Solute Carrier Family 11 Member A1 Research Articles

Systemic assessment of solute carrier family 11-member A1 (rs17235409) gene polymorphism and Mycobacterium Tuberculosis Risk in Asian and caucasian population: A comprehensive updated meta-analysis.

The present meta-analysis was assessed to confirm the association between solute carrier family 11-member A1 (SLC11A1) gene (rs17235409) polymorphism with the Mycobacterium tuberculosis infection in the Asian and Caucasian populations. A search was conducted using the databases including Google Scholar, Science Direct, Embase, and PubMed to find the case-control studies related to SLC11A1 gene polymorphism and tuberculosis (TB) infection. The MetaGenyo programme was used to perform statistical analyses of the data. The odds ratio and 95% confidence interval were calculated based on genetic models such as allelic model, dominant model, recessive model, and overdominant. The heterogeneity and publication bias for the present study were examined to assess its quality. The study was registered in PROSPERO (ID Number: 461434). This current study revealed the association between the SLC11A1 gene polymorphism with TB. The statistical value obtained at P < 0.05 was deemed to be statistically significant. The meta-analysis results revealed that allele contrast and recessive models are significant association between SLC11A1 gene polymorphism with risk of TB infections, and dominant and overdominant models have no significant association with TB risk. In addition, the subgroup analysis based on the ethnicity dominant revealed a significant association with the risk of TB. Therefore, this results that the gene SLC11A1 has a significant association for allelic and recessive and has no significant association for dominant and overdominant with the risk of TB. According to the data retrieved from the database with respect to the present study revealed that SLC11A1 gene polymorphism rs17235409 for allelic, recessive models have been associated with TB infections, but dominant and overdominant models have not been associated with TB infections.

PHYLOGENETIC STUDY OF SLC11A1 GENE IN DOMESTIC ANIMALS

Solute carrier family 11-member a1 gene (SLC11a1) previously is a functionalmember of metal ion-transport protein, earlier known as natural resistance-associated macrophageprotein 1 (NRAMP1). The cellular expression of this gene is restricted to phagocytic cells. Thefunction of this gene is to transport bivalent metal cations from the cytosol. The complex reaction ofFenon and Haber-Weiss of this gene reacts toxic antimicrobial radicals against microorganisms. Thisstudy investigates the evolutionary divergence of the SLC11a1 gene in domesticated farm animals.SLC11a1 gene sequences of domesticated farm animals were retrieved from NCBI GenBank. Theresults of this study revealed that there was substantial genetic variation in aligned sequences of theSLC11a1 gene within selected species. One ns-mutation (Q312K) was found in this study which isharmful. The phylogenetic trees showed some form of differentiation in the SLC11a1 gene sequence.The information on SLC11a1 polymorphism might be used to associate with disease resistance of farmanimals in Pakistan.

Microsatellite markers reveal polymorphisms at the 3′ untranslated region of theSLC11A1gene in Zhongdian Yellow cattle (Bos taurus)

Solute carrier family 11-member A1 (SLC11A1) gene encodes natural macrophage resistance-associated protein which regulates activity of macrophages against intracellular pathogens. The objective of this study was to study the polymorphism in the microsatellites present at 3′ untranslated region (UTR) of the SLC11A1 gene in 113 Zhongdian Yellow cattle (Bos taurus). Using DNA bi-directional sequencing, we detected seven alleles (GT10–16) for the first microsatellite (MS1), five alleles (GT12–16) for MS2, and four alleles (GT4–7) for MS3. MS3 is studied for the first time and revealed four novel variants (alleles GT4–7). Alleles GT12 (45.1%), GT13 (59.3%), and GT5 (85.4%) were the most frequent alleles at MS1, MS2, and MS3, respectively, Genotypes G12/12, G13/13, and G5/5 had the highest frequency 0.239, 0.540, and 0.743 at MS1, MS2, and MS3, respectively. Haplotypic data revealed that GT12/GT13 was the most frequent haplotype observed followed by GT12/14 haplotype. Three nucleotide variations were observed in MS1 and MS2. Comparative analysis of GT12/GT12 and GT13/GT13 genotype with other bovine genotypes showed significant difference (P &gt; 0.05). Our results suggest that the homozygous genotypes GT12/GT12 and GT13/GT13 in Zhongdian Yellow cattle might be related to disease resistance. The findings reported in this study would be helpful in cattle breeding programs.

