VDR and NRAMP1 gene polymorphisms in susceptibility to pulmonary tuberculosis among the Chinese Han population: a case-control study.

OBJECTIVE: To explore the potential role of vitamin D receptor (VDR) gene and natural-resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms in susceptibility to pulmonary tuberculosis (PTB) in the Chinese Han population. DESIGN: In an unmatched case-control study, 120 well defined PTB patients and 240 unrelated normal controls were enrolled. Information on potential risk factors of PTB was collected using a standard questionnaire. Genetic polymorphisms of VDR gene (TaqI and FokI) and NRAMP1 gene (INT4, D543N and 3'UTR) were analysed using PCR and RFLP. Unconditional logistic regression was performed, and odds ratios (ORs), their 95% confidence intervals (CI) and P values were estimated using maximum likelihood methods. RESULTS: Univariate analysis demonstrated that FokI-ff homozygotes, D543N G/A and 3'UTR TGTG+/del heterozygotes occurred more frequently in patients than in controls. The crude ORs were 2.345 (95%CI 1.222-4.499), 2.590 (95%CI 1.043-6.434) and 1.890 (95%CI 1.171-3.051), respectively, compared with their corresponding common genotypes. The P values were 0.033, 0.041 and 0.030, respectively. After adjusting for exposure history and BCG immunisation in the multivariate analysis, the adjusted ORs were 4.625 (95%CI 1.737-12.312), 2.415 (95%CI 1.079-8.759) and 2.187 (95%CI 1.146-4.175), with P values of 0.002, 0.036 and 0.018, respectively. Neither univariate nor multivariate analysis disclosed any significant association between the disease and TaqI or INT4. CONCLUSIONS: Polymorphisms in the VDR and NRAMP1 gene are statistically associated with susceptibility to PTB in the Chinese Han population.     

NRAMP1 gene polymorphism and susceptibility to nontuberculous mycobacterial lung diseases

STUDY OBJECTIVES: Pulmonary disease caused by nontuberculous mycobacteria (NTM) may occur in patients with no underlying lung disease and no known immunodeficiency. The purpose of this study was to evaluate a potential role for natural-resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms for human susceptibility to the NTM lung disease. DESIGN: A case-control study. SETTING: Tertiary university medical center. PARTICIPANTS: Forty-one adult patients with NTM lung disease (Mycobacterium avium complex infection, 18 patients; Mycobacterium abscessus infection, 23 patients) were included in the study population. The diagnosis of NTM lung disease was made when the patients fulfilled the diagnostic criteria published by the American Thoracic Society. All patients had findings on high-resolution CT scans, such as bilateral bronchiectasis combined with multiple small nodules and branching linear structures, that were characteristic of the nodular bronchiectatic form of NTM lung disease. Fifty healthy individuals were selected as control subjects. RESULTS: Heterozygotes at intron 4 (469 + 14G/C) [INT4], codon 543 in exon 15 (D543N), and 3' untranslated region (3'UTR) were observed at significantly higher frequencies in patients with NTM lung disease than in control subjects. The odds ratios (ORs) were 2.78 (95% confidence interval [CI], 1.12 to 6.89; p = 0.026) for INT4 G/C, 5.74 (95% CI, 1.48 to 22.30; p = 0.006) for D543 G/A, and 9.54 (95% CI, 2.49 to 36.53; p < 0.001) for 3'UTR TGTG+/del. Subjects who were heterozygous for two NRAMP1 polymorphisms in INT4 and D543N were particularly overrepresented among those with NTM lung disease, compared with those with the most common NRAMP1 genotype (OR, 10.88, 95% CI, 1.18 to 100.45; p = 0.035). There were no significant differences in the frequencies of INT4, D543N, and 3'UTR polymorphisms between the patients with M avium complex infection and those with M abscessus infection. CONCLUSIONS: These findings suggest that the NRAMP1 genetic polymorphisms are associated with human susceptibility to NTM lung disease.     

NRAMP1 polymorphism and susceptibility to lung tuberculosis in Surabaya, Indonesia

The aim of this study was to evaluate the role of three polymorphisms (D543N, TGTG deletion in 3' UTR, INT4 G/C) of NRAMP1 to susceptibility to lung tuberculosis (TB) disease. The results showed that homozygous TGTG deletion in 3'UTR of NRAMP1 was found more frequent in lung tuberculosis patients than in healthy nurses working in a TB ward. This 4 base deletion might cause malfunction of NRAMP1 protein so that it fails as Fe2+ ion transporter causing macrophage unable to eliminate Mycobacterium tuberculosis.     

