Association of Toll-like receptor 2 Arg753Gln and Toll-like receptor 1 Ile602Ser single-nucleotide polymorphisms with leptospirosis in an argentine population

Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an important role in the recognition of and subsequent immune response activation against leptospirosis in humans. The genetic polymorphism in TLR2 of an arginine to glutamine substitution at residue 753 (Arg753Gln) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to Leptospira spp. This bacterium signals through TLR2/TLR1 heterodimers in human cells. The aim of the present study was to investigate the Arg753Gln single-nucleotide polymorphism (SNP) of the TLR2 gene, and the isoleucine to serine transversion at position 602 (Ile602Ser) of the TLR1 gene (previously associated with Lyme disease), in leptospirosis patients compared to healthy controls, carrying out a retrospective case/control study. The TLR2 polymorphism adenine (A) allele was observed in 7.3% of leptospirosis patients but was not found in the control group, whereas the guanine (G) allele of the TLR1 polymorphism was found in 63.6% of patients and 41.6% of controls. Susceptibility to leptospirosis disease was increased 10.57-fold for carriers of the TLR2 G/A genotype (P = 0.0493) and 3.85-fold for carriers of the TLR1 G/G genotype (P = 0.0428). Furthermore, the risk of developing hepatic insufficiency and jaundice was increased 18.86- and 27.60-fold for TLR2 G/A carriers, respectively. Similarly, the risk of developing jaundice was increased 12.67-fold for TLR1 G allele carriers (G/G and T/G genotypes). In conclusion, the present data suggest that the TLR2 Arg753Gln and TLR1 Ile602Ser SNPs influence the risk of developing leptospirosis and its severity.     

No association of the TLR2 gene Arg753Gln polymorphism with rheumatic heart disease and Beh?et’s disease

Behçet’s disease (BD) is a multisystem inflammatory disorder of unknown etiology, and infections with different microorganisms including streptococci have been claimed as triggers of inflammatory attacks in BD pathogenesis. Toll-like receptor 2 (TLR2) has been known to recognize several microbial antigens including that of streptococci, and TLR2 gene Arg753Gln polymorphism has been reported to be strongly associated with acute rheumatic fever with an odds ratio of 100. This study aimed to investigate the TLR2 gene Arg753Gln polymorphism in a group of patients with BD and rheumatic heart disease (RHD) and to analyze the role of genotyping errors resulting from duplicated gene segments. The study group consisted of 211 patients with BD, 95 patients with RHD, and 94 matched Turkish healthy controls. Because of the duplicated exon 3 in 23-kb upstream of the TLR2 gene, genotyping for the Arg753Gln polymorphism with polymerase chain reaction–restriction fragment length polymorphism method was carried out using a new set of primers and PstI restriction enzyme. TLR2 gene Gln753 allele was observed in two of 211 (1.0%) patients with BD, five of 95 (5.3%) patients with RHD, and two of 94 (2.1%) healthy controls. All patients and controls were found to be heterozygous for Arg753Gln polymorphism, except one patient with BD, who was homozygous for Gln753. Although a slight increase of heterozygosity was noted in patients with RHD, no statistically significant difference was observed in the distribution of Arg753Gln polymorphism in BD and RHD compared to healthy controls. In conclusion, TLR2 gene Arg753Gln polymorphism is not associated with BD nor with RHD; and a duplicated region of the TLR2 exon 3 located 23-kb upstream of the polymorphic region may explain contradictory association findings described so far.     

TLR4基因Asp299Gly及TLR2基因Arg753Glu、Arg677Trp多态性与中国湖北汉族炎症性肠病无相关性

目的:研究TLR4基因Asp299Gly及LTLR2基因 Arg753Glu及Arg677Trp多态性在中国汉族人群中的分布,探讨其与炎症性肠病的相关性．方法:采用聚合酶链反应-限制性片段长度多态性方法,检测120例中国湖北汉族炎症性肠病患者与110例正常对照者TLR4 基因ASp299Gly及TLR2基因Arg753Glu及 Arg677Trp基因型,分析该基因多态性与炎症性肠病以及临床亚型的相关性．结果:炎症性肠病患者和健康对照者均未检测出TLR4基因ASp299Gly及TLR2基因 Arg753Glu及Arg677Trp突变型．结论:TLR4基因Asp299Gly及TLR2基因 Arg753Glu及Arg677Trp基因多态性与中国湖北汉族人群炎症性肠病的易感性无相关性．     

