Natural Resistance-associated Macrophage Protein 1 Gene Research Articles

Comparative analysis of natural resistance-associated macrophage protein 1 gene expression and anti-PGL-1 antibodies in multibacillary leprosy and household contacts.

Leprosy continues to pose a significant challenge to public health, particularly in certain global regions. Accurate diagnosis and understanding of the disease's etiology are crucial for effective management and prevention. This study aimed to explore the contribution of Natural resistance-associated macrophage protein 1 (NRAMP1) and its genetic variations, as well as the levels of anti-PGL-1 antibodies, to the pathology of multibacillary leprosy in affected individuals and their household contacts. The study included 23 multibacillary leprosy patients and 28 household contacts. NRAMP1 protein expression and anti-PGL-1 IgG and IgM levels were measured using PCR and ELISA techniques, respectively. Genotypic variants of the NRAMP1 gene were also examined. Statistical analyses, including Mann-Whitney tests and univariate logistic regression, were employed to evaluate the data. Significant differences were observed in NRAMP1 protein expression and IgG and IgM levels between the patient and household contact groups. The study also highlighted the role of the NRAMP1 gene and its D543N and 3'UTR polymorphisms in leprosy susceptibility. No significant differences were observed in the genotype variants of INT4 between the two groups. These findings emphasize the potential of integrating PCR technology with serological tests to enhance diagnostic precision in leprosy. They also suggest the need for further research to clarify the role of NRAMP1 and its polymorphisms in leprosy susceptibility and resistance.

Detection and Analysis of Antidiarrheal Genes and Immune Factors in Various Shanghai Pig Breeds

The aim of this study was to identify effective genetic markers for the Antigen Processing Associated Transporter 1 (TAP1), α (1,2) Fucosyltransferase 1 (FUT1), Natural Resistance Associated Macrophage Protein 1 (NRAMP1), Mucin 4 (MUC4) and Mucin 13 (MUC13) diarrhea-resistance genes in the local pig breeds, namely Shanghai white pigs, Fengjing pigs, Shawutou pigs, Meishan pigs and Pudong white pigs, to provide a reference for the characterization of local pig breed resources in Shanghai. Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLR) and sequence sequencing were applied to analyze the polymorphisms of the above genes and to explore the effects on the immunity of Shanghai local pig breeds in conjunction with some immunity factors. The results showed that both TAP1 and MUC4 genes had antidiarrheal genotype GG in the five pig breeds, AG and GG genotypes of the FUT1 gene were detected in Pudong white pigs, AA antidiarrheal genes of the NRAMP1 gene were detected in Meishan pigs, the AB type of the NRAMP1 gene was detected in Pudong white pigs, and antidiarrheal genotype GG of the MUC13 gene was only detected in Shanghai white pigs. The MUC13 antidiarrhea genotype GG was only detected in Shanghai white pigs. The TAP1 gene was moderately polymorphic in Shanghai white pigs, Fengjing pigs, Shawutou pigs, Meishan pigs and Pudong white pigs, among which TAP1 in Shanghai white pigs and Shawutou pigs did not satisfy the Hardy–Weinberg equilibrium. The FUT1 gene of Pudong white pigs was in a state of low polymorphism. NRAMP1 of Meishan pigs and Pudong white pigs was in a state of moderate polymorphism, which did not satisfy the Hardy–Weinberg equilibrium. The MUC4 genes of Shanghai white pigs and Pudong white pigs were in a state of low polymorphism, and the MUC4 genes of Fengjing pigs and Shawutou pigs were in a state of moderate polymorphism, and the MUC4 genes of Fengjing pigs and Pudong white pigs did not satisfy the Hardy–Weinberg equilibrium. The MUC13 gene of Shanghai white pigs and Pudong white pigs was in a state of moderate polymorphism. Meishan pigs had higher levels of IL-2, IL-10, IgG and TNF-α, and Pudong white pigs had higher levels of IL-12 than the other pigs. The level of interleukin 12 (IL-12) was significantly higher in the AA genotype of the MUC13 gene of Shanghai white pigs than in the AG genotype. The indicator of tumor necrosis factor alpha (TNF-α) in the AA genotype of the TAP1 gene of Fengjing pigs was significantly higher than that of the GG and AG genotypes. The indicator of IL-12 in the AG genotype of the Shawutou pig TAP1 gene was significantly higher than that of the GG genotype. The level of TNF-α in the AA genotype of the NRAMP1 gene of Meishan pigs was markedly higher than that of the AB genotype. The IL-2 level of the AG type of the FUT1 gene was obviously higher than that of the GG type of Pudong white pigs, the IL-2 level of the AA type of the MUC4 gene was dramatically higher than that of the AG type, and the IgG level of the GG type of the MUC13 gene was apparently higher than that of the AG type. The results of this study are of great significance in guiding the antidiarrhea breeding and molecular selection of Shanghai white pigs, Fengjing pigs, Shawutou pigs, Meishan pigs and Pudong white pigs and laying the foundation for future antidiarrhea breeding of various local pig breeds in Shanghai.

