Polymorphisms in Genes Coding for the NK-Cell Receptor NKG2D and its Ligand MICA in Recurrent Miscarriage

Hizem, Sondes; Mtiraoui, Nabil; Massaoudi, Safia; Fortier, Catherine; Boukouaci, Wahid; Amokrane, Kahina; Charron, Dominique; Mahjoub, Touhami; Tamouza, Ryad

doi:10.1111/aji.12314

Cited by 9 publications

(16 citation statements)

References 30 publications

(34 reference statements)

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“…A SNP in a NK receptor gene NKG2D was associated with lower risk of recurrent miscarriages in women (Hizem et al . ). These studies demonstrate that SNPs within these genes can have an adaptive role in other mammals; therefore, these SNPs in the devil may also have adaptive potential.…”

Section: Discussionmentioning

confidence: 97%

“…Also in humans, a nonsynonymous SNP in FASLG has been associated with autoimmune lymphoproliferative syndrome (Bi et al 2007) and SNPs in the intron of FASLG have been associated with increased risk of cutaneous malignant melanoma (Li et al 2006) and HIV progression (Nasi et al 2005). A SNP in a NK receptor gene NKG2D was associated with lower risk of recurrent miscarriages in women (Hizem et al 2014). These studies demonstrate that SNPs within these genes can have an adaptive role in other mammals; therefore, these SNPs in the devil may also have adaptive potential.…”

Section: Snp Diversity Across Devil Immune Genesmentioning

confidence: 99%

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Lack of genetic diversity across diverse immune genes in an endangered mammal, the Tasmanian devil (Sarcophilus harrisii)

et al. 2015

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The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction due to the spread of devil facial tumour disease. Polymorphisms in immune genes can provide adaptive potential to resist diseases. Previous studies in diversity at immune loci in wild species have almost exclusively focused on genes of the major histocompatibility complex (MHC); however, these genes only account for a fraction of immune gene diversity. Devils lack diversity at functionally important immunity loci, including MHC and Toll-like receptor genes. Whether there are polymorphisms at devil immune genes outside these two families is unknown. Here, we identify polymorphisms in a wide range of key immune genes, and develop assays to type single nucleotide polymorphisms (SNPs) within a subset of these genes. A total of 167 immune genes were examined, including cytokines, chemokines and natural killer cell receptors. Using genome-level data from ten devils, SNPs within coding regions, introns and 10 kb flanking genes of interest were identified. We found low polymorphism across 167 immune genes examined bioinformatically using whole-genome data. From this data, we developed long amplicon assays to target nine genes. These amplicons were sequenced in 29-220 devils and found to contain 78 SNPs, including eight SNPS within exons. Despite the extreme paucity of genetic diversity within these genes, signatures of balancing selection were exhibited by one chemokine gene, suggesting that remaining diversity may hold adaptive potential. The low functional diversity may leave devils highly vulnerable to infectious disease, and therefore, monitoring and preserving remaining diversity will be critical for the long-term management of this species. Examining genetic variation in diverse immune genes should be a priority for threatened wildlife species. This study can act as a model for broad-scale immunogenetic diversity analysis in threatened species.

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Section: Discussionmentioning

confidence: 97%

Section: Snp Diversity Across Devil Immune Genesmentioning

confidence: 99%

Lack of genetic diversity across diverse immune genes in an endangered mammal, the Tasmanian devil (Sarcophilus harrisii)

et al. 2015

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“…Three studies investigated infections or their complications, i.e., HBV infection and HBV-induced HCC (34), left ventricular systolic dysfunction (LVSD) in chronic Chargas heart disease (38), and ocular toxoplasmosis (39). One study investigated an association of the MICA-129Met/Val dimorphism with recurrent miscarriage (40). The two studies on HSCT (36, 37) investigated besides relapse also other outcomes including graft-versus-host disease (GVHD).…”

Section: Mica-129met/val Disease Association Studiesmentioning

confidence: 99%

“…Three studies, on recurrent miscarriage (40), ocular toxoplasmosis (39), and malignant melanoma (35), failed to demonstrate an association with the SNP. Thus, 81% of the studies showed an association at least for a subgroup, e.g., juvenile AS, whereas in all patients with AS, the association was dependent on HLA-B27 (26), or a sub-phenotype, e.g., severe LVSD (38).…”