Arg753Gln TLR-2 polymorphism in familial mediterranean fever: linking the environment to the phenotype in a monogenic inflammatory disease

OBJECTIVE: Familial Mediterranean fever (FMF) is an autoinflammatory disease common in eastern Mediterranean populations. The most severe complication is the development of secondary amyloidosis. Toll-like receptor (TLR-2) plays a critical role in linking the recognition of microbes to immune activation. We investigated whether the Arg753Gln TLR2 polymorphism affected the development of secondary amyloidosis in patients with FMF. METHODS: We studied 75 patients with FMF, 40 patients with FMF who developed secondary amyloidosis, and 116 healthy controls. TLR2 gene Arg753Gln mutations were analyzed with a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequency of the Arg753Gln TLR2 polymorphism among the Turkish population was 6%, whereas it was 25.2% among patients with FMF (p < 0.01). The difference of the frequency of the polymorphism between FMF patients with and without amyloidosis was significant: 15/40 (37.5%) and 14/75 (18.6%), respectively (p = 0.02). CONCLUSION: The Arg753Gln polymorphism may affect the severity of this monogenic disease by influencing the innate immune response to pathogens. The presence of the polymorphism may influence the phenotype of FMF in geographic areas where bacterial insult is more common.     

Lack of association of single nucleotide polymorphisms in toll-like receptors 2 and 4 with enthesitis-related arthritis category of juvenile idiopathic arthritis in Indian population

Toll-like receptors 2 and 4 are over expressed in patients with enthesitis-related arthritis and cause increased production of pro-inflammatory cytokines. This aberrant functioning could be due to polymorphisms in TLR2 and TLR4. Hence, we genotyped ERA patients for Arg753Gln and Arg677Trp polymorphism in TLR2 gene and Asp299Gly and Thr399Ile polymorphism in TLR4 gene. DNA was extracted from blood from ERA patients and healthy controls. All four polymorphisms were studied by PCR–RFLP method. 200 healthy controls and 97 ERA patients were enrolled. All healthy controls and patients had wild-type allele for Arg753Gln and Arg677Trp TLR2 polymorphism. Regarding TLR4, Asp299Gly polymorphism A allele frequency was 90 % in controls and 96 % in patients (OR 2.7, 95 % CI 0.81–8.8). GG homozygous genotype was detected in one healthy control and was absent from patients. The TLR4 Thr399Ileu variant was not detected in patients. Out of 200 healthy controls, 10 were heterozygous (5 %) and only one was homozygous for rare variant (0.5 %). Polymorphisms in TLR2 and TLR4 are not associated with ERA.     

Toll-Like Receptor 2 Gene Polymorphisms Arg677Trp and Arg753Gln in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, with a continually rising mortality rate. As COPD is driven by abnormal pulmonary and systemic inflammation, Toll-like receptors (TLRs) seem to be important. TLRs play a key role in innate response, and in particular TLR2 gene polymorphisms Arg677Trp and Arg753Gln have been linked to an increased risk of infection. The purpose of this study was to investigate whether there is a link between polymorphisms in TLR2 and the onset or course of COPD. We analyzed 149 Caucasian COPD patients and 150 healthy individuals by using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. To further characterize the disease, patients were classified according to GOLD and divided into two subgroups comprising a stable (60/149) course and an unstable (89/149) course. The TLR2 Arg677Trp mutant allele was not found in any of the subjects. With a prevalence of 8.72% (13/149) for TLR2 Arg753Gln, the patients did not differ from the controls, with a prevalence of 10.67% (16/150). No significant difference was apparent (P = 0.571). None of the individuals showed homozygosity for TLR2 Arg753Gln. With regard to the course of COPD, the prevalence of TLR2 Arg753Gln in the control group did not differ significantly either from the stable subgroup (P = 0.196) or from the unstable subgroup (P = 0.891). Our results suggest that there is no association of the TLR2 polymorphisms Arg677Trp and Arg753Gln with either the onset or the course of COPD.     