Genetic Polymorphism of g.3768T>C loci of NRAMP1 gene in Kampung and KUB Chickens

Natural Resistance-Associated Macrophage Protein 1 (NRAMP1) is a gene that regulates the body's resistance to illness. The genetic diversity of Kampung and KUB chicken population in Lombok island West Nusa Tenggara province was investigated based on g.3768T>C loci of NRAMP1 gene. Experimental animal consisted of 105 KUB and 67 Kampung chickens. The NRAMP1 gene polymorphisms in both population were identified using PCR-RFLP method. Genetic parameters of g.3768T>C loci were calculated using PopGene32. In this study, the locus g.3768T>C of the NRAMP1gene found three genotypes (TT, CT, CC) with the frequency of the C allele was higher than the T allele, respectively 0.709 and 0.210 in Kampung chicken, and 0.738 and 0.262 in KUB chicken. The mean value of observed heterozygosity (Ho) and expected heterozygosity (He) of g.3768T>C loci in both populations revealed low to medium genetic diversity, with the values 0.222 and 0.400, respectively. The mean value of observed heterozygosity is lower than expected, indicating that the population is heading towards a heterozygosity deficit and proving that the two populations are not in Hardy-Weinberg equilibrium. The mean PIC value of the NRAMP1 gene (g.3768T>C) in both chicken population was 0.319 and classified as fairly informative (0.50 > PIC > 0.25). Meanwhile, the value of the genetic differentiation index (Fst) for Kampung and KUB chicken population were 0.385 and 0.433, indicating that there is differentiation between two chicken population at the observed loci.

A Systemic Review and Meta-analysis on Natural Resistance-associated Macrophage Protein 1 (3'-Untranslated Region) and Nucleotide-binding Oligomerization Domain-2 (rs8057341) Polymorphisms and Leprosy Susceptibility in Asian and Caucasian Populations.

The current meta-analysis aims to explore the potential correlation between natural resistance-associated macrophage protein 1 (NRAMP1) (3'-Untranslated region [3'-UTR]) and nucleotide-binding oligomerization domain-2 (NOD2 [rs8057341]) gene polymorphisms and their association with leprosy susceptibility in both Asian and Caucasian populations. Datas were retrieved from case control studies with NOD 2 and NRAMP 1 gene polymorphism associated with leprosy disease. Leprosy emerges as a particularly distinctive ailment among women on a global scale. The NRAMP1 (3'-UTR) and NOD2 (rs8057341) genetic variations play a crucial role in the progression of leprosy. A systematic review of relevant case-control studies was conducted across several databases, including ScienceDirect, PubMed, Google Scholar, and Embase. Utilizing MetaGenyo and Review Manager 5.4 Version, statistical analyses were carried out. Nine case-control studies totaling 3281 controls and 3062 leprosy patients are included in the research, with the objective of examining the potential association between NRAMP1 (3'-UTR) and NOD2 (rs8057341) gene polymorphisms and leprosy risk. The review methodology was registered in PROSPERO (ID520883). The findings reveal a robust association between NRAMP1 (3'-UTR) and NOD2 (rs8057341) gene polymorphisms and leprosy risk across various genetic models. Although the funnel plot analysis did not identify publication bias, bolstering these findings and elucidating potential gene-gene and gene-environment interactions require further comprehensive epidemiological research. This study identified a strong correlation between polymorphisms in the NOD2 (rs8057341) genes and susceptibility to leprosy across two genetic models. Further comprehensive epidemiological investigations are warranted to validate these findings and explore potential interactions between these genes and environmental factors.