Sequence characterization, structural analysis, SNP detection and expression profiling of SLC11A1 gene in Indian goats

The Solute Carrier Family 11 Member A1 (SLC11A1) is a candidate gene, encodes a divalent cation transporter, SLC11A1 protein, localizes in the phagolysosome membrane in macrophages, essential for immunity and resistance to intracellular pathogens. The indigenous goats of Kerala are known for disease resistance and adaptability, but the underlying genetic causes are to be unraveled. This study comprised of characterization of the caprine SLC11A1 gene, to detect SNPs and compare the relative abundance of SLC11A1 mRNA by quantitative-PCR in native goats (Attappady Black and Malabari) and crossbreds. The 1702 bp cDNA of SLC11A1 comprised of 15 exons, an ORF of 1647 bp, encoding a protein of 548 amino acids. SLC11A1 amino acid sequence was 83–99% identical to that of other species. SLC11A1 peptide contains 10 serine and 2 threonine phosphorylation loci and 12 transmembrane domains. The study indicated the presence of four synonymous and three non-synonymous mutations (p.Ile132Thr; p.Phe294Leu; p.Gln541His). The amino acid substitution p.Ile132Thr was deleterious and p.Phe294Leu and p.Gln541His were neutral. p.Phe294Leu was located in the 7th transmembrane helix. The relative abundance of the SLC11A1 mRNA in leukocytes in Malabari and Attappady Black were significantly higher than crossbreds (P < 0.01). The significantly higher SLC11A1 expression in native goats indicates higher disease resistance than crossbreds, gives an insight into the necessity of conservation of native breeds, important role of SLC11A1 in disease resistance. The detected SNPs would benefit the use of this gene as a candidate gene for disease resistance in goat breeding programs.

Evaluation of the association of SLC11A1 gene polymorphism with incidence of paratuberculosis in goats.

Paratuberculosis is one of the chronic granulomatous enteritis that predominantly affects ruminants world wide, caused by Mycobacterium avium ssp. paratuberculosis (MAP). In ruminants, microsatellite polymorphisms of the 3' untranslated region (3'UTR) of the solute carrier family 11 member A1 (SLC11A1) gene were associated with resistance to intracellular pathogen infections. This research was carried out to detect the polymorphisms in A and B regions of the 3'UTR of SLC11A1 gene and to evaluate the potential association between these polymorphisms and MAP infection in goats. MAP-specific antibodies were detected by ELISA and MAP infection was confirmed by IS900 PCR in 150 adult goats from different regions of Kerala, India. The polymorphism of microsatellite regions A and B at 3'UTR of the SLC11A1 gene was analysed in goats by an automated technique, fragment analysis, using fluorescent-tagged forward primers. Eight alleles with sizes ranging from 221 to 239 bp were found in region A. Region B revealed two alleles, 117 bp (B₇) and 119 bp (B₈). Animals with B₈ alleles were found to have higher incidence of paratuberculosis than animals with B₇ alleles (P < 0.01). There was no statistically significant association found between region A genotypes and paratuberculosis incidence. These results suggest that caprine SLC11A1 gene has significant role in paratuberculosis resistance in goats and further studies might help in development of a PCR-based genotyping test for paratuberculosis resistance and selection of superior animals for future goat breeding programmes.

Sequencing and phylogenetic analysis of the SLC11A1 gene in pigs

ABSTRACTThe solute carrier family 11 member A1 (SLC11A1), also known as natural resistance-associated macrophage protein 1 (NRAMP1), is a divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. To study the genetic diversity of the SLC11A1 gene in Doom pigs of Assam especially on its evolution and differentiation within and among species, the partial sequence of the SLC11A1 gene was sequenced, characterized and compared with other published sequences of pigs and other species livestock. The gene sequence of Doom pigs showed the highest sequence identity with EF200584.1 (exotic pig) and the lowest similarity AY368475.1 (large white strain 008). One single nucleotide polymorphism (SNP) was identified in the heterozygous sequence at the 736 bp position (A→G). The sequence showed the highest sequence identity (81.74%) with that of O. aries and the lowest similarity (39.12%) with B. bubalis (Mehsana breed), respectively. Phylogenetic analysis revealed that the Doom pig is more closely related to EU135795.1 (Chinese local pig) and EF200584.1 (Pig, Iowa State University). The sequencing and phylogenetic analysis of the SLC11A1 gene of Doom pigs could be used for genetic selection with disease-resistance varieties and upgradation of indigenous germplasm of domestic livestock.