Variant Toll-like receptor4 (Asp299Gly and Thr399Ile alleles) and Toll-like receptor2 (Arg753Gln and Arg677Trp alleles) in colorectal cancer

The innate immune system recognizes the presence of bacterial products through the expression of a family of membrane receptors known as Toll-like receptors (TLRs). Polymorphisms in TLRs have been shown to be associated with increased susceptibility to diseases such as inflammatory bowel disease. The aim of this study was to determine whether there was a correlation between polymorphisms of TLR4 (Asp299Gly; Thr399Ile) and TLR2 (Arg677Trp; Arg753Gln) genes and risk of colorectal cancer. DNA from 60 colorectal carcinoma patients from 3 major races in Malaysia (22 Malays, 20 Chinese and 18 Indians) and blood from 50 apparently healthy individuals were evaluated. Control group were matched to study group by race and age. The polymorphisms were determined by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Genotyping results showed two out of sixty tumour specimens (3.3%) harbored both variant TLR4 Asp299Gly and Thr399Ile alleles. In contrast, DNA isolated from blood cells of 50 apparently healthy individuals harbored wild type TLR4. In the case of TLR2 Arg753Gln genotyping, all of the fifty normal and 60 tumours were of the wild type genotype. TLR2 Arg677Trp genotyping showed a heterozygous pattern in all samples. However, this may not be a true polymorphism of the TLR2 gene as it is likely due to a variation of a duplicated ( pseudogene) region. There was only a low incidence (2/60; 3.3%) of TLR4 polymorphism at the Asp299Gly and Thr399Ile alleles in colorectal cancer patients. All normal and tumour samples harbored the wild type TLR2 Arg753 allele. Our study suggests that variant TLR4 (Asp299Gly and Thr399Ile alleles) as well as TLR2 (Arg753Gln allele) are not associated with risk of colorectal cancer.     

The lack of genetic association of the Toll-like receptor 2 (TLR2) Arg753Gln and Arg677Trp polymorphisms with rheumatic heart disease

Acute rheumatic fever (ARF) is a non-suppurative inflammatory disease after group A, beta haemolytic streptococcal pharyngitis. Certain individuals can develop ARF. This finding implies variability in host predisposition to ARF. A variety of studies have linked specific genetic markers with ARF or rheumatic heart disease (RHD) as a sequelae of ARF. For this purpose, we aimed to search the role of polymorphisms in Toll-like receptor-2 and -4 (TLR2 and TLR4) gene in Turkish patients with RHD. This study included a total 84 patients with RHD, ages ranging between 18 and 65, 25 male and 59 female, fulfilling the revised classification criteria of Jones. One hundred forty healthy unrelated persons were selected as a control group. Genotype analysis: DNA was extracted from whole blood. TLR4 gene (Asp 299Gly and Thr399Ile) and TLR2 gene (Arg753Gln and Arg677Trp) polymorphisms were genotyped by the previously reported method. Statistical analysis: binary logistic regression models were used. Results were expressed as odds ratios (OR) with corresponding 95% confidence intervals (95% CI). Significant level was predefined at 0.05. There was a significant difference for carrying Ile allele in the 399 position in the patients compared to healthy controls (OR = 5.26, 95% CI, 1.40-19.73, p = 0.014). In the TLR4 gene, Asp 299Gly polymorphism did not reach to a statistically significant value (OR = 3.02). We found no Arg753Gln polymorphism of the TLR2 gene in the patient group. There were three heterozygote samples in the healthy group. We did not detect Arg677Trp polymorphism of the TLR2 gene in both patient and control groups.     

Genetic polymorphism in CD14 gene,a co-receptor of TLR4 associated with non-alcoholic fatty liver disease

AIM To evaluate the pathogenic role of toll-like receptor(TLR) gene polymorphisms in patients with nonalcoholic fatty liver disease(NAFLD).METHODS Two hundred and fifty subjects(NAFLD = 200, healthy volunteers = 50) underwent polymerase chain reaction and restriction fragment length polymorphism to assess one polymorphism in the toll-like receptor 2(TLR2) gene(A753G), two polymorphisms in the TLR4 gene(TLR4 Asp299 Gly and Thr399 Ile allele), and two polymorphisms in the cluster of differentiation 14(CD14)(C-159 T and C-550T) gene, a co-receptor of TLR4. Association of TLR gene polymorphisms with NAFLD and its severity was evaluated by genetic models of association.RESULTS On both multiplicative and recessive models of gene polymorphism association, there was significant association of CD14 C(-159) T polymorphism with NAFLD; patients with TT genotype had a 2.6 fold increased risk of developing NAFLD in comparison to CC genotype. There was no association of TLR2 Arg753 Gln, TLR4 Asp299 Gly, Thr399 Ile, and CD14 C(-550) T polymorphisms with NAFLD. None of the TLR gene polymorphisms had an association with histological severity of NAFLD.CONCLUSION Patients with CD14 C(-159) T gene polymorphism, a co-receptor of TLR4, have an increased risk of NAFLD development.     