藏族肺结核患者140例的溶质转运蛋白家族11成员1基因单倍型研究

目的 研究溶质转运蛋白家族11成员1(SLC11AI)基因单倍型与中国藏族人群肺结核易感性的关系.方法 2004年6月至2005年1月选取藏族肺结核患者140例,感染MTB未发病的藏族对照139例,用变性高效液相色谱检测和PCR限制性片段长度多态性分析方法对SLC11A基因4种多态性[5'(GT)n、INT4、D53N和3'UTR]进行基因分型,用SHESIS软件进行连锁不平衡与单倍型分析,以X2检验研究基因单倍型与肺结核易感性的关系.结果 病例组5'(CT)9/INT4 G单倍型频率(181/280,64.8%)显著低于对照组(217/276,78.1%),差异有统计学意义(X2=11.026,P<0.01);病例组3['UTR TGTG/D543N G单倍型频率(215/280,76.6%)显著低于对照组(235/276,84.4%),差异有统计学意义(X2:6.547,P<0.05);3'UTR TGTG缺失/D543N A单倍型频率(34/280,12.0%)显著高于对照组(18/276,6.4%),差异有统计学意义(X2=6.547,P<0.05).结论 SL11AI摹闪中5'(GT)/INT4 G、3'UTR TGTG/D543N G及其3'UTR TGTG缺失/D543N A单倍型与中国藏族人群肺结核易感性有关.     

中国汉族人群结核易感相关基因多态性研究

目的通过病例对照研究明确结核感染与NRAMP1基因多态性的关系。方法选择127例活动性肺结核患者,均为汉族,平均年龄52.5岁,另选与民族匹配的58例健康对照者。对上述入选者通过聚合酶链反应限制性片段长度多态性(PCRRFLP)分析对NRAMP1基因多态性——内含子4(INT4)、D543N进行检测。结果两种NRAMP1基因多态性均与痰涂片阳性的结核显著相关。在结核患者中INT4与D543N的杂合子形式为对结核易感的多态性。NRAMP1的不同基因多态性的协同作用导致了对结核的易感性。结论NRAMP1基因多态性可以影响中国汉族人群对结核的易感性。     

SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis.

OBJECTIVE: Although many case-control studies have investigated the association between the SLC11 A1 gene polymorphisms and tuberculosis (TB) susceptibility, results were conflicting due to limited power. We reviewed the literature systematically by means of meta-analysis, provided a quantitative summary estimate on the association with TB, and examined some sources of between-study heterogeneity. DESIGN: We searched databases (MEDLINE, PUBMED and OVID) from January 1995 to December 2004 using 'gene' or 'SLC11A1' or 'NRAMP1', in combination with 'tuberculosis', performed a manual search of citations from relevant original studies and review articles, or corresponded with authors. RESULTS: The summary ORs for studies with 3'UTR, D543N, INT4 and 5'(GT)n loci allele variants in the SLC11A1 gene were 1.33 (95%CI 1.08-1.63), 1.67 (95%CI 1.36-2.05), 1.14 (95%CI 0.96-1.35) and 1.32 (95%CI 1.03-1.68), respectively, compared with their corresponding common alleles. The pooled ORs by sub-group analyses for the four loci described above were 1.20 (95%CI 0.86-1.68), 1.69 (95%CI 1.14-2.50), 1.50 (95%CI 1.17-1.91), and 1.31 (95%CI 1.05-1.64) in subjects of African descent, 1.46 (95%CI 1.10-1.94), 1.65 (95%CI 1.29-2.12), 0.91 (95%CI 0.66-1.25) and 1.86 (95%CI 1.33-2.62) in Asian subjects, 1.81 (95%CI 0.66-4.93), 1.79 (95%CI 0.72-4.47), 0.87 (95%CI 0.61-1.22) and 1.02 (95%CI 0.35-2.99) in European subjects. CONCLUSIONS: Polymorphisms at the four loci had no statistically significant association between the SLC11A1 variants and susceptibility to TB in subjects of European descent, while they showed a statistically significant association in Asian subjects (except the INT4 variant), African subjects (except the 3'UTR variant) and the population as a whole (except the INT4 variant).     