Characterisation of exon 9 of solute carrier family 11 member A1 gene in Vechur cattle

The solute carrier family 11 member A1 (SLC11A1) gene has been associated with natural resistance to intracellular pathogens such as Brucella, Salmonella, Leishmania and Mycobacterium in several species including bovine and plays a critical role in elimination of pathogens by generating hydroxyl free radicals. The objective of the present study was to investigate the polymorphism in exon 9 of SLC11A1 gene in Vechur cattle, one of the dwarf cattle of India which is known for its disease resistance. A 198 bp fragment containing exon 9 of the gene was amplified by polymerase chain reaction (PCR). The amplicons upon single strand conformation polymorphism (SSCP) analysis revealed two different banding patterns. A novel non synonymous SNP (g.46C&gt;T) with predominance of CC genotype was also detected in Vechur cattle. These results suggest that there exists a considerable genetic variation at SLC11A1 locus and further association studies may help in development of a PCR based genotyping assay to select cattle with better immunity to intracellular pathogens.

Polymorphisms at the 3′ untranslated region of SLC11A1 gene are associated with protection to Brucella infection in goats

Goats are susceptible to brucellosis and the detection of Brucella-infected animals is carried out by serological tests. In other ruminant species, polymorphisms in microsatellites (Ms) of 3′ untranslated region (3′UTR) of the solute carrier family 11 member A1 (SLC11A1) gene were associated with resistance to Brucella abortus infection. Goats present two polymorphic Ms at the 3′UTR end of SLC11A1 gene, called regions A and B. Here, we evaluated if polymorphisms in regions A and/or B are associated with Brucella infection in goats. Serum (for the detection of Brucella-specific antibodies) and hair samples (for DNA isolation and structure analysis of the SLC11A1 gene) were randomly collected from 229 adult native goats from the northwest of Argentina. Serological status was evaluated by buffer plate antigen test (BPAT) complemented by the fluorescent polarization assay (FPA), and the genotype of the 3′UTR of the SLC11A1 gene was determined by capillary electrophoresis and confirmed by sequence analysis. Polymorphisms in regions A and B of the 3′UTR SLC11A1 gene were found statistically significant associated with protection to Brucella infection. Specifically, the association study indicates statistical significance of the allele A15 and B7/B7 genotype with absence of Brucella-specific antibodies (p=0.0003 and 0.0088, respectively). These data open a promising opportunity for limiting goat brucellosis through selective breeding of animals based on genetic markers associated with natural resistance to B. melitensis infection.

Genetic association analysis of paratuberculosis forms in holstein-friesian cattle.

A genetic susceptibility to Mycobacterium avium subsp. paratuberculosis (MAP) infections in ruminants has been longtime suspected to exist. Recently, natural infections in cattle have been reclassified into latent and patent forms based on histopathological findings and their associations with immunological and microbiological variables. This study aims to explore whether these newly defined phenotypes are associated with twenty-four single-nucleotide polymorphisms (SNPs) in six bovine candidate genes: nucleotide-binding oligomerization domain 2 (NOD2), solute carrier family 11 member A1 (SLC11A1), nuclear body protein SP110 (SP110), toll-like receptors (TLRs) 2 and 4, and CD209 (also known as DC-SIGN, dendritic cell-specific ICAM3-grabbing nonintegrin). SNPs were genotyped for 772 Holstein-Friesian animals (52.6% apparently free; 38.1% latent; 9.3% patent) by TaqMan OpenArray technology. Genotypic-phenotypic associations were assessed by logistic regression analysis adjusted for age at slaughter, under five models (codominant, dominant, recessive, overdominant, and log-additive), and corrected for multiple testing. The rs208222804 C allele (CD209 gene) was found to be associated with latent paratuberculosis (log-additive model: P < 0.0034 after permutation procedure; OR = 0.64, 95% CI = 0.48–0.86). No significant association was detected between any SNP and the patent phenotype. Consequently, CD209 gene may play a key role in the pathogenesis of bovine paratuberculosis.