瘦素受体基因Gln223Arg多态性与非酒精性脂肪性肝病的关系

目的 探讨瘦素受体基因多态性与非酒精性脂肪肝患者临床表型间的关系.方法 以非酒精性脂肪肝患者和正常对照人群为研究对象,应用聚合酶链反应及限制性片段长度多态性方法(PCR-RFLP),对167例中国人(包括85例非酒精性脂肪肝患者和82例正常对照)的瘦素受体基因Gln223Arg进行研究,同时进行临床参数的检测.结果 (1)非酒精性脂肪肝患者和正常对照组人群中Gln223Arg基因型频率和等位基因频率差异无显著性(P>0.05).(2)非酒精性脂肪肝男性患者中AA AG基因型者TC、BMI高于GG基因型(P<0.05).(3)进一步用Logistic回归分析发现:在非酒精性脂肪肝男性患者中该基因变异与TC相关(P=0.019).结论 非酒精性脂肪肝男性患者瘦素受体基因Gln223Arg多态性与TC水平相关.瘦素受体基因Gln223Arg可能参与非酒精性脂肪肝的脂质代谢.     

瘦素受体基因Gln223Arg多态性与阻塞性睡眠呼吸暂停低通气综合征的关系

目的　探讨瘦素受体 (Lepr)基因Gln2 2 3Arg多态性与阻塞性睡眠呼吸暂停低通气综合征 (OSAHS)之间的关系。方法　采用聚合酶链反应 限制性片段长度多态性 (PCR RFLP)方法 ,测定181例中国北方地区汉族人Gln2 2 3Arg多态性的基因型 (其中OSAHS组 10 3例 ,非OSAHS对照组 78例 ) ,同时测定体重指数 (BMI)、颈围 (NC)、腰臀比 (WHR)以及醒后血压 (Bp)、醒后心率 (HR)、多导睡眠图 (PSG)。其中OSAHS组 6 0例 ,非OSAHS对照组 4 0例进行了血清空腹血糖 (FBG)、甘油三酯 (TG)、胆固醇 (Chol)、空腹真胰岛素 (TI)及血清瘦素 (Lep)的测定。结果　携带瘦素受体GG基因型的OSAHS患者颈围明显较 (GA +AA)基因型颈围大 [(41 4 6± 0 34)cmvs (39 85± 0 70 )cm ,P =0 0 31];Gln2 2 3Arg多态性与北方地区汉族人OSAHS无显著相关性 (χ2 =0 783,P =0 6 76 ) ;Gln2 2 3Arg不同基因型与OSAHS的总体脂、Bp、Lep、TI、FBG、TG、Chol及PSG各参数间不存在相关性 (P >0 0 5 )。结论　Lepr基因Gln2 2 3Arg多态性可能参与了OSAHS颈部脂肪选择性分布的调节 ,但其在北方地区汉族OSAHS的发病中可能无重要作用 ;目前的研究未发现Gln2 2 3Arg的基因型与OSAHS的BMI、高血压、FBG、TI、Lep、TG、Chol水平以及PSG参数之间存在相关性。     

