Research Article: Influence of Genetic Ancestry on INDEL Markers of NFKβ1, CASP8, PAR1, IL4 and CYP19A1 Genes in Leprosy Patients

Date Published: September 14, 2015

Publisher: Public Library of Science

Author(s): Pablo Pinto, Claudio Salgado, Ney Pereira Carneiro Santos, Sidney Santos, Ândrea Ribeiro-dos-Santos, Christian Johnson.

Abstract: BackgroundLeprosy is an insidious infectious disease caused by the obligate intracellular bacteria Mycobacterium leprae, and host genetic factors can modulate the immune response and generate distinct categories of leprosy susceptibility that are also influenced by genetic ancestry.Methodology/Principal FindingsWe investigated the possible effects of CYP19A1 [rs11575899], NFKβ1 [rs28362491], IL1α [rs3783553], CASP8 [rs3834129], UGT1A1 [rs8175347], PAR1 [rs11267092], CYP2E1 [INDEL 96pb] and IL4 [rs79071878] genes in a group of 141 leprosy patients and 180 healthy individuals. The INDELs were typed by PCR Multiplex in ABI PRISM 3130 and analyzed with GeneMapper ID v3.2. The NFKβ1, CASP8, PAR1 and IL4 INDELs were associated with leprosy susceptibility, while NFKβ1, CASP8, PAR1 and CYP19A1 were associated with the MB (Multibacilary) clinical form of leprosy.Conclusions/SignificanceNFKβ1 [rs28362491], CASP8 [rs3834129], PAR1 [rs11267092] and IL4 [rs79071878] genes are potential markers for susceptibility to leprosy development, while the INDELs in NFKβ1, CASP8, PAR1 and CYP19A1 (rs11575899) are potential markers for the severe clinical form MB. Moreover, all of these markers are influenced by genetic ancestry, and European contribution increases the risk to leprosy development, in other hand an increase in African contribution generates protection against leprosy.

Partial Text: Leprosy is an insidious infectious disease caused by the obligate intracellular bacteria Mycobacterium leprae that affects the skin and peripheral nerves, causing a chronic granulomatous infection [1]. Leprosy patients may be classified in two major groups, based on clinical manifestations using a simple system introduced by the WHO (World Health Organization) in 1982. Paucibacillary (PB) is the primary characteristic of Tuberculoid (TT) leprosy and is characterized by a few lesions and scarce bacilli, and Multibacillary (MB) is the primary characteristic of anergic Lepromatous (LL) leprosy. From an epidemiological perspective, the situation in Brazil is critical because, along with India and Indonesia, it has the highest rate of new cases detected worldwide [2, 3, 4].

The data of clinical and demographic distribution of leprosy patients and healthy individuals is shown in Table 1. The mean age was higher in healthy individuals (55.7±12 versus 43.3±21, p<0.001), and male patients were more frequent among leprosy patients (97 [68.8%] versus 65 [36.1%], p<0.001). Analysis of ethnicity showed that the mean frequency of Africans was higher among leprosy patients (0.284 versus 0.236, p<0.001) and Europeans were more frequent in healthy individuals (0.461 versus 0.427, p = 0.004). NF-κB belongs to family of protein transcription factors that modulate many inflammatory processes. In the resting state, IκBα (inhibitor of NF-kβ activity) sequesters NF-κB in the cytoplasm and prevents its activity, but in response to specific stimuli, IkBα is ubiquitinated and degraded allowing NF-kB to migrate to the nucleus and stimulate the transcription of proinflammatory genes [19,20]. The allele DEL (rs28362491) has been shown to be associated with a decrease of transcriptional activity of variety genes of immune response [21] and with auto immune disease such as Systemic Sclerosis [22] and lupus erythematosus [23]. Source:


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