English

The pathogenic bacterial infection is the main cause of decreased cow productivity. This study aimed to investigate the relationship of Natural Resistance Associated Macrophage Protein 1 (NRAMP1) gene polymorphisms with pathogenic bacterial resistance traits in Indonesian cattle. A total of seventeen (17) animals of mixed-breed cattle comprising two categories healthy (7 heads) and infected with bacteria (10 heads) were used in this study. Forward sequencing analysis was performed to detect single nucleotide polymorphisms (SNPs) in the partial NRAMP1 gene (954 bp) using polymerase chain reaction (PCR). Results showed that a novel SNP of g.109Y (intron 5) and two common SNPs of g.221K (intron 5) and g.642R (intron 6) were detected in the NRAMP gene in Indonesian native cattle. In addition, these SNPs have a moderate polymorphic information content (PIC) value (0.30 - 0.50). Therefore, eight (8) haplotypes of the NRAMP1 gene were determined in the present study. Thus, the highest bacterial infection frequency was shown in the TT/GT/AG haplotype. In conclusion, three (3) nonsense SNP in the NRAMP1 gene have the potency as a genetic marker for bacterial resistance trait in Indonesian cattle

A systematic review of natural resistance-associated macrophage protein 1 (NRAMP1) gene and susceptibility to tuberculosis: What is the link for ocular tuberculosis?

Link of Video Abstract: https://youtu.be/hxFKCtWwc3c Introduction: The host genetic factors play a crucial role in determining susceptibility to tuberculosis (TB), and one such candidate gene is Natural Resistance-Associated Macrophage Protein 1 (NRAMP1). NRAMP1 is involved in the regulation of intracellular iron homeostasis, an essential nutrient for MTb survival within macrophages. Several polymorphisms of the NRAMP1 gene have been extensively studied for their association with TB susceptibility. However, the specific role of these NRAMP1 gene polymorphisms in the development of ocular tuberculosis, a rare but potentially severe form of TB, remains poorly understood. Methods: This study was a systematic review conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). A comprehensive search was performed in the PubMed, Cochrane, and Science Direct databases for original, full-text studies of NRAMP1 gene related to tuberculosis infection. Ethnic, polymorphisms of NRAMP1 evaluated, and its association to TB susceptibility were recorded and summarized qualitatively. Results: There were 41 studies included in our systematic review. No study of NRAMP1 gene polymorphism in regards to ocular tuberculosis was found. Polymorphisms of the NRAMP1 gene, such as 3'UTR TGTG ins/del, D543N, INT4, and (GT)n, have been investigated for their potential role in determining the susceptibility or immunity to Mycobacterium tuberculosis infection. However, the findings regarding the relationship between NRAMP1 gene polymorphism and tuberculosis are still inconsistent, with controversies and discrepancies among different studies. Conclusion: NRAMP1 gene polymorphisms showed important involvement to tuberculosis infection susceptibility, therefore its relation to ocular tuberculosis is suggested.

Serum iron levels in tuberculosis patients and household contacts and its association with natural resistance-associated macrophage protein 1 polymorphism and expression.

Iron deficiency can impair immune function, increasing tuberculosis (TB) susceptibility and severity. The research aimed to investigate iron deficiency anemia in TB patients and household contacts and its association with natural resistance-associated macrophage protein 1 (NRAMP1) polymorphism and expression. The levels of iron, ferritin, and transferrin were measured in the serum by ELISA (Enzyme-Linked Immunosorbent Assay). NRAMP1 polymorphisms were determined by polymerase chain reaction (PCR) and sequencing. NRAMP1 gene expression was measured by real-time PCR. Interferon-gamma release assay (IGRA) checked on household contacts to screen household contacts with positive IGRA as the control. This study involved 35 TB cases and 35 TB contacts. The results showed that the serum Fe levels were found to be lower in the TB case group (median 149.6 μmol/L) than in the positive IGRA household contacts group (median 628.53 μmol/L) with a p-value <0.001. Meanwhile, ferritin levels in TB cases tended to be higher, in contrast to transferrin, which was found to tend to be lower in TB cases than household contacts but did not show a significant difference. This study found no association between the polymorphism of exon 15 D543 and active TB. However, NRAMP1 gene expression was lower in TB cases than in positive IGRA household contacts (p= 0.011). Besides, there was a positive correlation between NRAMP1 gene expression and serum Fe levels (r = 0.367, p= 0.006). TB was associated with decreased NRAMP1 gene expression (OR 0.086 95% CI 0.02-0.366, p= 0.001). Besides, TB was associated with low Fe levels (OR 0.533 95% CI 0.453-0.629, p< 0.001). Comparing the TB case to the household contacts group, decreased serum Fe levels were discovered in the TB case group. This study also shows a correlation of NRAMP1 gene expression to Fe levels in TB patients and household contacts and describes that TB may lead to decreased Fe levels by downregulating NRAMP1 expression.