Polymorphisms in NRAMP1 and MBL2 genes and their relations with tuberculosis in Turkish children

In this study, we aimed to determine genetic susceptibility of children group who are under follow up at outpatient and inpatient clinics or newly diagnosed pediatric tuberculosis according to healthy control group. Patient group consists of 50 cases aged between 0-18 years who are under follow up at outpatient and inpatient clinics or newly diagnosed pediatric tuberculosis between 1996-2009 in Cukurova University, Faculty of Medicine, Department of Pediatrics and the control group consists of 50 healthy cases aged between 0-18 years who have neither chronic nor acute diseases and have no history of tuberculosis contact. Analysis of NRAMP1 (D543N, 3'-UTR and INT4 loci) and MBL (codon 54 and 57) gene polymorphisms carried out in Cukurova University, Faculty of Medicine, Department of Medical Biology and Genetics. In this study comprising in total 50 individuals we did not observe any significant association with microsatellite polymorphisms at the INT4, G543A and 3-UTR loci situated in the NRAMP1 gene (p> 0.005). There was no significant difference of MBL gen frequency polimorphisms of codon 54 and 57 polimorphisms between patient and control group statistically (p> 0.05). We reported that the INT4, G543A and 3-UTR loci microsatellite polymorphisms in the NRAMP1 gene were not associated with tuberculosis. No significant associations were also observed for codons 54 and 57 in the MBL2 gene. These results shed light on the role of NRAMP1 in susceptibility to tuberculosis disease and provide a plausible explanation for NRAMP1 and MBL genetic heterogeneity in tuberculosis susceptibility.     

Genetic susceptibility to Beh?et’s syndrome is associated with NRAMP1 (SLC11A1) polymorphism in Turkish patients

Natural resistance associated macrophage protein 1 (NRAMP1), also named as solute carrier family 11 member A1 gene (SLC11A1), has multiple pleiotropic effects on macrophage activation pathways such as up-regulation of the CXC chemokine KC, tumor necrosis factor α (TNF-α), interleukin-1 b (IL-1 b), inducible nitric oxide syntase (iNOS), and major histocompatibility complex (MHC) class II expression. Since NRAMP1 plays a role in the up-regulation of the TNF-α, iNOS and MHC expression, it may also be a candidate gene for Behçet’s syndrome (BS). We analyzed the association of NRAMP1 polymorphisms [(GT) _n , INT4, 3′UTR and D543N] in 102 Turkish patients with BS and 102 healthy subjects by using amplification refractory mutation system-polymerase chain reaction (ARMS–PCR). We found a significant association between BS and NRAMP1 INT4 G/C allele frequency (p = 0.004, OR = 1.88, 95% CI = 1.21–2.93). However, there were no significant differences in the distribution of allele frequencies of NRAMP1 (GT) _n , 3′UTR, D543N polymorphisms between BS patients and healthy controls. There was also no correlation between NRAMP1 polymorphisms and clinical manifestations of BS. Our study suggests that NRAMP1 may be one of the plausible candidate genes for BS. However, it is likely that INT4 polymorphism is not disease-specific and seems to be common to immune-mediated diseases.     

NRAMP1 and TNF-alpha polymorphisms and susceptibility to tuberculosis in Thais

OBJECTIVE AND BACKGROUND: Polymorphisms in the natural resistance-associated macrophage protein gene 1 (NRAMP1) and tumour necrosis factor (TNF)-alpha gene have been found to be associated with susceptibility to tuberculosis in different populations. However, the results are inconsistent. This study aimed to determine whether NRAMP1 and TNF-alpha variants are associated with tuberculosis in Thais. METHODS: Polymorphisms of NRAMP1 at INT4, D543N and the 3' untranslated region, and of TNF-alpha at +488, -238, and -308, were examined in 149 tuberculosis patients and 147 healthy controls. PCR using sequence-specific oligonucleotides and sequence-specific priming were used to genotype the NRAMP1 and TNF polymorphisms, respectively. RESULTS: There were no significant differences in the distribution of the genotype frequencies for the NRAMP1 and TNF-alpha polymorphisms between the patients and controls. CONCLUSIONS: The NRAMP1 and TNF-alpha genes are not associated with susceptibility to tuberculosis in Thais.     