北京地区汉族妇女瘦素受体基因Gln223Arg多态性和骨密度的关系

目的　探讨瘦素受体基因Gln2 2 3Arg多态性与青年妇女骨峰值和绝经后骨质疏松妇女骨密度的关系。方法　筛选 2 19例健康青年妇女和 10 2例绝经后骨质疏松妇女 ,用双能X线吸收测定法检测研究对象腰椎和髋部的骨密度 ,用PCR 限制性片段长度多态性分析方法检测研究对象的瘦素受体基因Gln2 2 3Arg的基因型。 结果　本研究人群中瘦素受体基因Gln2 2 3Arg基因型及基因频率的分布符合Hardy Weinberg定律 ,提示本研究人群是一个平衡群体。青年妇女组瘦素受体基因Gln2 2 3Arg的GG基因型组腰椎 2～ 4的骨密度高于GA和AA基因型组 [(1.2 13± 0 .12 7) g/cm2 比(1.15 4± 0 .12 4 ) g/cm2 ,P <0 .0 5 ],在股骨颈、Ward三角区、大转子部位各基因型组间骨密度值无统计学差异 ;10 2例绝经后骨质疏松妇女中LEPR基因Gln2 2 3Arg各基因型组间在腰椎 2～ 4、股骨颈、Ward三角区、大转子部位的骨密度值均无统计学差异。偏相关分析进一步表明青年妇女组的瘦素受体基因多态性与腰椎 2～ 4的骨密度相关 (r =- 0 .15 1,P <0 .0 5 )。结论　瘦素受体基因Gln2 2 3Arg的多态性与青年妇女腰椎 2～ 4骨峰值的获得和维持有关 ,可能是骨峰值独立的影响因素 ,等位基因G可能是骨量的保护因子 ,可作为预测汉族妇女骨质疏松发生危险性的遗传     

Analysis of TLR4 and TLR2 polymorphisms in inflammatory bowel disease in a Guangxi Zhuang population

AIM: To study the polymorphisms of toll-like receptor 4 (TLR4) gene Asp299Gly, Thr399Ile and TLR2 gene Arg753Gln, Arg677Trp and susceptibility to inflammatory bowel disease (IBD) in the Zhuang population from Guangxi, China.METHODS: A case-control study was performed from February 2007 to October 2011 which included 146 Zhuang patients with IBD in the experimental group and 164 healthy Zhuang subjects who acted as the control group. All patients and healthy subjects were from the Guangxi Zhuang Autonomous Region of China. Genomic DNA was extracted from intestinal tissue by the phenol chloroform method. TLR4 gene Asp299Gly, Thr399Ile and TLR2 gene Arg753Gln, Arg677Trp were amplified by polymerase chain reaction (PCR), and then detected by PCR-restriction fragment length polymorphism (RFLP).RESULTS: The TLR4 gene Asp299Gly was digested using Nco I restriction enzyme, and a single band of 249 bp was observed which showed that it was a wild type (AA). The TLR4 gene Thr399Ile was digested using Hinf Irestriction enzyme and only the wild type (CC) was detected. In addition, the TLR2 gene Arg677Trp was digested using Aci I restriction enzyme and only the wild type (CC) was detected. The TLR2 gene Arg753Gln was digested using Pst I restriction enzyme. Only the wild type (GG) as a single band of 254 bp was observed during RFLP. Overall, no heterozygous or homozygous single nucleotide polymorphism mutations were found in patients with Crohn’s disease and ulcerative colitis both in the TLR4 gene Asp299Gly, Thr399Ile and the TLR2 gene Arg677Trp, Arg753Gln in the Zhuang population from the Guangxi Zhuang Autonomous Region of China.CONCLUSION: The TLR4 gene Asp299Gly, Thr399Ile and TLR2 gene Arg753Gln, Arg677Trp polymorphisms may not be associated with IBD in the Zhuang population from the Guangxi Zhuang Autonomous Region of China.     

The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia

SETTING: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. Studies in a murine model of pulmonary TB have identified a role for Toll-like receptor 4 (TLR4) in the development of chronic lung infection with Mycobacterium tuberculosis. The Asp299Gly polymorphism in the human TLR4 gene is associated with in vivo hyporesponsiveness to lipopolysaccharide (LPS) in Caucasians. OBJECTIVE: To determine whether TLR4 Asp299Gly influences LPS responses or susceptibility to pulmonary TB in humans in a Gambian population sample. DESIGN: We compared whole blood monokine responses to LPS in 245 healthy blood donors stratified by TLR4 Asp299Gly genotype to assess whether this polymorphism was functional in this population. A case-control study of 640 subjects was conducted to investigate whether TLR4 Asp299Gly was associated with TB. RESULTS: LPS-induced tumour necrosis factor, interleukin-1 beta and interleukin-10 production was not influenced by TLR4 Asp299Gly genotype. There was no association between TLR4 Asp299Gly and TB. CONCLUSION: Our data suggest that TLR4 Asp299Gly has no influence on monocyte LPS responses or susceptibility to TB in Gambians and could be an ancient neutral polymorphism.     