Section: Mica-129met/val Disease Association Studiesmentioning

confidence: 99%

Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

et al. 2016

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The major histocompatibility complex (MHC) class I chain-related A (MICA) is the most polymorphic non-classical MHC class I gene in humans. It encodes a ligand for NKG2D (NK group 2, member D), an activating natural killer (NK) receptor that is expressed mainly on NK cells and CD8+ T cells. The single-nucleotide polymorphism (SNP) rs1051792 causing a valine (Val) to methionine (Met) exchange at position 129 of the MICA protein is of specific interest. It separates MICA into isoforms that bind NKG2D with high (Met) and low affinities (Val). Therefore, this SNP has been investigated for associations with infections, autoimmune diseases, and cancer. Here, we systematically review these studies and analyze them in view of new data on the functional consequences of this polymorphism. It has been shown recently that the MICA-129Met variant elicits a stronger NKG2D signaling, resulting in more degranulation and IFN-γ production in NK cells and in a faster costimulation of CD8+ T cells than the MICA-129Val variant. However, the MICA-129Met isoform also downregulates NKG2D more efficiently than the MICA-129Val isoform. This downregulation impairs NKG2D-mediated functions at high expression intensities of the MICA-Met variant. These features of the MICA-129Met/Val dimorphism need to be considered when interpreting disease association studies. Particularly, in the field of hematopoietic stem cell transplantation, they help to explain the associations of the SNP with outcome including graft-versus-host disease and relapse of malignancy. Implications for future disease association studies of the MICA-129Met/Val dimorphism are discussed.

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“…It has been reported that MICA rs1051792 affects the affinity of binding MICA molecules to the NKG2D receptor and NKG2D signalling [35,36]. The role of this SNP has been investigated in studies regarding malignant diseases [35,37,38], pathogen infections [38][39][40], recurrent miscarriage [41] as well as autoimmune disorders, including RA [42][43][44], ankylosing spondylitis (AS) [45], type I diabetes [46], inflammatory bowel disease (IBD) [47,48], systemic lupus erythematosus [44] and psoriasis [49]. However, in accordance to our knowledge, the significance of MICA polymorphism with respect to the effectiveness of anti-TNF biological drugs in the treatment of RA has not been investigated to date.…”

Section: Introductionmentioning

confidence: 99%

Association of MICA-129Met/Val polymorphism with clinical outcome of anti-TNF therapy and MICA serum levels in patients with rheumatoid arthritis

et al. 2020

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MHC class I polypeptide-related sequence A (MICA) is a stress-induced protein involved in activation of NK and T cells through interaction with NKG2D receptor. These molecules are atypically expressed in synovium of patients diagnosed with rheumatoid arthritis (RA). A total of 279 patients with RA, qualified to TNF-blockade therapy, were genotyped for MICA rs1051792 SNP. The effectiveness of anti-TNF agents was assessed with European League Against Rheumatism criteria. Significant relationship between MICA rs1051792 and outcome of TNF-blockade therapy has been found. The MICA rs1051792 GG genotype was overrepresented in patients non-responsive to anti-TNF drugs in comparison with other genotypes (p = 0.010). On the other hand, beneficial therapeutic response was more frequently detected among RA subjects possessing heterozygous genotype than those with homozygous genotypes (p = 0.003). Furthermore, increased MICA concentrations in serum were observed in patients possessing MICA rs1051792 GG genotype as compared with those with GA or AA genotypes (p = 1.8 × 10 −5). The results from this study indicate the potential influence of MICA rs1051792 polymorphism on modulation of therapeutic response to TNF-blockade treatment in RA.

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Polymorphisms in Genes Coding for the NK-Cell Receptor NKG2D and its Ligand MICA in Recurrent Miscarriage

Abstract: The NKG2D gene polymorphisms may influence the success of pregnancy in Tunisian women.

Cited by 9 publications

References 30 publications

Lack of genetic diversity across diverse immune genes in an endangered mammal, the Tasmanian devil (Sarcophilus harrisii)

Lack of genetic diversity across diverse immune genes in an endangered mammal, the Tasmanian devil (Sarcophilus harrisii)

Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

Association of MICA-129Met/Val polymorphism with clinical outcome of anti-TNF therapy and MICA serum levels in patients with rheumatoid arthritis

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