Effect of breastfeeding on children's health and its relationship to NRAMP1 expression: A cross-sectional study

Toddlers with exclusive breastfeeding can increase immunity in preventing infectious diseases such as Upper Respiratory Tract Infections (ARI). The body's resistance to disease is controlled by Natural Resistance-Associated Macrophage Protein 1 (NRAMP1). NRAMP1 contributes to the pathophysiology of several intercellular infections, including ARI. The purpose of this study was to determine the effect of breastfeeding on children's health and its relationship to NRAMP1 expression. A cross-sectional study was conducted on 124 toddlers in October 2020–June 2021. Toddlers were selected purposively from three Community Health Centers in Central Jakarta. The first group (n = 62) was exclusive breastfeeding and the second group (n = 62) was not exclusive breastfeeding. The characteristics of mothers and toddlers were collected using a structured questionnaire supported by medical record data. Meanwhile, NRAMP1 expression and NRAMP1 protein levels were obtained from the examination of blood samples. Examination of NRAMP1 gene mRNA expression by real-time PCR method and serum NRAMP1 protein levels by ELISA method. Data were analyzed using t-test, ANOVA, and multiple linear regression. The results obtained that the average mRNA expression of NRAMP1 gene and protein levels of NRAMP1 in infants who were not exclusive breastfeeding were 6.88 fold change (FC) and 315.02 pg/ml compared to those who received exclusive breastfeeding of 11.36 FC and 1087.74 pg./ml. Parity, immunization history, exclusive breastfeeding, and frequency of ARI were significantly associated with NRAMP1 gene mRNA expression and NRAMP1 protein levels (P < 0.05). Maternal and under-five age, gender, and nutritional status were not significantly related (P > 0.05). Exclusive breastfeeding was the dominant factor influencing NRAMP1 gene mRNA expression (OR: 4268) and NRAMP1 protein content (OR: 737,362). Antibodies obtained from exclusive breastfeeding in synergy with the NRAMP1 gene form the body's immunity in infants suffering from ARI.

Contribution of NRAMP1 gene expression and protein level in pulmonary and latent TB infection in Indonesia

Natural resistance-associated macrophage protein 1 (NRAMP1) gene is regarded to play an important role in human vulnerability against various infections, including mycobacterial infection. This research purpose was to investigate the correlation between NRAMP1 gene expressions and protein level with susceptibility to tuberculosis (TB) infection and their contacts. NRAMP1 gene expression and protein level from 30 active TB patients, 27 latent TB infection household contacts, and 33 healthy subjects as control were examined by the real-time polymerase chain reaction and enzyme-linked immunosorbent assay method. NRAMP1 gene expression value in the healthy group was 4.61 times higher than active TB patients (p = 0.025) and the NRAMP1 expression value in the healthy group was 4.02 times higher than in the latent TB group (p = 0.117). The mean protein level of NRAMP1 was 196.41, 199.27, and 224.70 ng/ ml in the active TB, latent TB, and healthy groups, respectively (p > 0.05). NRAMP1 expression was downregulated and protein level was lower in active TB patients than latent TB patients and healthy individuals.