SLC11A1 (formerly NRAMP1) polymorphisms associated with multidrug-resistant tuberculosis

The solute carrier family 11 member 1 gene (SLC11A1, formerly known as NRAMP1: natural resistance-associated macrophage protein 1) is one of the host genetic factors reported to affect susceptibility to tuberculosis. The aim of this study was to determine whether SLC11A1 polymorphisms affect the incidence of multidrug-resistant tuberculosis (MDR-TB) and other clinical features of pulmonary tuberculosis. Using polymerase chain reaction and the restriction fragment-length polymorphism analyses, we investigated four previously reported SLC11A1 polymorphisms, variations in 5'(GT)n, INT4, D543N, and 3'UTR in 95 patients with pulmonary tuberculosis including 10 MDR-TB patients. Clinical information, including elapsed time for sputum culture conversion, extent of pulmonary involvement, and presence or absence of cavitary lesions, was based on a review of charts and chest radiographs. For the 10 MDR-TB patients, previous therapy and treatment compliance were also evaluated. Although the number of MDR-TB patients was small, our preliminary study showed that the variations of D543N and 3'UTR are significantly associated with the incidence of MDR-TB (odds ratio [OR]=5.03, 95% confidence interval [CI]=1.24-20.62; P=0.02), longer time to sputum culture conversion (OR=3.86, 95% CI=1.23-12.23; P=0.02), and cavity formation (OR=5.04, 95% CI=1.51-23.13; P=0.02). Three out of the 10 MDR-TB patients with good treatment compliance had at least one genetic variation in SLC11A1. These data suggested that genetic variations in SLC11A1 may affect the incidence of MDR-TB and clinical features of pulmonary tuberculosis. Further studies are needed to confirm this association with increased number of MDR-TB patients.     

NRAMP1基因3′UTR多态现象与汉族结核病易感性的研究

目的 研究人类自然抵抗相关巨噬细胞蛋白(NRAMP1)基因3’UTRR多态现象与汉族结核病易感性的关系。方法 选取汉族活动性结核病患147例，正常对照145人，用聚合酶链反应-限制性片断长度多态性(PCR—RFLP)的方法对NRAMP1基因3’UTR进行基因分型，根据基因型对样本分组，经统计学处理，研究3’UTR多态现象与结核病易感性的关系。结果 在活动性结核病患中3’UTR TGTG／TGTG基因型95例(64．6％)，TGTG／TTTG缺失基因型50例(34．0％)，TGTG缺失／TGTG缺失基因型2例(1．4％)；正常对照TGTG／TGTG基因型则为115例(79．3％)，TGTG／TGTG缺失基因型29例(20．0％)，TGTG缺失／TGTG缺失基因型1例(0．7％)。正常对照组TGTG／TGTG基因型明显高于结核病患(x^2＝7．79；P＜0．01)。研究发现TGTG的等位基因频率为0．85，TGTG缺失的等位基因频率为0．15。结论 NRAMP1基因3’UTR多态现象与结核病易感性相关，汉族3’UTR TGTG缺失等位基因频率明显高于白种人，可部分解释汉族比白种人更易患结核病。     

Variations in the NRAMP1 gene and susceptibility of tuberculosis in Taiwanese.

SETTING: National Taiwan University Hospital, Taipei, Taiwan. OBJECTIVE: To study the variations in the NRAMP1 gene using five genotypes (274C/T, 577-18G/A, A318V, D543N and 3' untranslated region [UTR]), and the susceptibility of tuberculosis and HIV infection in Taiwanese. DESIGN: The study sample included 49 patients with tuberculosis, 48 healthy control subjects and 60 HIV-infected patients. The polymerase chain reaction (PCR) products amplified from their genomic DNA were subjected to restriction enzyme digestion and were analysed using agarose gel electrophoresis. RESULTS: A318V was not polymorphic in the studied population. Only D543N and 3'UTR were more heterozygous. In 274 C/T and 577-18G/A, the allele frequencies showed the predominant type to be the homozygous patterns C/C (94%) and G/G (94%), respectively. There were no statistically significant differences between the tuberculosis patients and the healthy control subjects. Despite the high susceptibility to Mycobacterium tuberculosis in HIV-infected patients, genotypic frequencies in the HIV-positive patients were not significantly different between tuberculous (n = 29) and non-tuberculous patients (n = 31). In comparison with previous studies, there were significant differences between different ethnic groups in allele frequencies for 274C/T, D543N and 3'UTR. CONCLUSION: The allele and genotype of NRAMPI polymorphism among Taiwanese differed from those of Caucasians, Africans and Hispanics. No allelic associations were identified between the NRAMP1 alleles and tuberculosis susceptibility.     

