TREX1 polymorphisms associated with autoantibodies in patients with systemic lupus erythematosus

Three-prime repair exonucleases 1 and 2 (TREX1 and TREX2) play a role in the metabolism and clearance of DNA. The objective of this study was to confirm whether polymorphisms of TREX1 and TREX2 are associated with genetic susceptibility to systemic lupus erythematosus (SLE), and examine associations with autoantibodies (auto-Abs) in SLE. We investigated the genetic variants in 24 Korean individuals by direct sequencing. The genotype distributions of single-nucleotide polymorphisms (SNPs) and haplotypes were analyzed with multiple logistic regression models while controlling for covariates. We identified 12 and 5 SNPs of TREX1 and TREX2, of which −20260G>C, −389T>C, −381C>T, and +531C>T SNPs of TREX1; −23386G>C, −14703G>A, −7279C>T, and +1747C>T SNPs of TREX2; and each of three haplotypes were selected for larger scale genotyping (n = 1,053). No statistically significant association with the risk of SLE was observed in TREX1 and TREX2. TREX1 polymorphism −20260G>C showed protective effect on the production of anti-Ro Ab, and +531C>T in exon 16 and ht2 [G–T–C–T] showed also protective effect on the production of anti-dsDNA Ab, although the effect of +531C>T disappeared after multiple correction. An erratum to this article can be found at     

Putative association of SMAPIL polymorphisms with risk of aspirin intolerance in asthmatics

Background. Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes. Objective. To verify our hypothesis that SMAP1L could play a role in the development of AIA, this study investigated associations between single-nucleotide polymorphisms (SNPs) of the SMAP1L gene and AIA. Methods. We conducted an association study between 19 SNPs of the SMAP1L gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of SMAP1L and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates. Results. Logistic analyses revealed that three common polymorphisms, rs2982510, rs2294752, and rs446738, were putatively associated with the increased susceptibility to AIA (p = .003, p^corr = .004, OR = 0.24, 95% CI = 0.09–0.62 for rs2982510 and rs2294752; p = .008, p^corr = .03, OR = 0.44, 95% CI = 0.24–0.80 for rs446738, in the recessive model). In addition, rs2982510 and rs2294752 were significantly associated with the fall of forced expiratory volume in 1 s (FEV₁) by aspirin provocation (p = .001, p^corr = .04 in the recessive model for both SNPs). Conclusions. Our findings suggest that SMAP1L might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance.     

Role of tagged SNPs of the AGT gene in causing susceptibility to essential hypertension

Aim: Angiotensinogen (AGT) is one of the candidate genes that has been extensively investigated for association of its variants with essential hypertension. Studies focusing on the contribution of tagged single nucleotide polymorphisms (SNPs) in the AGT gene are limited and lacking from Indian population. Hence, the present study was carried out to examine the role of five tagged SNPs viz., g.6147G>A (rs7539020), g.5978A>G (rs2493134); g.6241T>C (rs1078499), g.7781G>T (rs11122577), and g.5855G>A (rs3789678) in the development of hypertension. Materials and Methods: 202 hypertensives and 222 normotensives were screened for five tagged SNPs using the method of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results: The present study revealed significant association of g.5855G>A polymorphism with essential hypertension in different logistic regression models wherein protection was conferred by g.5855G>A against developing the condition. The polymorphism led to the creation of new exonic splicing enhancer and destruction of exonic splicing silencer site thereby enhancing the process of mRNA splicing. The haplotypes AGTG and GACG were found to have a significant protective effect. Other polymorphisms did not show any significant association with hypertension. Conclusion: The present study is the first one to report the protective role of g.5855G>A polymorphism in the development of essential hypertension. The results reflect possibility of ethnic variation in the contribution of g.5855G>A polymorphism of the AGT gene to essential hypertension.     