In vitro expression of the SLC11A1 gene in goat monocyte-derived macrophages challenged with Mycobacterium avium subsp paratuberculosis

Johne’s disease or paratuberculosis is a chronic, progressive intestinal disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). One of the genes that have been targeted with regard to resistance or sensitivity to paratuberculosis is the SLC11A1 (solute carrier family 11 member A1). Here we extend our previous work to the sequence and structure analysis of the caprine SLC11A1 gene and we assess the functional impact of the most frequent polymorphisms of the 3′ UTR region of the SLC11A1 gene to its expression in goat macrophages exposed in vitro to MAP. The role of these polymorphisms in primary immune response is also investigated with connection to gene expression of two interleukins (IL), one of which pro (IL-1a), and the other anti-inflammatory (IL-10). In order to assess gene response, quantitative detection of the SLC11A1, IL-10 and IL1a mRNA was performed by real time PCR before, and at 1, 3 and 24h after exposure of primary cultures of peripheral blood monocyte-derived macrophages to MAP, collected from 54 goats of the Greek native goat breed. Sequence analysis of the 3′ UTR end of the caprine SLC11A1 gene determined its full length to be 522 bases. Structure analysis confirmed the presence of two microsatellites consisted of a variable number of guanine-thymine repeats (regions A and B). The homozygous B7 genotype [B(GTn)7/7] was associated at a statistically significant level with increased expression of the SLC11A1 and IL-1α genes indicating increased in vitro responsiveness and therefore resistance of mononuclear derived macrophages to MAP infection.

The role of monocytes and SLC11A1 polymorphisms in the pathogenesis of Chlamydia-induced reactive arthritis

Objectives: To investigate the role that monocytes and solute carrier family 11 member A1 (SLC11A1) gene polymorphisms play in the pathogenesis of reactive arthritis (ReA).Methods: SLC11A1 274C/T and 823C/T polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The phagocytic activity of monocytes was analysed by flow cytometry after they were co-cultured with Chlamydia trachomatis. The inclusions in the monocytes were demonstrated by immunohistochemistry staining. Bactericidal activity was determined by immunofluorescence staining with the recovered inclusions.Results: There was no significant difference in the phagocytic activity of monocytes between the ReA patients and healthy controls. The bactericidal activity of monocytes from the healthy controls was more efficient than that from the ReA patients. The patients with SLC11A1 823T tended to have a higher bactericidal activity of monocytes than those with SLC11A1 823 C/C. Moreover, the bactericidal activity of monocytes in the patients with SLC11A1 274T seemed to decrease in comparison with that in the patients with SLC11A1 274C/C.Conclusions: The bactericidal activity of monocytes in patients with ReA is lower than that in healthy controls. The SLC11A1 274C/T and 823C/T polymorphisms may be associated with the decreased bactericidal activity of the monocytes.

Genetic analysis of the 3′ untranslated region of the bovine SLC11A1 gene reveals novel polymorphisms

Polymorphisms in microsatellites at the 3' untranslated region (3'UTR) of the SLC11A1 (solute carrier family 11 member A1) gene have been associated with natural resistance to Brucella abortus and Mycobacterium bovis infection in livestock species. Here, we carried out an individual genetic analysis of the two microsatellites present at the 3'UTR SLC11A1 gene in 254 Bos taurus purebred, 125 B. indicus purebred and 54 B. taurus × B. indicus crossbred cattle. The genotyping by capillary electrophoresis showed the presence of four alleles (157, 159, 161 and 163) for the first microsatellite (MS1) and six alleles (175, 177, 179, 181, 183 and 185) for the second microsatellite (MS2). The alleles 159 and 175 were the most frequent in all breeds analyzed. B. taurus showed the most homogeneous haplotype and genotype for both microsatellites, whereas B. indicus showed the most heterogeneous haplotype and genotype. Two novel variants (alleles 161 and 163) within the MS1 are reported as well as novel variants in MS2 in Holstein breed. The knowledge of the polymorphisms distribution in both microsatellites at the 3'UTR of the SLC11A1 gene in cattle breeds is useful for future experimental design to evaluate the association between reported genotypes and natural resistance to pathogens infection.

Role of SLC11A1 gene in disease resistance

Genetic improvement in livestock was achieved earlier by selective breeding of individuals with superior phenotypes. Now due to the advances in molecular genetics and biotechnology candidate genes of economic traits can be included in selection for breeding programmes. Genes responsible for the resistance/susceptibility to infections with various pathogens (Major Histo Compatibility (MHC) genes, Solute Carrier family11 member A1 (SLC11A1) gene, Toll Like Receptor (TLR) genes etc.), have been recently identified and characterized in human beings as well as in many animals. Among these the role of SLC11A1 gene is very important due to its association with resistance/ susceptibility to various intracellular pathogens in human as well as in livestock species. The SLC11A1 gene, formerly known as natural resistance-associated macrophage protein 1 (NRAMP1) encodes an integral membrane protein regulating the activity of macrophages. Genetic resistance/ susceptibility to diseases due to candidate gene polymorphisms could be used in selection and breeding for disease resistance in animals.