Natural resistance-associated macrophage protein-1 gene polymorphisms and genetic susceptibility to pulmonary tuberculosis in sudanese patients

Genetic susceptibility to tuberculosis has been investigated worldwide, however a few studies conducted in Sudanese patients. Polymorphisms in NRAMP1 have shown an important association with susceptibility to tuberculosis and progression to active disease. However, whether there is an association of these polymorphisms with pulmonary tuberculosis among Sudanese patients is not investigated yet. The aim of this study was to determine the association of NRAMP1 polymorphisms with development of pulmonary tuberculosis in Sudanese subjects with pulmonary tuberculosis. A case-controls study (100 in each arm) was conducted at Al-Shaab Teaching Hospital in Khartoum, Sudan during the period of March through September 2017. Genotyping for NRAMP1 (rs3731865) INTR4 and (rs17235409) D543N was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).There was no significant difference in the mean± SD of the age and body mass index (BMI) between the cases (tuberculosis) and the controls [37.7 ± 4.1 vs. 35.9 ± 3.9 years; P=0.702] and [24.6 ± 1.9 vs. 24.7 ± 2.1; P=0.444], respectively. None of the genotype frequencies investigated in the two polymorphisms were associated with the development of pulmonary tuberculosis. There was a significant association with the development of tuberculosis with illiteracy P=&lt;0.001. Gene polymorphisms of NRAMP1 (rs3731865) INTR4 and (rs17235409) D543N were not associated with pulmonary tuberculosis development in this setting. Further study is needed with larger sample size and different design and settings. Increase public awareness about tuberculosis infections and specially in those who are illiterate.

Correlation of Polymorphisms of Natural Resistance-Associated Macrophage Protein 1 (NRAMP1) Gene and Smoking with the Risk of Rheumatoid Arthritis in Chinese Han People.

BackgroundIn this study we report on the possible connection between single nucleotide polymorphisms (SNPs) in natural resistance-associated macrophage protein 1 (NRAMP1) gene and the risk of rheumatoid arthritis (RA) in the Chinese Han population.Material/MethodsA total of 248 participants consisting of 116 RA cases and 132 healthy individuals were recruited for the current study. Genotyping for NRAMP1 gene polymorphisms was implemented using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The chi-square test was used to detect discrepancies in genotype and allele frequencies between the RA case group and the control group. Odds ratios (ORs) with 95% confidence intervals (CIs) was used to evaluate relative risk of RA. The results were adjusted by logistic regression analysis.ResultsThe TT genotype and T allele in rs17221959 showed dramatically different distribution between RA cases and healthy controls. After adjustment, TT genotype (OR=0.338, 95%CI=0.278–1.214, P=0.028) and T allele (OR=0.608, 95%CI=0.298–0.956, P=0.005) showed close association with reduced risk of RA. For rs1059823, no obvious diversity was uncovered in either genotype or allele distribution between the 2 groups. Interaction analysis showed that smoking decreased the protective function of TT in rs17221959.ConclusionsThis study suggested that the TT genotype and T allele in rs17221959 decreased RA risk. Smoking could decrease the protective effect of TT.

Sequence Variability in the NRAMP1 Gene among Indigenous and Exotic Chicken Types

The natural resistance-associated macrophage protein 1 ( NRAMP1 ) gene in chickens, which exists on chromosome 7, is thought to play a significant role in disease resistance. Variations in this gene have been documented and have played crucial roles in the variations in the resistance and/or susceptibility that is expressed by individuals and different groups of animal species. In this study, the NRAMP1 gene was studied for single nucleotide polymorphism (SNP) variability between indigenous and exotic chicken breeds. The gene was amplified using the polymerase chain reaction (PCR) method and sequenced and analyzed. Six SNPs, both synonymous and non-synonymous (C3700T, G3702C, A3712C, C3714G, C3693G, and G3705T), were detected in the gene in both indigenous and exotic chicken types. One allele form was detected among all the sample animals that were studied. A phylogenetic tree revealed that the indigenous chicken type and the exotic broiler chicken type are genetically similar with respect to this gene. However, the exotic layer chicken type is genetically suggested to be distantly related to both the indigenous and broiler chicken types, indicating that the gene has probably been evolving both within and among different poultry species.

