The +3187A/G HLA‐G polymorphic site is associated with polar forms and reactive reaction in leprosy

Abstract

Considering that variability in immune response genes has been associated with susceptibility to leprosy and with disease severity, leprosy presents clinicopathological variants that are highly associated with the immune response, HLA-G has a well-recognized role in the modulation of the immune response, and polymorphisms at the 3′ untranslated region (UTR) of the HLA-G gene may influence HLA-G production, we studied the polymorphic sites at the 3′ UTR of the HLA-G gene in leprosy and their association with disease severity. We evaluated by sequencing analysis the allele, genotype, and haplotype frequencies of the 3′ UTR HLA-G polymorphic sites (14-bpINDEL/+3003C-T/+3010C-G/+3027A-C/+3035C-T/+3142C-G/+3187A-G/+3196C-G) in 146 individuals presenting reactive leprosy from a highly endemic area, and associated with bacillary load and the type of reactive leprosy. A total of 128 healthy subjects were also studied. Allele, genotype, and haplotype frequencies for the 3′ UTR HLA-G polymorphisms in leprosy patients did not differ from those observed in healthy donors. The +3187A allele was responsible for protection against the development of multibacillary leprosy in a dominant model (AA + AG)/GG, OR = 0.11, P = 0.018), and the +3187A allele and +3187A-A genotype were overrepresented in type II reactive leprosy reaction. The effect of genetic factors on leprosy susceptibility may be hidden by environmental components in highly endemic areas. The HLA-G + 3187A polymorphic site, which is related to unstable mRNA production, was associated with the development of polar forms of leprosy and reactive leprosy reaction.

Immunogenetics of prostate cancer and benign hyperplasia – the potential use of an HLA‐G variant as a tag SNP for prostate cancer risk

“…A perfect LD (D′ = 1; r 2 = 1) was observed between the SNP +3010C/G and +3142G/C ( P < 0.001) in control and BPH groups, and also between 14 bp Ins/Del and +3027A/C ( P < 0.001) in PCa group (data not shown). LD was not observed among the SNP +3003 T/C and +3027A/C (in control and BPH groups) or +3035C/T (in control group), corroborating data for these polymorphic sites in others studies . Altogether, our results suggest a strong LD between HLA‐G 3′UTR polymorphic sites.…”

“…As the 3′UTR is a regulatory region encompassing genetic variants that influence HLA‐G mRNA availability and stability as well as determine differential binding of specific microRNAs, it is very important to evaluate such variants in patients with prostate tumors . In the Southern Brazilian population assessed in this study, strong LD between HLA‐G 3′UTR polymorphic sites was observed, corroborating previous data . Seven haplotypes here identified (UTR‐1 to ‐7) among the three studied groups (control, BPH and PCa) correspond to frequent haplotypes previously described to worldwide populations .…”

Advances in the Immunology and Genetics of Leprosy

“…Leprosy-associated class II HLA genes include HLA-DQA1 in Brazilians (123), HLA-DQB1 * 06 and HLA-DQB1 * 07 in Mestizo populations (121), HLA-DRB1 * 11 in Brazilians (124), HLA-DRB1 * 1501 in Chinese and Indians (125,126), and HLA-DRB1 * 1501 in Indians (125,126). In addition, other antigen-processing and presentation-related genes were found to be associated with leprosy, such as the MICA gene (127), MICB gene (127), HLA-G gene (128), and TAP1 gene (129). Interestingly, even in the same population, some HLA genes showed susceptibility to leprosy and others showed resistance to leprosy, which indicated that some HLA molecules could activate T cells by presenting M. leprae antigens, while others are responsible for the T cell anergy in leprosy (121).…”

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

“…Other associations have only been found once, and the implication of the tested genes in leprosy pathogenesis must be considered with caution: IFNγ and HLA-G in Brazil [ 63 , 64 ]; TLR4 and leukotriene A4 hydrolase ( LTA4H ) in Ethiopia [ 65 , 66 ]; vitamin D receptor ( VDR) [ 67 , 68 ], killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 3 ( KIR2DS3 ) [ 69 ], heat shock protein 1A ( HSPA1A ), and IL-23R in India [ 70 , 71 ]; lymphotoxin-α ( LTA ) in Malawi [ 53 ]; complement fraction 4 ( C4A ) in Thailand [ 72 ]; IL-12B in Mexico [ 73 ]; IL-12RB2 in Japan [ 74 ]; natural resistance-associated macrophage protein 1 ( NRAMP1 ) in Mali [ 75 ]; laminin 2 ( LAMA2 ) in Indonesia [ 76 ]; defensin-β1 ( DEFB1 ) in Mexico [ 77 ]; and optic atrophy 1 ( OPA1 ) in China [ 78 ]. Interestingly, for VDR, one study identified a polymorphism associated with leprosy when comparing MB to PB [ 67 ], while a second study identified a haplotype when comparing MB to controls and another haplotype when comparing PB to controls [ 68 ].…”