Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

Study of the correlation between NRAMP1 gene polymorphisms and susceptibility to tuberculosis in Tibetan people in Qinghai / 中华微生物学和免疫学杂志

Objective To investigate the correlation between NRAMP1 gene polymorphisms and susceptibility to tuberculosis ( TB) in Tibetan people in Qinghai. Methods A case-control study was con-ducted in this study, involving 99 Tibetan patients with TB and 89 healthy Tibetans. The single nucleotide polymorphisms of NRAMP1 gene at rs17235409 and rs3731865 sites were detected by using TaqMan probe method. Gene cloning and sequencing typing were performed to analyze the single nucleotide polymorphisms of NRAMP1 gene at the rs17235416 site. SPASS20. 0 software was used to statistically analyze the correla-tion between NRAMP1 gene polymorphisms and susceptibility to TB in Tibetan people. Results No signifi-cant difference in the genotype frequencies of rs3731865 and rs17235409 was found between the two groups (χ2=0. 852, P=0. 356;χ2=0. 279, P=0. 597). The genotype frequencies of TGTG/TGTG and TGTG/del+del/del at the rs17235416 site were 70. 7% ( 70/99 ) and 29. 3% ( 29/99 ) in patients with TB and 86. 5% (77/89) and 13. 5% (12/89) in healthy subjects. There were significant differences in the geno-type frequencies of TGTG/TGTG and TGTG/del+del/del between the two groups (χ2=6. 870, P=0. 009). The genotypes of TGTG/del and del/del at rs17235416 were risk factors for TB ( OR=0. 376; 95%CI:0. 178-1. 794 as compared with the TGTG/TGTG genotype in Tibetan people in Qinghai. Conclusion This study suggested that the NRAMP1 gene polymorphisms at rs3731865 and rs1723409 sites had no correlation with the susceptibility to TB in Tibetans in Qinghai. However, the NRAMP1 gene polymorphisms at rs17235416 site were correlated with the susceptibility to TB. The TGTG/del alleles at the rs17235416 site might be the risk factors for tuberculosis in Tibetans in Qinghai.

Differential expression of solute carrier family 11a member 1 and inducible nitric oxide synthase 2 in skin biopsies from leprosy patients.

Background: Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae, an intracellular parasite that resides within macrophages and cannot be eliminated effectively. Solute carrier family 11a member 1 (Slc11a1) and inducible nitric oxide synthase (iNOS), both expressed in macrophages, play major roles in host defense against several intracellular pathogens. However, the roles of these molecules in natural infection with M. leprae remain unknown. Objective: We aimed to investigate the expression of Slc11a1 and iNOS in macrophages (CD68+ cells) infi ltrating skin lesions in leprosy. Methods: Skin biopsies from 48 Mexican patients of leprosy [(33 lepromatous (LL), 15 tuberculoid (TT)] and from 10 healthy controls, were subjected to immunohistochemistry to determine expression of CD68, Slc11a1 and iNOS. Results: We found a high expression of Slc11a1 and iNOS in most lepromatous leprosy samples. In tuberculoid leprosy samples, Slc11a1 expression was moderate or low, and that of iNOS was almost always low. In addition, Slc11a1 and iNOS expression levels were positively associated with bacillary loads in lepromatous leprosy lesions (P = 0.05). Conclusions: These observations suggest that M. leprae infection promotes the expression of Slc11a1 and iNOS in macrophages and that lepromatous leprosy can occur despite this response.

The NRAMP1 polymorphism as a risk factor for tuberculous spondylitis

In the present study, we analysed the association between the incidence of tuberculous spondylitis with the Natural Resistance Associated Macrophage Protein 1 (NRAMP1, also known as Solute Carrier Family 11a member1) polymorphism by studying the genetic segregation of this polymorphism and the incidence of the disease among members of the West Javanese population undergoing surgery for tuberculous spondylitis at our institution. We compared the distribution of NRAMP1 polymorphism at two specific sites, namely D543N, and 3’UTR, among subjects with pulmonary tuberculosis and tuberculous spondylitis. We found no significant differences in distribution of polymorphism between the two groups, or between pulmonary tuberculosis and tuberculous spondylitis compared to healthy subjects. However, a pattern emerged in that polymorphisms at the two sites seemed to be protective against development of tuberculous spondylitis in our study population. We concluded that in the West Javanese population, there is no association between NRAMP1 polymorphism with the propensity for development of pulmonary tuberculosis or tuberculous spondylitis. In fact, NRAMP1 may provide protection against the development of tuberculous spondylitis.

Distribution of D543N NRAMP1 polymorphism in tuberculosis patients from Kupang, east region of Indonesia.