Putative association of transforming growth factor‐α polymorphisms with clearance of hepatitis B virus and occurrence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Summary. Previous studies showed that several genetic polymorphisms might influence the clinical outcome of chronic hepatitis B virus (HBV) infection, including HBV clearance or development of hepatocellular carcinoma (HCC). The aim of this study was to determine whether polymorphisms of the transforming growth factor‐α (TGF‐α) gene are associated with clinical outcome of HBV infection. A total of 1096 Korean subjects having either present or past evidence of HBV infection were prospectively enrolled between January 2001 and August 2003. Among 16 genetic variants in TGFA gene, nine variants were genotyped using TaqMan assay and the genetic association with HBV clearance and HCC occurrence was analysed. Statistical analyses revealed that TGFA+103461T>C, TGFA+106151C>G and TGFA‐ht2 were marginally associated with clearance of HBV infection. However, only TGFA‐ht2 retained significance after multiple correction (OR = 0.39, P^corr = 0.007 in recessive model). Although no variants were significant after multiple correction, TGFA+88344G>A and TGFA+103461T>C were weakly associated in recessive model in the analysis of HCC occurrence. In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RH = 1.46, P^corr = 0.04). TGF‐α polymorphisms might be an important factor in immunity, progression of inflammatory process and carcinogenesis, which explains the variable outcome of HBV infection at least in part. Further biological evidence is warranted in the future to support these suggestive associations.     

ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer

Purpose  The aim of this study was to determine the significance of three most common single-nucleotide polymorphisms (SNPs) of ABCB1 gene in the development of colorectal cancer and to estimate the influence of these SNPs to surviving patients' treatment combination adjuvant therapy 5-fluorouracil/leucovorin. Haplotype structure of ABCB1 was analysed, and degree of linkage disequilibrium (LD) between SNPs of ABCB1 was estimated. Materials and methods  Tumour specimens of 95 patients with colorectal cancer and blood samples of 95 healthy cases were studied. Genotyping of ABCB1 gene was performed by automated sequencing or polymerase chain reaction-restriction fragment length polymorphism method. Comparison of frequencies of alleles/genotypes/haplotypes between the studied group (colorectal cancer samples) and the control group (blood samples) were analysed. These results were correlated with the surviving patients after treatment of adjuvant chemotherapy. Results  Significant differences in ABCB1 _1236C>T (p = 0.00043) and ABCB1 _2677G>T/A (p = 0.04) genotype distribution and T₁₂₃₆ allele distribution (CT₁₂₃₆ or TT₁₂₃₆ vs CC₁₂₃₆; p = 0.0499, OR = 0.55, Fi–Yule coefficient = 0.14) were found. A strong LD between ABCB1 _1236C>T and ABCB1 _2677G>T/A SNPs (D′ = 0.621, r ² = 0.318) was detected. All SNPs were located in one haplotype block. There were significant differences in haplotype distributions between colorectal cancer patients and healthy population (p = 0.03). Significant differences in survival probability of colorectal cancer patients' treatment chemotherapy according to allele of ABCB1 _3435C>T was observed. Survival probability of patients with wild-type C₃₄₃₅ allele were higher than among patients without this allele (p = 0.04572). Conclusions  These results suggested that three studied SNPs of ABCB1 were located in one haplotype block. Differences in ABCB1 _1236C>T and ABCB1 _2677G>T/A genotypes and T₁₂₃₆ allele distribution between investigated populations indicate significant impact of these SNPs on risk of development of colorectal cancer. Polymorphism ABCB1 _3435C>T may be a prediction marker of cancer chemotherapy effectiveness. Differences in haplotype distributions between colorectal cancer patients and healthy population suggested that other potential SNPs, especially in regulatory region of ABCB1 gene, may influence P-glycoprotein expression and function.     

Strong association of the APOA5-1131T>C gene variant and early-onset acute myocardial infarction

Objective

Genome-wide association study recently identified the chromosome 3q22.3 as a novel locus associated with coronary artery disease (CAD). This study was designed to identify the critical haplotype blocks within this region in Han Chinese populations.

Methods

We selected 1920 CAD patients and healthy participants from Han Chinese and genotyped 22 single nucleotide polymorphisms (SNPs) spanning 150 kilobases (kb) chromosomal region flanking rs9818870, a SNP associated with CAD at 3q22.3 in Caucasian.