3'UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans.

SETTING: Korea University and the Korean Institute of Tuberculosis, Seoul, Korea. OBJECTIVE: To determine whether polymorphisms in the 3' untranslated region (UTR) of the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. DESIGN: A case-control study design was used to compare the frequency of 3'UTR of NRAMP1 among 192 tuberculosis patients and 192 healthy individuals. All of the samples were diagnosed by X-ray, smear and culture tests between 1998 and 1999 in the Cross of Lorraine Clinic at the Korean Institute of Tuberculosis. RESULTS: A significant association was found between the Korean tuberculosis patients and polymorphisms in the 3'UTR of the NRAMP1 gene (odds ratio [OR] 1.845; 95% confidence interval [CI] 1.097-3.104; chi2 = 5.424; P = 0.020). CONCLUSION: This study showed that genetic variations in the human NRAMP1 gene are associated with susceptibility to smear-positive tuberculosis in Korean patients. The 3'UTR variant allele associated with susceptibility to tuberculosis is very uncommon in Caucasians, but is present in Koreans and West Africans. These observations may explain in part why African Americans and Koreans have greater susceptibility to tuberculosis than Caucasians.     

NRAMP1 polymorphisms,susceptibility and clinical features of tuberculosis

OBJECTIVES: To study whether NRAMP1 gene polymorphisms in a Japanese population affect susceptibility to tuberculosis and clinical features of tuberculosis. METHODS: Polymerase chain reaction and restriction fragment-length polymorphism analyses were used to type NRAMP1 polymorphisms in 95 patients with pulmonary tuberculosis and 90 controls. Clinical features of patients also were investigated. RESULTS: No association was seen between susceptibility to tuberculosis and NRAMP1 polymorphisms. Patients with the D543N A allele were significantly more likely than others to develop a cavitary lesion; by logistic regression analysis with adjustment for gender, age, and presence of diabetes, the odds ratio in patients with an A allele was 5.16 (95% confidence interval, 1.30-20.45). CONCLUSIONS: Genetic variation in the human NRAMP1 gene may be associated with cavitation in patients with tuberculosis.     

5' dinucleotide repeat polymorphism of NRAMP1 and susceptibility to tuberculosis among Caucasian patients in Houston, Texas.

SETTING: Houston Tuberculosis Initiative (HTI) and Baylor College of Medicine, Houston, Texas. OBJECTIVE: To further explore the association between the polymorphisms of NRAMP1 and human susceptibility/resistance to tuberculosis (TB), specifically to determine whether the reported association shown for blacks and Asians holds true for Caucasian populations. DESIGN: In a case-control study, 135 adult Caucasian TB patients and 108 adult Caucasian HIV-seronegative non-TB controls were analyzed for the association between the polymorphisms in NRAMP1 gene and clinical TB. RESULTS: Heterozygote at 5'(GT)n, a dinucleotide repeat polymorphism in the promoter of NRAMP1, was observed at significantly higher frequencies among HIV-negative patients with pulmonary TB (41.6%; OR 2.02; 95%CI 1.11-3.64), extra-pulmonary TB (66.7%; OR 4.80; 95%CI 1.34-17.15), and HIV-seropositive TB patients (50%; OR 3.77; 95%CI 1.33-10.66) in comparison with the controls (27.8%). Homozygotes (GT)(10,10) were over-represented among HIV-positive TB patients (18.2%; OR 6.86; 95%CI 1.55-30.21) compared to the controls (5.5%). CONCLUSION: These findings suggest that the 5'(GT)n polymorphism of NRAMP1 modifies TB susceptibility in this Caucasian population, and could possibly be related to the site of infection among HIV-negative individuals and HIV-coinfected TB.     

