Combined promoter haplotypes of the IL10R genes are associated with protection against severe malaria in Gabonese children

The critical barrier in control of infections remains the failure of the immune system to clear parasites despite antigen recognition. We examined and validated possible association of regulatory immune gene polymorphisms in a cohort of children with mild and severe malaria. We focussed on two precursors of the Interleukin 10 Receptor (IL10R) gene namely the IL10R alpha and IL10R beta that play a fundamental role in initiation of signal transduction. Initial screening across 40 Gabonese adult individuals revealed two promoter variants for the IL10R alpha and three for the IL10R beta precursor, respectively. Validation of these variants for their allelic gene expression by transient transfection assays exhibited an altered expression in rs56356146 and rs7925112 of the IL10R alpha (P < 0.5); rs8178435 and rs999788 in the IL10R beta constructs (P < 0.0001), respectively. We further investigated the functional role of those SNP variants exhibiting altered expression in a cohort of children with mild and severe malaria. We genotyped 145 children with mild and 185 children with severe malaria for IL10R alpha; for IL10R beta, 102 children with mild and 101 children with severe malaria. We found that none of the SNP variants had any significant association neither in children with mild or severe malaria. The haplotype −185/−116 of IL10R alpha (TT) in combination with the haplotype −754/−750 of IL10R beta (AC) contributed towards mild malaria in comparison to severe malaria [TT + AC odds ratio of 0.73 (95% CI 0.56–0.94) P = 0.01]. This study may provide a better understanding on the role of IL10R promoter allelic variants contribution to a protective effect on the development of severe malaria.     

Circulating levels of the interleukin (IL)-4 receptor and of IL-18 in patients with Plasmodium falciparum malaria

Circulating levels of sIL-4R, IL-18 and IFN-gamma were studied by ELISA in 36 Gabonese patients with Plasmodium falciparum malaria (29 children, 7 adults). Drug induced clearance of parasitemia, studied in 22 patients with mild disease, was accompanied by a rapid decrease of sIL-4R and IFN-gamma to normal values and an increase of circulating IL-18, suggesting the downregulation of a type 2 biased immune response and a dissociated type 1 responsiveness while resolving parasitemia. Comparing subgroups with hyperparasitemia/severe anemia and mild malaria, children with severe malaria had significant higher levels of sIL-4R and IFN-gamma, whereas IL-18 levels were not statistically different. Furthermore, among those children, higher levels of circulating IL-18 correlated with a lower degree of parasitemia.     

Several polymorphisms of KCNQ1 gene are associated with plasma lipid levels in general Chinese populations

Background

Potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) is thought to be an important candidate gene of diabetes. Several single nucleotide polymorphisms (SNPs) in a 40-kb linkage disequilibrium (LD) block in its intron 15 have been identified to be associated with diabetes in East Asian populations in recent genome-wide association studies. The aim of this study was to investigate whether KCNQ1 polymorphisms influence the levels of the metabolic phenotypes in general Chinese populations.

Methodology/Principal Findings

We investigated the associations of two SNPs (rs2237892 and rs2237895) in the aforementioned 40-kb LD block, a missense variant rs12720449 (P448R) in exon 10, and a synonymous variant rs1057128 (S546S) in exon 13 with metabolic phenotypes in a Uyghur population (n = 478) and replicated these associations in a Han population (n = 2,485). We found that rs2237892-T allele was significantly associated with decreased triglyceride levels (p_combined = 0.001). The minor G allele of the rs12720449, with sharp difference of the allelic frequency between European and East Asian populations (0.2% versus 14%, respectively), was associated with a lower triglyceride levels than G allele in Uyghur subjects (p = 0.004), in Han subjects (p = 0.052), and in subjects of meta-analysis (p_combined = 0.001). Moreover, the minor A allele of the rs1057128 was also associated with decreased triglyceride levels in meta-analysis (p_combined = 0.010).

Conclusions

To the best of our knowledge, this is the first report associating a missense mutation of KCNQ1, rs12720449, with triglyceride levels. Rs2237892, representing the 40-kb LD block, is also associated with triglyceride levels in Han population. Further studies are required to replicate these findings in other East Asian populations.     