The glycine allele of a glycine/arginine polymorphism in the beta2-adrenergic receptor gene is associated with essential hypertension in a population of Chinese origin.

BACKGROUND: Several studies implicate polymorphisms in the human beta-adrenergic receptor gene (ADRB2) in the susceptibility to hypertension. We sought to replicate these results in a population of Chinese origin primarily from Taiwan and the San Francisco Bay area. METHODS: We genotyped >800 hypertensive subjects and individuals with low-normal blood pressure that were derived largely from the same families as the hypertensive patients for three polymorphisms in the ADRB2 gene: a C/T transition at position 47 (C-47T) in the 5' leader cistron; another C/T transition that results in a glycine/ arginine substitution at codon 16 (Gly16Arg), and a G/C transversion that causes a glutamate/glutamine substitution at codon 27 (Glu27Gln). RESULTS: The Gly16Arg was significantly associated with hypertension (P < .03). Under a dominant model, for hypertension the relative risk for the Gly/Gly and Gly/Arg genotypes versus the Arg/Arg genotype was 1.35 (95% confidence limits [CL] 1.08, 1.70); for low-normal blood pressure the relative risk was 0.79 (95% CL 0.66, 0.94). This polymorphism explained approximately 1% of the variance in systolic and diastolic blood pressures in our study population. There was no evidence of association between the C-47T and Glu27Gln polymorphisms and hypertension in this population. CONCLUSIONS: The Glyl6 allele in the beta2-adrenergic receptor gene is a susceptibility allele for essential hypertension in a population of Chinese origin.     

慢性阻塞性肺疾病伴营养不良患者瘦素受体基因Gln223Arg多态性研究

目的探讨瘦素受体基因Gln223Arg多态性与慢性阻塞性肺疾病伴营养不良的关系。方法观察158例COPD临床稳定期老年患者及108例健康对照者,并根据体重指数（BMI）、理想体重百分比（NW％）、三头肌皮皱厚度（TSF）、上臂中点臂围（MAC）、血清白蛋白（ALB）、总淋巴细胞（LYM）等营养参数,将COPD组分为营养不良组（COPD1组）66例,COPD非营养不良组（COPD2组）92例。用酶联免疫吸附试验（ELISA）法测定血清瘦素水平,采用聚合酶链式反应及连接酶检测反应方法（PCR—LDR）测定158例COPD患者与108例对照组的瘦素受体基因Gln223Arg多态性的基因型。结果COPD营养不良组Gln223Arg基因型GG、GA及AA的频率分别为0．924、0．061和0．015,G和A等位基因频率分别为0．955和0．045;COPD非营养不良组Gln223Arg基因型GG、GA及AA的频率分别为0．783、0．206和0．011,G和A等位基因频率分别为0．886和0．114;对照组Gln223Arg基因型GG、GA及AA的频率分别为0．769、O．222和0．009,G和A等位基因频率分别0．88和0．12;COPD1组Gln223Arg基因型及等位基因频率与COPD2组和对照组比较差异有显著性;COPD2组和对照组比较差异无显著性。不同基因表型血清瘦素水平GG型低于A／G型＋AA型（40．08±17．53ng／mLVS44．35±16．95ng／mL）,但差异无统计学意义。结论瘦素受体基因Gln223Arg多态性可能与COPD营养不良有关。     

Factor VII gene polymorphism, factor VII levels, and prevalent cardiovascular disease: the Framingham Heart Study

Elevated factor VII levels have been associated with increased cardiovascular risk in some studies. The arginine/glutamine (Arg/Gln) polymorphism of the factor VII gene has been previously shown to modify factor VII levels. However, the presence of a gene/environment interaction on factor VII levels or a link with cardiovascular disease (CVD) remains uncertain. We studied subjects from the Framingham Heart Study to determine (1) the extent to which this genetic polymorphism affects factor VII levels; (2) whether interactions exist between this polymorphism and environmental factors on factor VII levels; and (3) the association between the polymorphism and CVD. Genotype data and factor VII antigen levels were available in 1816 subjects. Factor VII levels differed significantly among genotypes in an additive fashion: Gln homozygous, 82.7+/-2.5%; heterozygous, 92.2+/-0.7%; and Arg homozygous, 100. 5+/-0.4% (P<0.0001). The polymorphism was the strongest, single predictor of factor VII levels, explaining 7.7% of the total variance of factor VII levels, whereas other traditional risk factors combined explained an additional 11.5% of the variance. There was an interaction (P=0.02) between the genotype and total cholesterol on factor VII levels, such that the correlation coefficient and slope (factor VII level/total cholesterol) were greatest in Gln/Gln subjects. Among 3204 subjects characterized for genotype and CVD, there was no significant relationship between the genotype and CVD (P=0.12). In the Framingham Heart Study, the Arg/Gln polymorphism was significantly associated with factor VII antigen levels. The strength of the association suggests that genetic variation plays an important role in determining factor VII levels. However, despite being associated with factor VII levels, the Arg/Gln polymorphism was not associated with prevalent CVD.     