Results

Seven SNPs were found to be strongly associated with CAD in females and clustered in two haplotype blocks of ESYT3 gene. This was validated in two geographically isolated case-control populations. The two blocks were 14 and 25 kb long, respectively. In a combined haplotype analysis, the odds ratios (95% confidence interval, permuted P value) were 0.70 (0.58–0.83, 2 × 10⁻⁵) and 1.44 (1.20–1.72, 5 × 10⁻⁵) for haplotypes TTG and CCA in block 1 as well as 0.73 (0.61–0.87, 3 × 10⁻⁴) and 1.35 (1.13–1.62, 0.0013) for haplotypes TCG and CTT in block 2, respectively. ESYT3 was expressed in human lymphocyte, vascular endothelial cell, and smooth muscle cell. The risk factors including gender, obesity, hypertension, diabetes, and hyperlipidemia exhibited strong effects on the genetic contribution to CAD.

Conclusion

We identified two haplotype blocks of ESYT3 gene in 3q22.3 region that likely harbor functional variants, which cooperate with other risk factors and play a role in the pathogenesis of coronary artery disease in females.     

Effect of RBP4 gene variants on circulating RBP4 concentration and Type 2 diabetes in a Chinese population

Aims Retinol binding protein 4 (RBP4) is a newly discovered adipokine, which plays a role in insulin resistance and obesity. The aim of this study was to determine the relationship between genetic variants of the RBP4 gene, circulating RBP4 concentrations and phenotypes related to glucose and lipid metabolism in the Chinese population. Methods We sequenced exons and the putative promoter region to identify single nucleotide polymorphisms (SNPs) in the RBP4 gene in 32 Chinese subjects. Additional SNPs were selected from a public database to increase marker density. Taking account of the pairwise linkage disequilibrium and minor allele frequencies, a subset of SNPs was further genotyped in 255 Type 2 diabetic patients and 372 normal control subjects. Circulating RBP4 concentrations and phenotypes related to glucose and lipid metabolism were measured. Results Ten SNPs were identified and five were further genotyped in the full sample. No individual SNP was significantly associated with Type 2 diabetes, but a rare haplotype CAA formed by +5388 C>T, +8201 T>A and +8204 T>A was more frequent in diabetic patients (P = 0.0343, empirical P = 0.0659 on 10 000 permutations). In both groups, non‐coding SNPs were associated with circulating RBP4 concentrations (P < 0.05). In the normal control subjects, the SNP +5388 C>T was associated with serum C‐peptide levels both fasting and 2 h after an oral glucose tolerance test (P = 0.0162 and P = 0.0075, respectively). Conclusion Our findings suggest that genetic variants in the RBP4 gene may be associated with circulating RBP4 concentration and phenotypes related to glucose metabolism.     

Mild β+-Thalassemia Associated With Two Linked Sequence Variants: IVS-II-839 (T>C) and IVS-II-844 (C>A)

We report four unrelated families with a mild β⁺-thalassemia (β⁺-thal) allele consisting of two sequence variants at the 3' end of IVS-II: IVS-II-839 (T>C) (HBB: c.316-12T>C) and IVS-II-844 (C>A) (HBB: c.316-7C>A). These sequence variants alter the conserved polypyrimidine tract of the consensus splice acceptor sequence (Y₁₁NYAG/G), which could reduce splicing efficiency. This may represent a common, yet under-diagnosed β⁺-thal allele in African populations.     