Chromosomal localisation and genetic variation of the SLC11A1 gene in goats (Capra hircus)

The solute carrier family 11 member A1 (SLC11A1) gene is associated with resistance to infectious diseases. Chromosomal localisation, genomic regions corresponding to functional domains and the genetic variability of microsatellites in the 3' untranslated region (3'-UTR) of this gene were investigated in 427 goats (Capra hircus) of six breeds. Using dual colour fluorescence in situ hybridisation, SLC11A1 was localised to goat chromosome 2. Single strand conformation polymorphism was used to screen for polymorphisms in SLC11A1 exons 2, 10 and 15. There was no variation among goat breeds in the sarcoma homology 3 (SH3) binding motif, the protein kinase C phosphorylation site or the two N-linked glycosylation sites. Exon 15 exhibited variability due to the presence of two polymorphic microsatellites. Genotyping of the upstream guanine-thymine repeat (GTn) at 3'-UTR revealed eight alleles (GT11, GT12, GT14-GT19) in goats, whereas GT13 (present in cattle) was absent. Most goats carried the GT16 allele and no allele was found to be exclusive to only one breed. The coefficient of genetic differentiation value (G(ST)) was 0.084. This microsatellite appears to be an informative DNA marker for genetic linkage analysis in goats.

Investigation of the association of the SLC11A1 gene with resistance/sensitivity of goats ( Capra hircus) to paratuberculosis

SLC11A1 (solute carrier family 11 member A1) protein is located on the phagolysosome membrane of macrophages and participates in bacterial killing. Here we have extended our previous work on the investigation of the potential association of polymorphisms of the 3′untranslated region (UTR) of SLC11A1 gene with test-positivity of goats to Mycobacterium avium subsp. paratuberculosis (MAP). Blood, serum and faeces were collected from 223 adult goats, from nine goat farms from Greece with a long-term record of paratuberculosis but no vaccination or tuberculin testing. The samples were subjected to sequence and structure analysis of the SLC11A1 gene and were evaluated by ELISA, culture and real time polymerase chain reaction. The 3′UTR region of the targeted gene revealed 2 microsatellites consisting of a variable number of guanine-thymine repeats named regions A and B. Statistically significant association was recorded between genotypes of region B and ELISA results, whereas the presence of B 7 allele was found to contribute to ELISA negativity. The comparison of the SLC11A1 mRNA level pre- and post-exposure to MAP shows elevated gene expression especially at the 3-h time point, in all macrophages tested regardless of their genotype. Unfortunately the latter could not be linked at a statistically significant level with any of the targeted genetic polymorphisms separately. In conclusion it can be stated that the evidence reported here provide the first indications on the association of B genotypes of the SLC11A1 gene and the detection of MAP-specific antibody by ELISA in goats.

Association of SLC11A1 promoter polymorphisms with the incidence of autoimmune and inflammatory diseases: A meta-analysis

Solute carrier family 11 member a1 ( SLC11A1) exerts pleiotropic effects on macrophage function. Expression of SLC11A1 is regulated by a (GT) n microsatellite promoter repeat polymorphism of which nine alleles have been described. Enhanced activation of macrophages, associated with increased expression from allele 3, may be functionally linked to the development of autoimmune and inflammatory diseases. Conversely, low expression, driven by allele 2, may afford resistance. We have performed a meta-analysis to determine the association of SLC11A1 promoter alleles 2 and 3 with autoimmunity and inflammation. A random effects pooled odds ratio (OR) of 1.04 (95% confidence interval [CI] = 0.20) for allele 3 suggested a weak association of this allele with an increased risk of disease. Calculation of the OR in the absence of asymmetry yielded a random effects pooled OR of 0.88 (95% CI = 0.66), effectively reversing the above association. A fixed effects pooled OR of 0.90 (95% CI = 0.24) was obtained for allele 2, suggesting a weak predominance of disease in the absence of this allele. Application of the trim-and-fill method resulted in a fixed effects OR of 0.80 (95% CI = 0.22), thus strengthening this association. Associations of allele 3 with autoimmune and inflammatory diseases reported in several association studies may be attributable to some form of bias amongst published results.