Background: Natural resistance associated macrophage protein (NRAMP) is a proton/ divalent cation transporter which play a role in iron trafficking in the phagosomes. Variations in NRAMP1 gene have been reported to be associated with susceptibility to tuberculosis (TB) because Mycobacterium tuberculosis (MTb), the causative agent of TB, compete with its host to uptake iron for its metabolism. The study aimed to describe the polymorphism of NRAMP among TB patients in Kupang, East Nusa Tenggara. Methods: This is a case-control study, cases were pulmonary TB, new patients, aged 15-55 years with sputum smear positive for acid fast bacili. Control were surrounding neighbours without symptoms and history of TB. All demographic information and blood sample were taken for polymorphism. PCR/RFLP method was performed to explore whether single nucleotide polymorphism D543N of NRAMP1 gene is associated with susceptibility to TB. Results: The study involved 64 pulmonary TB patients and 51 healthy controls. We observed a significant different in the distribution of NRAMP1 genotypes frequencies between TB patients and healthy controls (p = 0.014). Moreover, D543N polymorphism gave significant association only in male subjects. Though the numbers of the subjects are limited, D543N NRAMP1 polymorphism in endemic region in Kupang, the eastern part of Indonesia, seems to be associated with the susceptibility to TB. This is in contrary to studies reported in other part of Indonesia: i.e from west part (Jakarta, Bandung) and central part (Makassar). The population from Kupang may similar genetic background as African population, as Mycobacterium infected in population from Kupang is mostly Mycobacterium africanum. Increasing the number of subjects may enhance the power of the study and possibility to meet Hardy-Weinberg Equilibrium to detect the true associations of this polymorphism in susceptibility to TB. Conclusion: There was a significant difference of polymorphism NRAMP1 which more pronounced among male subjects, however this has not yet fulfilled the Hardy-Weinberg equilibrium.

Study on the association of 3'UTR polymorphisms of NRAMP1 gene with susceptibility to tuberculosis in Uighurs / 中华微生物学和免疫学杂志

Objective To determine whether 3'UTR polymorphisms of the NRAMP1 gene are as-sociated with tuberculosis in Uighurs. Methods 3'UTR polymorphisms of NRAMP1 gene were typed by PCR-RFLP among 224 patients with active tuberculosis and 225 healthy individuals. The relationship be-tween 3'UTR polymorphisms and susceptibility to tuberculosis was studied, and cases were grouped accord-ing to genotypes. Results In the tuberculosis patients, genotype TGTG/TGTG,TGTG/TGTG deleted, and TGTG deleted/TGTG deleted were observed in 159,56 and 9 cases respectively, while the genotypes of the healthy controls were TGTG/TGTG in 185, TGTG/TGTG deleted in 36 and TGTG deleted/TGTG deleted in 4 case. The frequency of the genotype TGTG/TGTG was found more often among controls than that in pa-tients (X2=7.94 ,P <0.01). The frequency of allele TGTG and the frequency of variant allele were 0.87 and 0.13 respectively. Conclusion 3'UTR polymorphisms of NRAMP1 gene are associated with suscepti-bility to tuberculosis in Uighurs.

Relations between Polymorphism of NRAMP1 Gene and Susceptibility to Pulmonary Tuberculosis / 결핵및호흡기질환

Background: Several lines of evidence suggest that a host's genetic factors influence the outcome of exposure to Mycobacterium tuberculosis. The aim of this study was to determine whether polymorphism in NRAMP1 (natural resistance associated macrophage protein 1) gene is associated with the susceptibility or resistance to tuberculosis infection for patients with drug-sensitive pulmonary tuberculosis (DS-TB) and multi-drug resistant pulmonary tuberculosis (MDR-TB). Methods: Eight genetic polymorphisms of the NRAMP1 gene were investigated in patients suffering with DS-TB (n=100) or MDR-TB (n=102), and in healthy normal controls (NC, n=96). The genetic polymorphisms of NRAMP1 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The frequency of D543N A/G heterogygotes was significantly higher in the DS-TB subjects than the NCs (OR=2.10, 95% CI: 1.00 to 4.41, p=0.049). The frequency of 823C/T T/C heterozygotes was significantly higher in the DS-TB subjects (OR=2.79, 95% CI: 1.11 to 7.04, p=0.029) and the MDR-TB subject (OR=3.30, 95% CI 1.33 to 8.18, p=0.010) than in the NCs. However, the frequency of these genotypes was not different between the DS-TB and MDR-TB subjects. Conclusion: A significant association was found between NRAMP1 823 C/T polymorphism and pulmonary tuberculosis. This result suggests that NRAMP1 polymorphism may be involved in the development of pulmonary tuberculosis in Koreans.