Common variations in the ALMS1 gene do not contribute to susceptibility to type 2 diabetes in a large white UK population

Aims/hypothesis Alström syndrome is a rare monogenic disorder characterised by retinal dystrophy, deafness and obesity. Patients also have insulin resistance, central obesity and dyslipidaemia, thus showing similarities with type 2 diabetes. Rare mutations in the ALMS1 gene cause severe gene disruption in Alström patients; however, ALMS1 gene polymorphisms are common in the general population. The aim of our study was to determine whether common variants in ALMS1 contribute to susceptibility to type 2 diabetes in the UK population.Methods Direct sequencing was performed on coding regions and intron/exon boundaries of the ALMS1 gene in 30 unrelated probands with type 2 diabetes. The linkage disequilibrium (LD; D′ and r ²) and haplotype structure were examined for the identified variants. The common (minor allele frequency [MAF] >5%) single-nucleotide polymorphisms tagging the common haplotypes (tagged SNPs [tSNPs]) were identified and genotyped in 1985 subjects with type 2 diabetes, 2,047 control subjects and 521 families.Results We identified 18 variants with MAF between 6 and 38%. Three SNPs efficiently tagged three common haplotypes (rs1881245, rs3820700 and rs1320374). There was no association (all p>0.05) between the tSNPs and type 2 diabetes in the case–control study and minor alleles of the tSNPs were not overtransmitted to probands with type 2 diabetes in the family study.Conclusions/interpretation Common variations in the ALMS1 gene were not associated with type 2 diabetes in a large study of a white UK population.Electronic Supplementary Material Supplementary material is available for this article at     

Obesity in aspirin-tolerant and aspirin-intolerant asthmatics

Background and objective: Obesity is an important factor in the development of asthma. Aspirin hypersensitivity affects 5–10% of asthmatics. The association between obesity and aspirin hypersensitivity in asthma is unclear. This study evaluated the association of BMI and asthma in patients with aspirin-tolerant asthma (ATA) and aspirin-intolerant asthma (AIA). Methods: Aspirin provocation tests were performed in 667 asthmatic patients and changes in FEV₁ were used to categorize patients as ATA or AIA. The BMI of asthmatics was graded using the percentile BMI of 406 normal controls. Results: Aspirin-induced changes in FEV₁% ranged from 15% to 68%. Compared with the controls, the ATA group had a higher BMI (24.5 ± 0.1 vs 23.8 ± 0.2 kg/m², P = 0.001). The AIA group had a lower BMI. The aspirin-induced percentage fall in FEV₁ was inversely correlated with BMI in asthmatic patients (r = −0.094, P = 0.016). BMI was correlated with age and PC20, but not with FEV₁ in asthmatic patients. In a logistic regression adjusted for age, gender, and smoking status, FEV₁ and PC20 were associated with AIA with odds ratios of 0.986 and 0.586, respectively. BMI was associated with AIA with an odds ratio of 0.916. Conclusions: Aspirin intolerance in asthmatics explains the lesser association with obesity. Obesity is not a risk factor in the development of asthma in patients with AIA.     

Association between thromboxane A2 receptor polymorphisms and asthma risk: A meta-analysis

Objective: To determine whether there is an association between thromboxane A2 receptor (TBXA2R) gene polymorphisms (+924C/T and +795C/T) and asthma risk by conducting a meta-analysis. Data Sources: Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang database were searched (updated May 1, 2015). Study Selections: Articles evaluating the association between TBXA2R gene polymorphisms and asthma risk were selected. Results: A total of 7 studies on +924C/T polymorphism and 6 studies on +795C/T polymorphism were included in this meta-analysis. There was a significant association between TBXA2R +924C/T polymorphism and asthma risk in the recessive model (OR = 1.33, 95% CI = 1.01–1.75, P = 0.045). No significant association between +795C/T polymorphism and asthma risk in the overall population was demonstrated. In subgroup analyzes, significant association was observed in atopic asthma risk in the recessive model (OR = 1.43, 95% CI = 1.01–2.01, P = 0.043), but no significant association was found between TBXA2R +924C/T polymorphism and asthma risk in Asians (OR = 1.14, 95% CI = 0.80–1.63, P = 0.457). TBXA2R +795C/T polymorphism was associated with aspirin-intolerant asthma (AIA) risk when stratified by asthma subphenotype in the allelic model (OR = 1.30, 95% CI = 1.05–1.60, P = 0.014) and dominant model (OR = 1.50, 95% CI = 1.11–2.03, P = 0.008). Conclusion: Our results suggested that TBXA2R +924C/T polymorphism is associated with asthma risk, and +795C/T polymorphism may be a risk factor for AIA. Larger-scale and well-designed studies are required to validate the association identified in the current meta-analysis.     

Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia

Objective

Atherogenic dyslipidemia is highly associated with coronary heart disease and is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). The combination of statins and fibrates is a common modality to treat individuals with atherogenic dyslipidemia.We sought to identify single nucleotide polymorphisms (SNPs) associated with HDL-C, TG, and apolipoprotein A1 (ApoA-I) response to combination therapy with statins and fenofibric acid (FA) in individuals with atherogenic dyslipidemia.

Methods

2228 individuals with mixed dyslipidemia who were participating in a multicenter, randomized, double-blind, active-controlled study comparing FA alone, in combination with a statin, or statin alone for a 12-week period, were genotyped for 304 candidate SNPs. A multivariate linear regression analysis for percent change in HDL-C, ApoA-I and TG levels was performed.

Results

SNPs in the apolipoprotein (APO) A5-ZNF259 region rs3741298 (P = 1.8 × 10⁻⁷), rs964184 (P = 3.6 × 10⁻⁶), rs651821 (P = 4.5 × 10⁻⁵), and rs10750097 (P = 1 × 10⁻⁴), were significantly associated with HDL-C response to combination therapy with statins and FA, with a similar association identified for ApoA-I. A haplotype composed of the minor alleles of SNPs rs3741298, rs964184, and rs10750097, was associated with a positive response to statins and FA (P = 8.7 × 10⁻⁷) and had a frequency of 18% in the study population.

Conclusion

In a population with atherogenic dyslipidemia, common SNPs and haplotypes within the APOA5-ZNF259 region are highly associated with HDL-C and ApoA-I response to combination therapy with statins and FA.     

Synergistic effects of gene polymorphisms of the renin–angiotensin–aldosterone system on essential hypertension in Kazakhs in Xinjiang

Objective: To assess the synergistic effects of gene polymorphisms of the renin–angiotensin–aldosterone system (RAAS) on essential hypertension (EH) in Kazakhs in Xinjiang. Methods: A cross-sectional case-control association study was conducted in 52 1 hypertensive and 623 normotensive subjects of Kazakh ethnicity on eight common single nucleotide polymorphisms (SNPs) interspersed over five genes of the RAAS. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Interactions among the SNPs were analyzed by the multifactor dimensionality reduction method (MDR). Results: In single-locus analysis, subjects with AGT -6G, ACE D, and CYP11B2 -344C had increased susceptibility to EH (OR: 1.249; 1.425; 1.201). When subgrouped by sex, males with the t allele of REN Taq I had decreased risk for EH (OR: 0.529), and those with AGT -6G and CYP11B2 -344 C had increased risk for EH (OR: 1.498; 1.449). In females, carrying ACE D increased the risk for EH. (OR: 1.327). In six AGT haplotypes, H1 was protective, while H3 increased susceptibility to EH (OR: 0.683; 2.025). Interaction analysis by MDR showed that there was a strong synergistic effect between ACE I/D and CY11B2 (T-344C) and a moderate interaction between both ACE I/D and CY11B2 T-344C and AGT A-6G. Conclusions: There was a strong synergistic effect between ACE I/D and CY11B2 T-344C and a moderate effect between both ACE I/D and CY11B2 T-344C and AGT A-6G. AGT -6G, ACE D, and CY11B2 -344C increased susceptibility to EH. REN Taq I, AGT -6G, CY11B2 -344 C and ACE D were associated with male and female EH, respectively. H1 and H3 of AGT were protective and risk haplotypes, respectively.     