Haplotypes of IL12B promoter polymorphisms condition susceptibility to severe malaria and functional changes in cytokine levels in Thai adults

Polymorphic variability in immune response genes, such as IL12B, encoding the IL-12p40 subunit is associated with susceptibility to severe malaria in African populations. Since the role of genetic variation in conditioning severe malaria in Thai adults is largely unexplored, the functional association between IL12B polymorphisms [i.e. IL12Bpro (rs17860508) and IL12B 3′ UTR T/G (rs3212227)], severe malaria and cytokine production was examined in patients with Plasmodium falciparum infections (n = 355) recruited from malaria endemic areas along the Thai–Myanmar border in northwest Thailand. Circulating IL-12p40 (p = 0.049) and IFN-γ (p = 0.051) were elevated in patients with severe malaria, while only IL-12p40 was significantly higher in severe malaria patients with hyperparasitaemia (p = 0.046). Carriage of the IL12Bpro1.1 genotype was associated with enhanced severity of malaria (OR, 2.34; 95% CI, 0.94–5.81; p = 0.066) and hyperparasitaemia (OR, 3.42; 95% CI, 1.17–9.87; p = 0.025) relative to the IL12Bpro2.2 genotype (wild type). Individuals with the IL12Bpro1.1 genotype also had the lowest IL-12p40 (p = 0.002) and the highest IFN-γ (p = 0.004) levels. Construction of haplotypes revealed that carriage of the IL12Bpro-2/3′ UTR-T haplotype was associated with protection against severe malaria (OR, 0.51; 95% CI, 0.29–0.90; p = 0.020) and reduced circulating IFN-γ (p = 0.06). Thus, genotypic and haplotypic variation at IL12Bpro and IL12B 3′ UTR in this population influences susceptibility to severe malaria and functional changes in circulating IL-12p40 and IFN-γ levels. Results presented here suggest that protection against severe malaria in Thai adults is associated with genotypic variants that condition enhanced IL-12p40 and reduced IFN-γ levels.     

Elevated serum levels of IL-1ra in children with Plasmodium falciparum malaria are associated with increased severity of disease

Animal models suggest that cytokines and chemokines play a role in cerebral malaria (CM) pathogenesis, but levels of a number of cytokines and chemokines thought to be important in the pathogenesis of other infectious diseases are not well characterized in children with CM. Serum levels of granulocyte-colony stimulating factor (G-CSF), interleukin-1 receptor antagonist (IL-1ra), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were measured in 77 children with CM, 70 children with uncomplicated malaria (UM) and 63 healthy community children (CC) in Uganda. Children with CM had elevated serum levels of IL-1ra and IL-8 as compared to children with UM (median levels in pg/ml, 11,891 vs. 6510, P = 0.05, and 63 vs. 41, P = 0.01, respectively). Children with CM who died (n = 4) had higher serum levels than survivors of IL-1ra (median levels in pg/ml, 65,757 vs. 10,355, P = 0.02), G-CSF (709 vs. 117, P = 0.02), and MCP-1 (1275 vs. 216, P = 0.03) but not IL-8 (76 vs. 62, P = NS). Elevated IL-1ra levels are associated with increased disease severity in children with malaria, and very elevated levels of IL-1ra, G-CSF and MCP-1 are seen in children who die of CM.     

Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans

Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p < 5 × 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10(-6) to 1.75 × 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 × 10(-6) to 1.63 × 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.     

IL6 and IL1B polymorphisms are associated with fat mass in older men: the MrOS Study Sweden

There is growing evidence that immune functions are linked to the regulation of body fat. Our studies of knockout mice indicate that both endogenous interleukin (IL)-6 and IL-1 can suppress mature-onset obesity. We now investigated whether four common polymorphisms of the IL6 and IL1 systems are associated with the fat mass measured with dual-energy X-ray absorptiometry (DXA) in elderly men (n = 3,014). The study subjects were from the Swedish part of the MrOS multicenter population study and 69-81 years of age. The IL6 -174 G>C (Minor allele frequency (MAF) = 48%) gene promoter polymorphism was associated with the primary outcome total fat mass (P = 0.006) and regional fat masses, but not with lean body mass. The IL1B -31T>C (MAF = 34%) polymorphism was also associated with total fat (P = 0.007) and regional fat masses, but not lean body mass. The IL-1 receptor antagonist (IL-1ra) gene (IL1RN) +2018 T>C (MAF = 27%) polymorphism (in linkage disequilibrium (LD) with a well-studied variable number tandem repeat of 86 base pair (bp)) and IL1B +3953 C>T (MAF = 26%) polymorphism were not associated with total fat mass. In conclusion, the IL-1 and IL-6 systems, shown to suppress mature-onset obesity in experimental animals, contain gene polymorphisms that are associated with fat, but not lean, mass in elderly men.     