甘露聚糖结合凝集素基因A/B位点与新疆维吾尔族结核病的相关性研究

目的 探讨甘露聚糖结合凝集素（mannan-binding lectin,MBL）基因的多态性是否与新疆维吾尔族人群结核病发病相关。 方法 通过使用引物序列特异性PCR(SSP-PCR)的方法分别对226例新疆维吾尔族活动性肺结核患者（简称病例组）及231例有结核分枝杆菌接触史的新疆同民族健康者（简称对照组）进行MBL基因的A/B多态性位点进行基因分型,统计学分析采用病例对照分析研究不同基因型与新疆维吾尔族结核病易感性的关系。 结果 在病例组中,MBL基因A/B位点 AA 基因型106例(占46.90%),AB基因型106例（占46.90%),BB基因型14例(占6.20%);对照组AA基因型则为146例(占63.20%),AB基因型80例(占34.63%),BB基因型5例(占2.17%)。病例组中MBL-AB突变基因频率显著高于健康对照组,两组的突变基因频率分别为6.20%、2.17%,差异有统计学意义(χ²=5.224,P_c＜0.05)。 结论 新疆维吾尔族人群中MBL基因AA基因型可能为结核病的保护性因素,BB基因型可能为结核病发病的危险性因素。新疆维吾尔族人群中MBL基因A/B位点多态性与结核病易感性有明显相关性。     

Utility of the Arg/Gln polymorphism of the factor VII (FVII) gene, serum lipid levels and body mass index in the prediction of the FVII:C and FVII:Ag in North Karelia; a cross-sectional and prospective study.

The arginine/glutamine (Arg/Gln) polymorphism of the factor VII (FVII) gene is associated with variation in coagulation activity (FVII:C) and antigen concentration (FVII:Ag) of the FVII protein. We estimated frequency distributions of the Arg and Gln alleles and respective genotypes in North Karelia, and evaluated the utility of this polymorphism, serum lipids, and body mass index (BMI) in the prediction of the distributions of FVII:C and FVII:Ag in a cross-sectional study and in a prospective cohort study. The sample comprised 203 males and 262 females (aged 45-64 years) who were seen twice, in 1992 and 1995. The Arg/Arg genotype and the Arg allele frequencies were among the highest reported so far (86 and 93% respectively, in men; and 89 and 94% respectively, in women). Intragenotypic means of both FVII:C and FVII:Ag were significantly higher in the Arg/Arg genotype than in the Arg/Gln genotype in both genders. Also, intragenotypic variances were different in different genotypes in females. Regression relationships between the FVII:C and FVII:Ag and serum triglyceride, and total cholesterol levels and BMI were positive in both genotypes in both genders, which has not been found in other populations. In prospective analyses, average changes in the FVII:C and FVII:Ag were genotype specific in both genders, as were also regression relationships between these changes and changes in triglyceride level in females (P = 0.065 for FVII:C and P = 0.061 for FVII:Ag). A consequence of these complex genetic architectures is that predictive utility of the Arg/Gln genotypes depends on population, gender, serum lipid levels, and BMI, and changes in these factors over time.     

The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania

Toll-like receptor 4 (TLR4) plays an important role in the pattern recognition of Mycobacterium tuberculosis, and polymorphisms in the TLR4 gene influence the function of the receptor. We therefore investigated in a cohort of HIV-infected Tanzanian patients whether the Asp299Gly TLR4 polymorphism is associated with the development of active tuberculosis. We found a greater risk of developing active tuberculosis as well as a reduction in CD4 T-cell counts in patients with the Asp299Gly TLR4 polymorphism.