ABCB1/MDR1 gene polymorphisms as a prognostic factor in colorectal cancer

Objective  

To analyse the single-nucleotide polymorphisms (SNPs): ABCB1 _1236C>T, ABCB1 _2677G>T/A, ABCB1 _3435C>T and haplotypes in the ABCB1/MDR1 gene, which could contribute to genetic risk of colorectal cancer (CRC). Disease association between the ABCB1/MDR1 genotype, allele, haplotype frequencies and histological features, such as TNM classification, localization of primary carcinoma, grade of malignancy, histological type of tumour, lymphoid infiltration and vessel invasion were estimated. In this study, the potential role of SNPs of the ABCB1/MDR1 gene as a prognostic marker for CRC was analysed.     

No associations of polymorphisms in ADPRT with hepatitis B virus clearance and hepatocellular carcinoma occurrence in a Korean population

Aim: The human adenosine diphosphate ribosyl transferase (ADPRT) gene might significantly affect cancer by encoding poly(ADP‐ribose) polymerase 1 enzyme (PARP‐1) and promoting an important role in cellular responses to DNA damage, genomic stabilization and regulation of tumor suppressor genes. We explored whether polymorphisms of ADPRT affect clearance of hepatitis B virus (HBV) infection or risk of hepatocellular carcinoma (HCC) occurrence in a Korean HBV cohort. Methods: Genotyping was performed in a total of 1066 subjects composed of 434 spontaneously recovered (SR) subjects as normal controls and 632 chronic carriers (CC) of HBV who were further classified into 325 patients with liver cirrhosis (LC)/chronic hepatitis (CH) and 307 patients with HCC. Results: Logistic analyses of six common single nucleotide polymorphisms (SNP) and their haplotypes revealed that none of the polymorphisms were significantly associated with clearance of HBV infection and HCC occurrence, except for nominal evidence of association between haplotype 2 (ht2) with HBV clearance (P = 0.05). In the analysis of age of HCC occurrence which is an important factor in disease progression to HCC, results from Cox proportional hazards showed that none of the variants were significantly associated with onset age of HCC occurrence, although a nominal signal in ht4 (P = 0.03, but P^corr > 0.05) was initially detected. Conclusion: Although ADPRT is an important gene for cellular responses and tumor regulations, our study provides evidence that ADPRT variations do not affect HBV clearance and HCC occurrence.     

Comparison of single nucleotide polymorphisms in the human interleukin-10 gene promoter between rheumatoid arthritis patients and normal subjects in Malaysia

Abstract

In this study, three single nucleotide polymorphisms (SNPs) located within the promoter of the human interleukin (IL)-10 gene [rs1800896 (position: ?1087G > A), rs1800871 (position: ?824C > T) and rs1800872 (position: ?597C > A)] were investigated in 84 rheumatoid arthritis (RA) patients and 95 age- and sex-matched healthy subjects using polymerase chain reaction-restriction fragment length polymorphism method. Production of IL-10 by peripheral blood lymphocytes from the RA patients and healthy subjects cultured in the presence of Concanavalin A (Con A) was determined by using enzyme-linked immunosorbent assay. The results show that the distribution of the IL-10 genotypes did not differ significantly between RA patients and healthy subjects (P > 0.05). However, a significant difference was observed in allele frequencies of ?824CT, ?824TT, ?597CA, and ?597AA between the RA patients and healthy volunteers (P = 0.04). The ?1087A/?824T/?597A (ATA) haplotype, which comprises all mutant alleles, was associated with lower IL-10 production when compared with the other haplotypes. In contrast, the RA patients who did not display the ATA haplotype produced significantly higher levels of IL-10 when compared with those carrying either one (P = 0.012) or two (P = 0.005) ATA haplotypes. Our findings suggest that there is an association between SNPs in the promoter of the human IL-10 gene and susceptibility to RA.     