Role of IL6, IL12B and VDR gene polymorphisms in Plasmodium vivax malaria severity,parasitemia and gametocytemia levels in an Amazonian Brazilian population

ObjectiveTo investigate the influence of IL6, IL12B and VDR single nucleotide polymorphisms (SNPs) in uncomplicated Plasmodium vivax infection symptoms intensity, parasitemia and gametocytemia levels in a Brazilian Amazonian population.MethodsA total of 167 malaria patients infected by P. vivax have parasitemia and gametocytemia levels estimated before treatment. Fourteen clinical symptoms were evaluated and included in a principal component analysis to derive a clinical symptom index. Patients were genotyped for IL6-174C > G, IL12B 735T > C, 458A > G, 159A > C, and VDR FokI, TaqI, BsmI SNPs by Taqman 5’ nuclease assays. A General Linear Model analysis of covariance with age, gender, exposure period and infection history and genetic ancestry was performed to investigate the association of genotypes with parasitemia and gametocytemia levels and with a clinical symptom index.ResultsHigher parasitemia levels were observed in IL6-174C carriers (p = 0.02) whereas IL12B CGT haplotype carriers presented lower parasitemia levels (p = 0.008). VDR TaqIC/BsmIA haplotype carriers showed higher gametocyte levels than non-carriers (p = 0.013). Based on the clinical index values the IL6-174C > G polymorphism was associated with malaria severity. The IL6-174C carriers presented a more severe clinical index when compared to GG homozygotes (p = 0.001).ConclusionThe present study suggests that IL6, IL12 and VDR influence severity, parasitemia and gametocytemia clearance in P. vivax infections, and highlights their potential role in malaria immune response in an Amazonian population.     

Comorbidities are associated with different features of severe asthma

Background

According to ATS/ERS document on severe asthma (SA), the management of these patients requires the identification and proper treatment of comorbidities, which can influence the control of asthma.

Methods

The aim of this study was to assess the independent effect of different comorbidities on clinical, functional and biologic features of SA. Seventy-two patients with SA according to GINA guidelines were examined. We collected demographic data, smoking habit, asthma history, and assessment of comorbidities. Pulmonary function, inflammatory biomarkers, upper airway disease evaluation, asthma control and quality of life were carefully assessed.

Results

The mean age of patients was 59.1 years (65.3% female, 5.6% current smokers). Comorbidities with higher prevalence were: chronic rhinosinusitis with or without nasal polyps (CRSwNP or CRSsNP), obesity and gastro-esophageal reflux (GERD), with some overlapping among them. In an univariate analysis comparing patients with single comorbidities with the other ones, asthmatics with CRSwNP had lower lung function and higher sputum eosinophilia; obese asthmatics had worse asthma control and quality of life, and tended to have lower sputum eosinophils; asthmatics with GERD showed worse quality of life. In multivariate analysis, obesity was the only independent factor associated with poor asthma control (OR 4.9), while CRSwNP was the only independent factor associated with airway eosinophilia (OR 16.2). Lower lung function was associated with the male gender and longer duration of asthma (OR 3.9 and 5.1, respectively) and showed a trend for the association with nasal polyps (OR 2.9, p?=?0.06).

Conclusion

Our study suggests that coexisting comorbidities are associated with different features of SA.

     

GRM7 polymorphisms are not associated with ischemic stroke in Iranian population

Abstract

Objectives: Ischemic stroke is the main neurological cause of acquired incapability in adults and a prominent cause of mortality. Several association studies have been conducted to explore the role of candidate genes in this neurological condition.

Methods: In the present study, we aimed at identification of association between Glutamate Metabotropic Receptor 7 (GRM7) and risk of ischemic stroke in Iranian population. Two intronic variants within this gene (rs6782011 and rs779867) were genotyped in 318 sporadic ischemic stroke cases and 300 unrelated, healthy controls individuals.