深圳市汉族人群转化生长因子β1基因位点多态性与结核病的相关性研究

目的 检测深圳市汉族人群TGF β1基因rs4803455位点单核苷酸多态性（SNP）的基因类型,探讨其基因多态性与不同临床表现的结核病之间的关系。
方法 采用基于TaqMan探针技术的实时荧光PCR法,检测373例结核病患者（结核组）和350名健康人（对照组）TGF β1基因rs4803455位点的等位基因型并分层分析,然后观察结核组中有病理学或者细菌学证据的肺结核患者（肺结核组）和结核性胸膜炎患者（结核性胸膜炎组）等位基因频率差异。 结果 rs4803455位点等位基因C/A频率在结核组373例A为31.8%（237/746）,C为68.2%（509/746）;对照组350名A为40.6%（284/700）,C为59.4%（416/700）;两组间差异有统计学意义（χ²=12.139,OR=1.466,95%CI=1.182～1.819,P=0.000）。年龄≤25岁的结核组121例A为33.5%（81/242）,C为66.5%（161/242）;对照组111名A为41.0%（91/222）,C为59.0%（131/222）;两组间差异无统计学意义（χ²=2.807, OR=1.381,95% CI=0.946～2.015, P=0.094）。年龄＞25岁的结核组252例,A为31.0%（156/504）, C为69.0%（348/504）;对照组239名,A为40.4%（193/478）,C为59.6%(285/478);两组间差异有统计学意义（χ²=9.511,OR=1.511,95%CI=1.162～1.965, P=0.002）。有病理学或者细菌学证据的肺结核组111例,A为32.4%（72/222）,C为67.6%（150/222）;结核性胸膜炎组57例,A为21.1%（24/114）,C为78.9%（90/114）;对照组350名A为40.6%（284/700）,C为59.4%（416/700）;前两组分别与对照组比较,差异均有统计学意义（χ²值分别为4.710、15.879,OR值分别为1.422、2.560,95%CI分别为1.034～1.957、1.592～4.116,P值均<0.05）。等位基因C在肺结核组中的频率［78.9%（90/114）］比在结核性胸膜炎组中的频率［67.6%（150/222）］高。 结论 TGF β1基因rs4803455位点的基因多态性和结核病特别是结核性胸膜炎有关,等位基因C可作为预测结核病特别是结核性胸膜炎的危险因素,其中在年龄＞25岁的患者中预测作用更大。     

Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis

The natural resistance-associated macrophage protein 1 (NRAMP1) is implicated in the pathophysiology of mycobacterial infections. We investigated by polymerase chain reaction previously published Nramp1 genotypes at 4 loci-INT4, N543D, 3'UTR, and 5'(CA)(n) microsatellite markers-in 104 human immunodeficiency virus-negative patients with tuberculosis and 176 healthy control subjects living in Denmark. No significant difference in genotype frequency was found between white patients with tuberculosis and control subjects (P>.16), but carriage of Nramp1 variant alleles at loci INT4 and 5'(CA)(n) conferred a significantly increased risk of having microscopy-positive compared with microscopy-negative tuberculosis (65% vs. 35% [P=.0004] and 63% vs. 38% [P=.047], respectively). The Nramp1 alleles were not associated with increased risk for the development of cavities seen on chest radiographs, or with extrapulmonary tuberculosis. These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease.     

No evidence of linkage between Mitsuda reaction and the NRAMP1 locus.

Thirty sib-pairs were ascertained through unrelated lepromatous probands. They consisted of 22 healthy individuals and 8 leprosy patients. The Mitsuda reactions of all sibs were evaluated both macroscopically and histologically, and high molecular weight genomic DNA was extracted from the white blood cells of all sib-pairs. Three DNA polymorphisms identified by polymerase chain reaction (274C/T, D543N, 1729 + 55del4) were used as chromosome markers at the NRAMP1 locus. Sib-pair comparisons did not disclose any sign of close linkage between the Mitsuda reaction and the genetic markers.     

Typhoid fever and genetic polymorphisms at the natural resistance-associated macrophage protein 1

Control of Salmonella enterica serovar Typhimurium (S. typhimurium) infection in the mouse model of typhoid fever is critically dependent on the natural resistance-associated macrophage protein 1 (Nramp1). In this study, we examined the role of genetic polymorphisms in the human homologue, NRAMP1, in resistance to typhoid fever in southern Vietnam. Patients with blood-culture-confirmed typhoid fever and healthy control subjects were genotyped for 6 polymorphic markers within and near NRAMP1 on chromosome 2q35. Four single base-pair polymorphisms (274 C/T, 469+14 G/C, 1465-85 G/A, and D543N), a (GT)(n) repeat in the promoter region of NRAMP1 and D2S1471, and a microsatellite marker approximately 130-kb downstream of NRAMP1 were examined. The allelic and genotypic frequencies for each polymorphism were compared in case patients and control subjects. No allelic association was identified between the NRAMP1 alleles and typhoid fever susceptibility. In addition, neither homozygotes nor heterozygotes for any NRAMP1 variants were at increased risk of typhoid fever.