IL28B genetic variation and hepatitis C virus–specific CD4+ T‐cell responses in anti‐HCV‐positive blood donors

Summary. Epidemiological, viral and host factors are associated with the outcome of hepatitis C virus (HCV) infection, and strong host immune responses against HCV favour viral clearance. Recently, genome‐wide association studies have shown a strong correlation between single‐nucleotide polymorphisms (SNPs) near the interleukin‐28B (IL28B) gene and spontaneous or treatment‐induced HCV clearance. We have investigated whether protective IL28B genetic variants are associated with HCV‐specific T‐cell responses among Spanish blood donors. The rs12979860 IL28B haplotype was determined in 69 anti‐HCV‐positive blood donors (21 HCV RNA negative and 48 HCV RNA positive) and 30 seronegative donors. In all cases, HCV‐specific CD4⁺ T‐cell responses to HCV recombinant proteins (core, NS3 and NS3 helicase) were assessed by ex vivo interferon‐γ ELISpot assay. The rs12979860‐CC genotype was highly overrepresented in donors with spontaneous HCV clearance when compared to those with chronic infection (76.2%vs 29.2%, P < 0.001; odds ratio, 7.77; 95% confidence interval, 2.4–25.3, P < 0.001). HCV‐specific CD4⁺ T‐cell responses were detected in 16 (76.2%) spontaneous resolvers especially towards nonstructural proteins, but with no correlation with IL28B genotype. Chronic individuals had a significantly lower overall T‐cell response again irrespective of IL28B genotype. When spontaneous resolvers and chronic individuals were stratified according to their IL28B genotype, significantly stronger T‐cell responses were only observed among those with non‐CC haplotypes. Although the protective rs12979860 IL28B CC genotype is associated with spontaneous HCV clearance, stronger CD4⁺ T‐cell responses towards NS3 were only evident among those with non‐CC haplotypes.     

IL-18 105 A>C polymorphism contributes to renal manifestations in patients with SLE

Systemic lupus erythematosus (SLE) is a multisystem autoimmune connective tissue disorder characterized by various aberrations including increased production of IL-18. As IL-18 105 A>C polymorphic variants have been linked to increased production of this cytokine, we investigated the prevalence of IL-18 105 A>C (rs549908) polymorphic variants in SLE patients (n = 111) and controls (n = 152). There were no significant differences in the distribution of IL-18 105 A>C polymorphic variants in SLE patients and controls. However, there was a significant association between the IL-18 105 AA genotype (recessive model) and renal manifestations OR = 3.360 (1.523–7.415, P = 0.0039) and the P value remained statistically significant after Bonferroni correction (P _corr = 0.0351).Our findings indicate that the IL-18 105 AA genotype variant can contribute to renal manifestations in patients with SLE.     

Sequence variants on 17q21 are associated with the susceptibility of asthma in the population of Lahore,Pakistan

Objective: Single nucleotide polymorphisms (SNPs) on 17q21 are known to be associated with asthma disease in multiple populations. This study was designed to know whether this region is associated with asthma in Lahore region population or not. Methods: A total of 200 asthma patients and 100 healthy controls were enrolled from different hospitals of Lahore, Pakistan. Twelve SNPs from chromosomal region 17q21 were analyzed in cases and controls by single base extension method and capillary-based genetic analyzers. Associations with asthma were checked using basic allelic model, genotypic model, and results were adjusted by logistic regression analysis using PLINK v1.9. Pair-wise linkage disequilibrium among the SNPs was analyzed by using Haploview software. Results: SNP rs3816470 showed a strong association (p?=?8.89?×?10^?5, Odd Ratio?=?3.082 [1.755-5.41]) with asthma, whereas rs3859192 and rs6503525 also showed a significant association with the development of asthma, especially in the case of positive family history. In LD block1 (93?kb) consisting of six SNPs (rs12936231, rs7216389, rs7216558, rs9894164, rs1007654 and rs7212938), none of the haplotypes show any significant association with asthma except the haplotype “CCTCAG”, which is a significant protective factor against asthma having frequency 0.051 in controls while 0.017 in cases (p?=?3.56?×?10^?2, χ²?=?4.415). Conclusion: The present study reports that the polymorphic genomic variant rs3816470 is significantly and independently associated with asthma in the studied population, while the variants, rs6503525 and rs3859192, also indicate a significant association with asthma in this population when family history of the disease is taken as a covariate.