Results: No significant difference was found in allele, genotype or haplotype frequencies of these SNPs between cases and controls after correction for multiple comparisons.

Conclusion: Consequently, the assessed GRM7 variants are not implicated in risk of ischemic stroke in Iranian population.     

IFNG polymorphisms are associated with tuberculosis in Han Chinese pediatric female population

Host genetic factors play a major role in determining differential susceptibility to human tuberculosis (TB), a re-emerging infectious disease throughout the world. Genetic variations in the IFNG gene coding for interferon gamma (IFN-γ), have been identified in TB patients. To investigate the association of the IFNG polymorphisms with TB susceptibility in Chinese pediatric population. A case–control study of 189 TB patients and 164 controls was performed using single-nucleotide polymorphism (SNP) analysis. Genomic DNA was extracted from leukocytes in peripheral blood. Three SNPs of IFNG, including ?1616C/T (rs2069705), +874A/T (rs2430561), and +3234C/T (rs2069718), were selected for genotyping and analysis. The +874A and +3234C alleles were more frequent among TB patients (P = 0.108 and P = 0.088), especially in females (both P = 0.029), although this difference was not significant since Bonferroni corrected significance threshold was 0.025 (two of three SNPs were found to be in linkage disequilibrium). More pronounced differences for the +874 and +3234 polymorphisms were found under the genotype comparison between TB cases and controls in the total population [P = 0.026 (borderline non-significance) and P = 0.020, respectively], and in the female subgroup (P = 0.020 and P = 0.020). The dominant model of inheritance was shown to be significant for +874A and +3234C alleles (both P = 0.019) in the female subgroup. The +874A and +3234C alleles were more frequently found in extrapulmonary TB patients than in controls (P = 0.039). Haplotype analysis carried out on these three SNPs showed the TTT haplotype to be more frequent in controls than in TB cases, and this difference showed a strong significance (P = 0.005). The +874A and +3234C alleles may be related to TB susceptibility in the female subgroup in the Chinese pediatric population of North China. The higher rate of +874A (known to correlate with lower IFN-γ expression) in the extrapulmonary TB subgroup suggests a sufficient IFN-γ expression to be not only an important factor for the onset of TB disease but also for limiting its dissemination to lungs.     

RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans

We previously found that plasma RBP4 levels were strongly associated with metabolic syndrome components. This study aimed to determine whether RBP4 variants are associated with the metabolic syndrome components and plasma RBP4 levels, and to investigate whether the associations between plasma RBP4 and the metabolic syndrome components are causal. Five tagSNPs were tested for their associations with plasma RBP4 levels and metabolic syndrome components in a population-based sample of 3,210 Chinese Hans. A possible causal relationship between plasma RBP4 levels and hypertriglyceridemia was explored by Mendelian randomization. Plasma RBP4 levels were significantly associated with rs10882273 (βz −0.10SD[−0.17, −0.03], P = 0.0050), rs3758538 (βz −0.13SD[−0.24, −0.02], P = 0.0249) in all participants, and with rs17108993 in Shanghai participants (βz −0.19SD[−0.32, −0.05], P = 0.0061). The single nucleotide polymorphism (SNP) rs3758538 was significantly associated with hypertriglyceridemia (OR 0.62[0.45–0.85], P = 0.0026) and triglycerides (βz −0.19SD[−0.30, −0.07], P = 0.001) in all participants. In Mendelian randomization analysis, the observed effect size of association between rs3758538 and hypertriglyceridemia was different from the expected effect size (P = 0.0213). This is the first study to show that the RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans. However, results of Mendelian randomization do not support the hypothesis that RBP4 levels are causally related to hypertriglyceridemia risk.     

