highlighted that precise phenotype characterization is crucial for the identification of genes driving polarization. Since there is no conventional animal model for leprosy while armadillo is not widely available, the “reverse genetics” approach through genetic epidemiology remains an attractive strategy to decipher the physiopathology of this neglected tropical disease, of which polarization is a major aspect. Importantly, such progress can only come from a close collaboration between physicians, biologists, epidemiologists, and geneticists. Leprosy, so long a cause of social isolation and stigmatization of those who suffer the disease, will only be eradicated by a joint effort of all components of the scientific community.