The relationship between polymorphisms of NRAMP1 gene and susceptibility to tuberculosis in Chinese Han nation / 中华传染病杂志

Objective To elucidate the relationship between polymorphisms of NRAMP1 gene and susceptibility to tuberculosis in Chinese Han nation by case control study. Methods We selected 127 patients with active pulmonary tuberculosis who were all Han people with mean age of 52.5 years and 58 ethnically matched healthy controls. We typed the polymorphisms of NRAMP1, INT4 and D543N, through polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) techniques. Results Two NRAMP1 polymorphisms were both significantly associated with smear positive pulmonary tuberculosis. Subjects who were heterozygous for polymorphisms in INT4 and D543N were related with tuberculosis. It was the cooperation of different polymorphisms of NRAMP1 that led to the susceptibility to tuberculosis. Conclusions The polymorphisms in NRAMP1 gene affect susceptibility to tuberculosis in Han people in China.

NRAMP1 Gene Expression in Patients with Kawasaki Disease / 소아알레르기및호흡기학회지

PURPOSE: Kawasaki disease (KD) is considered to be an immunologic disease, although the exact etiology of the disease is still unknown. It is well known that the erythema on the BCG injected site are observed in patients with KD. In mouse, bcg gene was reported to be involved in the natural immune response to Mycobacterium. The correspondent gene in human, NRAMP1, is studied recently for its role and function. This study was to investigate whether the erythema developed on BCG injected site in patients with KD is related to NRAMP1 gene activation. METHODS: Ten patients diagnosed as KD, 10 febrile controls and 10 healthy normal controls were enrolled in the study. Total RNA of PBMC was isolated and used to synthesize cDNA. RT-PCR was done and amplified products were subjected to electrophoresis on 1.5% agarose gel electrophoresis. The bands were quantified with densitometry and the values were corrected according to beta-actin values. RESULTS: The NRAMP1 expression was notably increased in patients with acute and subacute stage of KD and there was no difference in the degree of expression between the two groups. NRAMP1 expression was also increased in febrile control groups and was not different from patients group. CONCLUSION: Increased NRAMP1 expression in KD is suggested to be developed for the expression of heat shock protein, and not to be the specific finding of KD.

Correlation Between Primary Tuberculous Pleurisy and NRAMP1 Genetic Polymorphism / 결핵

BACKGROUND: The phagolysosomal function of alveolar macrophage against M. tuberculosis infection is influenced by Nramp1, which is encoded by the NRAMP1 gene. There are several genetic polymorphisms in NRAMP1, and these polymorphisms affect the innate host resistance through the defect in production and function of Nramp1. To investigate this relationship, we determined the NRAMP1 genetic polymorphism in patients with primary tuberculous pleurisy was determined. METHODS : 56 Fifty-six primary tuberculous pleurisy patient (,) who were diagnosed by pleural biopsy(,) were designated to the pleurisy group and 45 healthy adults were designated to the healthy control group. 3 Three genetic polymorphisms of NRAMP1 (,) such as a single point mutation in intron 4(469+14G/C, INT4), a nonconservative single-base substitution at codon 543 that changes aspartic acid to asparagine(D543N) and a TGTG deletion in the 3' untranslated region(1729+55del4, 3'UTR)(,) were determined. Polymerase chain reaction(PCR) and polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) were used. RESULTS: The frequencies of mutanat mutant genotypes of INT4 and 3'UTR were significantly high in pleurisy group(p=0.001, p=0.023). But the frequencies of D543N were not significantly different between the both two groups(p=0.079). Odds The odds ratios(,) which are a comparison with wild genotype for determining mutant genotypes(,) were 8.022(95% confidence interval=2.422 ~26.572) for INT4 and 5.733(95% confidence interval=1.137 ~28.916) for 3'UTR which were ;these were statistically significant. But the odds ratio for D543N was not significant. In the combined analysis of the INT4 and 3'UTR polymorphisms, as compared with GG/++ homozygotes, (delete) the odds ratios were 6.000(95% confidence interval=1.461 ~ 24.640) for GC/++ genotype and 14.000(95% confidence interval=1.610 ~121.754) for GC/+del when compared with GG/++ homozygotes which ;these were statisticallysignificant. CONCLUSION: Among the NRAMP1 genetic polymorphisms, a single point mutation in intron 4(469+14G/C, INT4) and a TGTG deletion in the 3' untranslated region(1729+55del4, 3'UTR) were closely related to the primary tuberculous pleurisy.