Effect of NRAMP1 Gene Polymorphism on levels of(TNF-α and IL-1β) cytokinesin Cutaneous Leishmaniasis patients in Iraq

Cutaneous leishmaniasis (CL) is vector-borne disease, and endemic in most regions of Iraq specially with poor populations. Natural resistance associated macrophage protein 1 (NRAMP1) gene play a essential role in susceptibility to CL and disease pathology, NRAMP1 influences aproduction and activation of pro-inflammatory cytokines (TNF-α and IL-1β). Pro- and anti-inflammatory cytokines play a essential role in susceptibility/ resistance and the immunopathogenesis of Leishmania infection, these cytokines are crucial factors in the initiationand enhances of protective immunity against Leishmania infection, this study aimed to studding effect of polymorphism in NRAMP1 genes on cytokines secretion, and their effect in susceptibility to CL infection. Samples of blood were collected from (60) patients with CL and (32) apparently healthy controls. Polymorphism of NRAMP1 (D543N) detected in patients and control groups by PCR-RFLP technique. While (TNF-α and IL-1β) cytokine concentration detected by ELIS technique using a quantitative sandwich enzyme immunoassay technique.indicate to effect of NRAMP1 Gene Polymorphism on levels of(TNF-α and IL-1β) cytokines and this a clearly recorded in present study were A allele is associated with lower levels of(TNF-α and IL-1β)in patients and control groups compression to that absorbed in allele Gwith statically significant (P ≤ 0.05).

The NRAMP1, VDR, TNF-α, ICAM1, TLR2 and TLR4 gene polymorphisms in Iranian patients with pulmonary tuberculosis: A case–control study

The innate immune response drives early events in Mycobacterium tuberculosis infection. Since human genetic variation is an important determinant in the outcome of infection with M. tuberculosis, we typed polymorphisms in the innate immune molecules, such as natural-resistance-associated macrophage protein 1 (NRAMP1), Vitamin D receptor (VDR), Tumor necrosis factor alpha (TNF-α), intercellular adhesion molecule1 (ICAM-1), Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) in a case–control study of pulmonary tuberculosis in Iranian population.We conducted an association study and included 96 patients and 122 matched healthy individuals. We used single ARMS-PCR technique to simultaneously genotype fourteen polymorphisms in this survey.Among all fourteen polymorphisms that were examined, three polymorphisms were significantly different between case and control groups. The TNF −308A polymorphism showed significant increase in allele and genotype frequencies among patients compared to control individuals [−308A allele: 19.3 vs. 9.4%, GA genotype: 28.1 vs. 17.2%, AA genotype: 5.2 vs. 0.8%; Corrected P (Pc)<0.05], and the TLR4 variant allele and genotypes prevalence (D299G and T399I) were significantly higher among patients compared to controls [DG genotype: 14.6 vs. 5.7%, Pc<0.05 and I399 allele: 4.2 vs. 0.8%, TI genotype: 8.3 vs. 1.6%; Pc<0.05], respectively.In conclusion, our data suggest that TLR4 (D299G and T399I) and TNF (−308G/A) genetic polymorphisms may influence the risk of developing tuberculosis after exposure to Mycobacterium.

Upregulation of NRAMP1 mRNA confirms its role in enhanced host immunity in post-artificial infections of Salmonella enteritidis in chicks

1. Salmonella enteritidis (SE) is reported as the most common food-borne pathogen transmitted through poultry products. The natural resistance-associated macrophage protein 1 (NRAMP1) is a candidate gene associated with SE-mediated immune response and is related to the phagocytosis of SE. In this study, the classical single-nucleotide polymorphism (SNP) G2357A in exon 8 of the NRAMP1 gene was detected. The expression of NRAMP1 mRNA was first investigated in heterophil granulocytes and spleen in chicks from two different Chinese native breeds at 1, 3 and 10 d post-infection. In addition, the association with the effect of SE challenge was identified.2. The G2357A SNP showed no significant association with Salmonella natural infection in birds from two different Chinese native breeds.3. The upregulation of NRAMP1 mRNA in heterophils and spleen was involved in the response to pathogenic SE colonisation during the acute infection period in chicks. The results suggest that genetics, age, gender and interactions among these factors play important roles in the modulation of NRAMP1 mRNA expression and copy number by SE-mediated immune response in different Chinese chickens.4. In conclusion, the enhancement of host immunity mediated by the upregulation of NRAMP1 mRNA in heterophil granulocytes and spleen might be more obvious and earlier in the chicks resistant to infections with SE than in susceptible chicks.