Mitochondrial DNA polymorphisms are associated with the longevity in the Guangxi Bama population of China

Human longevity is an interesting and complicated subject, with many associated variations, geographic and genetic, including some known mitochondrial variations. The population of the Bama County of Guangxi Province of China is well known for its longevity and serves as a good model for studying a potential molecular mechanism. In this study, a full sequence analysis of mitochondrial DNA (mtDNA) has been done in ten Bama centenarians using direct sequencing. Polymorphisms of the displacement loop (D-loop) region of mtDNA and several serum parameters were analyzed for a total of 313 Bama individuals with ages between 10 and 110 years. The results showed that there were seven mitochondrial variations, A73G, A263G, A2076G, A8860G, G11719A, C14766T, and A15326G, and four haplogroups, M(*), F1, D* and D(4) in 10 Bama centenarians. In the D-loop region of mtDNA, the mt146T occurred at a significantly lower frequency in those is the older age group (90-110 years) than in the middle (80-89 years) and in the younger (10-79 years) groups (P < 0.05). The mt146T also had lower systolic blood pressure and serum markers such as total cholesterol, triglyceride and low density lipoprotein than did mt146C in the older age group (P < 0.05). No significant differences were observed between the mt146C and the mt146T individuals in the middle and the younger groups (P > 0.05). The mt5178C/A polymorphisms did not show any significant differences among the three age-groups (P > 0.05), but different nationalities in the Bama County did show a significant difference in the mt5178C/A polymorphisms (P < 0.05). These results suggest that the mt146T/C polymorphisms in Guangxi Bama individuals may partly account for the Bama longevity whereas the mt5178C/A polymorphisms are strongly associated with the nationalities in the Guangxi Bama population.     

MMP-9 polymorphisms are related to serum lipids levels but not associated with colorectal cancer susceptibility in Chinese population

Matrix metalloproteinases (MMPs) play an important role in cancer development and aggression. MMP-9 polymorphisms may affect MMPs expression and contribute to interindividual differences in susceptibility to a wide spectrum of cancers. The purpose of this study was to investigate the association of MMP-9 P574R and R668Q polymorphisms with colorectal cancer (CRC); and to explore the relationship among the polymorphisms and clinicopathologic parameters, serum tumor markers and lipids. The genotypes were determined by polymerase chain reaction-restriction fragment lengthy polymorphism (PCR-RFLP). Tumor markers were measured with the Electro ChemiL uminescence method. Lipids levels were analyzed using an automatic biochemistry analyzer. The both polymorphisms were not associated with the risk of CRC risk. The clinicopathologic parameters, tumor markers were not associated with MMP-9 polymorphisms. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly higher in patients with P574R PP genotype compared with patients with P574R PR combined RR genotypes (P?=?0.043 and P?=?0.038 respectively). Our data suggested that MMP-9 P574R and R668Q were not associated with CRC risk, but P574R affected serum LDL-C and TC levels in CRC patients.     

Heat shock protein 70 gene polymorphisms are associated with paranoid schizophrenia in the Polish population

HSP70 genes have been considered as promising schizophrenia candidate genes based on their protective role in the central nervous system under stress conditions. In this study, we analyzed the potential implication of HSPA1A +190G/C, HSPA1B +1267A/G, and HSPA1L +2437T/C polymorphisms in the susceptibility to paranoid schizophrenia in a homogenous Caucasian Polish population. In addition, we investigated the association of the polymorphisms with the clinical variables of the disease. Two hundred and three patients with paranoid schizophrenia and 243 healthy controls were enrolled in the study. Polymorphisms of HSPA1A, -1B, and -1L genes were genotyped using the PCR-RFLP technique. Analyses were conducted in entire groups and in subgroups that were stratified according to gender. There were significant differences in the genotype and allele frequencies of HSPA1A polymorphism between the patients and controls. The +190CC genotype and +190C allele were over-represented in the patients and significantly increased the risk for developing schizophrenia (OR = 3.45 and OR = 1.61, respectively). Interestingly, such a risk was higher for females with the +190CC genotype than for males with the +190CC genotype (OR = 5.78 vs. OR = 2.76). We also identified the CGT haplotype as a risk haplotype for schizophrenia and demonstrated the effects of HSPA1A and HSPA1B genotypes on the psychopathology and age of onset. Our study provided the first evidence that the HSPA1A polymorphism may potentially increase the risk of developing paranoid schizophrenia. Further independent analyses in different populations to evaluate the role of gender are needed to replicate these results.     

TNF gene polymorphisms are associated with reduced survival in severe Chagas' disease cardiomyopathy patients

Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-alpha in the progression of heart failure, and the increased TNF-alpha plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the -308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction相似文献