Frequency of NRAMP1 Gene Polymorphisms among Canadian First Nations Peoples Experiencing Endemic Tuberculosis

Objectives: The natural resistance-associated macrophage protein 1 (NRAMP1) regulates susceptibility to infectious and autoimmune diseases. NRAMP1 gene polymorphisms have been implicated in susceptibility to tuberculosis. The frequency of NRAMP1 gene polymorphisms was therefore evaluated in three Manitoba First Nations sub-groups (Dene, Cree, and Saulteaux) with differential but high rates of tuberculosis (636/100,000, 496/100,000, and 0/100,000 respectively). Methods: Venous blood samples were collected from 281 study participants from three First Nations sub-groups (Dene (N=108), Cree (N=41), Saulteaux (N=49)), and a non-indigenous Canadian-born (European-descent) group (N=83). Genomic DNA was extracted and four single nucleotide polymorphisms in the NRAMP1 gene (5′ (GT)n, -274 (C/T), Intron 4 (469+14 G/C), D543N (G/A)) were genotyped using restriction fragment length polymorphism. NRAMP1 SNP allele frequencies were counted and compared between studied sub-groups. Results: The Dene sub-group had significantly different allele frequencies of NRAMP1 (5′(GT)n, -274 (C/T), Intron 4(G/C), D543N (G/A)) compared to the European-descent group. The NRAMP1 allele frequencies at D543N (G/A) and Intron 4(G/C) differed significantly between the Cree and the European-descent group while the allele frequencies of the Saulteaux were not significantly different from the European-descent group. Two sub-groups (Dene and Cree) had higher frequency of NRAMP1 D543N (A) allele, which is associated with tuberculosis in other populations. Conclusion: High, but differential rates of tuberculosis among the First Nation sub-groups in Manitoba are related to social determinants of health (i.e. poverty, racism, inadequate housing) but other potential risk factors such as gene polymorphisms associated with tuberculosis have only recently come under investigation. NRAMP1 allele frequencies were found to be different comparing the Dene, Cree and Saulteaux and their role in tuberculosis susceptibility/resistance needs further investigation.

Polymorphism, Expression of Natural Resistance-associated Macrophage Protein 1 Encoding Gene (NRAMP1) and Its Association with Immune Traits in Pigs.

Natural resistance-associated macrophage protein 1 encoding gene (NRAMP1) plays an important role in immune response against intracellular pathogens. To evaluate the effects of NRAMP1 gene on immune capacity in pigs, tissue expression of NRAMP1 mRNA was observed by real time quantitative polymerase chain reaction (PCR), and the results revealed NRAMP1 expressed widely in nine tissues. One single nucleotide polymorphism (SNP) (ENSSSCG00000025058: g.130 C>T) in exon1 and one SNP (ENSSSCG00000025058: g.657 A>G) in intron1 region of porcine NRAMP1 gene were demonstrated by DNA sequencing and PCR-RFLP analysis. A further analysis of SNP genotypes associated with immune traits including contain of white blood cell (WBC), granulocyte, lymphocyte, monocyte (MO), rate of cytotoxin in monocyte (MC) and CD4/CD8 T lymphocyte subpopulations in blood was carried out in four pig populations including Large White and three Chinese indigenous breeds (Wannan Black, Huai pig and Wei pig). The results showed that the SNP (ENSSSCG00000025058: g.130 C>T) was significantly associated with level of WBC % (p = 0.031), MO% (p = 0.024), MC% (p = 0.013) and CD4−CD8+ T lymphocyte (p = 0.023). The other SNP (ENSSSCG00000025058: g.657 A>G) was significantly associated with the level of MO% (p = 0.012), MC% (p = 0.019) and CD4−CD8+ T lymphocyte (p = 0.037). These results indicate that the NRAMP1 gene can be regarded as a molecular marker for genetic selection of disease susceptibility in pig breeding.

NRAMP1, VDR, HLA-DRB1, and HLA-DQB1 Gene Polymorphisms in Susceptibility to Tuberculosis among the Chinese Kazakh Population: A Case-Control Study

Background. To explore the potential role of natural-resistance-associated macrophage protein 1 (NRAMP1) gene, vitamin D receptor (VDR) gene, (human leukocyte antigen, (HLA-DRB1) HLA) -DRB1 gene, and HLA-DQB1 gene polymorphisms in susceptibility to tuberculosis (TB) in the Chinese Kazakh population. Methods. A case-control study was performed on the Chinese Kazak population. Genetic polymorphisms of NRAMP1 gene (3′UTR) and VDR gene (TaqI and FokI) were analysed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing analysis in TB patients and healthy controls. Genetic polymorphisms of HLA-DRB1 gene and HLA-DQB1 gene in the two groups were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique and sequencing analysis. Results. There was statistically significant difference in the 3′UTR polymorphism between the TB patients and healthy controls in the Chinese Kazak population (P = 0.002; OR = 1.859; 95% CI = 1.182–2.926). Significant difference was observed in the FokI polymorphism between the TB patients and healthy controls (P = 0.001; OR = 1.530; 95% CI = 1.007–2.325). It does not disclose any significant association between the disease and TaqI (P > 0.05). Alleles HLA-DRB1∗04 and HLA-DQB1∗0201 occurred more frequently in patients than in controls (P = 0.011 and 0.002; OR = 1.889 and 1.802; 95% CI = 1.153–3.095 and 1.230–2.639, resp.). Conclusions. Polymorphisms in the NRAMP1 gene, VDR gene, HLA-DRB1 gene, and HLA-DQB1 gene are statistically associated with susceptibility to TB in the Chinese Kazakh population.

Relationship between NRAMP1 gene polymorphism and efficacy of BCG vaccine in helminth-infected populations

Infection of mothers with schistosomiasis and filariasis has been shown to influence infant responses to neonatal Bacille Calmette-Guérin (BCG) immunization. The genetic makeup of infants is also considered an important determinant for the activity of BCG vaccine. The effect of natural resistance-associated macrophage protein 1 (NRAMP1) gene polymorphism on the efficacy of BCG vaccine was examined in neonates with helminth-infected mothers (63 infants) and the results were compared with neonates of uninfected mothers (187 infants). After BCG vaccination, assessment of scar presence, tuberculin test, stool analysis, and IgE level was performed. Polymorphism of the NRAMP1 gene was investigated by PCR amplification followed by RFLP analysis. We found that patients with heterozygosity of intron 4 (GC) and/or maternal infection with helminth parasites showed reduced efficacy of BCG vaccine against tuberculosis.

Polymorphisms of the NRAMP1 gene: Distribution and susceptibility to the development of pulmonary tuberculosis in the Greek population

SummaryBackgroundAmple evidence suggests that host genetic factors affect human susceptibility to tuberculosis. The natural resistance–associated macrophage protein 1 (NRAMP1) gene seems to play a role in the pathophysiology of a number of intracellular infections, including mycobacteria. A case-control study was conducted in the Greek population to determine whether NRAMP1 polymorphisms affect the susceptibility to development of overt pulmonary tuberculosis.Material/MethodsNRAMP1 polymorphisms (3′UTR, D543N, INT4) were evaluated among 142 patients with culture-positive pulmonary tuberculosis and 144 ethnically matched healthy controls having latent M. tuberculosis infection. Patients with human immunodeficiency virus infection were excluded.ResultsOut of the 3 NRAMP1 polymorphisms, a trend of increased incidence of INT4 polymorphism was found in the patients’ group compared to the control group. A lack of association was observed between the 2 groups as far as the other 2 polymorphisms (D543N, 3′UTR) are concerned. INT4-CC homozygotes were found to have a higher risk to develop pulmonary tuberculosis compared to GG homozygotes (p=0.022). An increased incidence G/TGTG/C genotype combination was found in the patients’ group as compared to controls. G/TGTG/C genotype combination was associated with a 36% higher risk of developing pulmonary tuberculosis (p=0.004) compared to the baseline expression of G/TGTG/G combination.ConclusionsINT4-NRAMP1 polymorphism may have a role in the development of culture-positive pulmonary tuberculosis after an initial M. tuberculosis latent infection. The possible role of INT4-NRAMP1 polymorphism in the development of active pulmonary tuberculosis needs further investigation.