Impact of variants of MMP‐7(‐181A>G) gene in susceptibility to the development of HIV‐associated neurocognitive disorder and its severity

The HIV‐1‐induced neurological toxicity has been associated with the deficiency of matrix metalloproteinases. Tat protein of HIV up regulates MMP‐7 release and activation, leading to neurotoxicity. The SNP ‐181A>G of MMP‐7 is known to have functional effects on its promoter activity. Therefore, we aimed to evaluate the association of variants of MMP‐7 ‐181A>G gene in HIV‐associated neurocognitive disorder (HAND). In the present case–control study, we recruited 50 HIV‐infected individuals with HAND, 130 HIV‐infected individuals without HAND and 150 unrelated healthy individuals. Polymorphism for MMP‐7 ‐181A>G gene was genotyped by PCR‐RFLP method. Frequency of ‐181GG and G allele of MMP‐7 did not differ significantly between patients with HAND and without HAND (8.0% vs 13.1%, p = 0.22 and 31% vs 38.1%, p = 0.21). Individuals with ‐181 AG, ‐181GG genotype, and G allele of MMP‐7 were found to have reduced the risk of development of HAND but not significant (50.0% vs 51.9%, p = 0.09, OR = 0.54; 13.1% vs 19.0%, p = 0.33, OR = 0.71 and 38.1% vs 44.9%, p = 0.09, OR = 0.75). Individuals in early HIV disease stage having ‐181AG genotype and ‐181AG + GG combined genotype of MMP‐7 were not associated with the development of HAND (OR = 1.27, p = 0.25 and OR = 1.25, p = 0.17). Tobacco and alcohol consumption among individuals with any genotype of MMP‐7 was not associated with the risk of development of HAND. In conclusion, individuals with ‐181GG genotype and G allele had no impact on susceptibility to the development of HAND and its severity.     

APOBEC3B deletion impacts on susceptibility to acquire HIV‐1 and its advancement among individuals in western India

APOBEC3B deletion polymorphism has been associated with risk of HIV‐1 acquisition and its progression. Therefore, we aimed to investigate the association of APOBEC3B ins/del polymorphism with risk of acquisition of HIV‐1 and its progression. In the present case–control study, we enrolled a total of 150 HIV‐infected individuals and 150 healthy controls. Polymorphism for APOBEC3B gene was genotyped by PCR. APOBEC3B ID, DD genotypes, and D allele were associated with higher risk of acquisition of HIV‐1 (p = 0.004, OR = 4.96; p = 0.03, OR = 3.55; and p = 0.004; OR = 1.60). The individuals with ID genotypes and combined genotype ID+DD of APOBEC3B in the presence of tobacco and alcohol showed the higher risk of advancement of HIV disease; however, risk could not reach statistical significance (OR = 1.14, 95% CI: 0.59–2.18; OR = 1.33, 95% CI: 0.83–2.15 and OR = 1.44, 95% CI: 0.77–2.69; OR = 1.50, 95% CI: 0.94–2.40). Individuals in advanced HIV disease stage and ID genotype and combined genotype ID + DD of APOBEC3B were more likely to be associated with advanced HIV disease stage but risk could not reach significant (OR = 1.50, 95% CI: 0.94–2.40; OR = 1.27, 95% CI: 0.88–1.84). Individuals with ID and DD genotype of APOBEC3B had influence on susceptibility to acquisition of HIV‐1. This suggests that APOBEC3B deletion may attenuate innate cellular immunity against HIV‐1 and thus confer the host persistence for HIV infection.     

Association of IL‐4 589 C/T promoter and IL‐4RαI50V receptor polymorphism with susceptibility to HIV‐1 infection in North Indians

The clinical course and outcome of HIV‐1 infection are highly variable among individuals. Interleukin 4 (IL‐4) is a key T helper 2 cytokine with various immune‐modulating functions including induction of immunoglobulin E (IgE) production in B cells, downregulation of CCR5 and upregulation of CXCR4, the main co‐receptors for HIV. Our objective is to investigate whether single‐nucleotide polymorphisms (SNPs) in the IL‐4 promoter 589 C/T and IL‐4 Rα I50V affect the susceptibility to HIV infection and its progression to AIDS in North Indian individuals. The study population consisted of 180 HIV‐1 seropositive (HSP) stratified on the basis of disease severity (stage I, II, III), 50 HIV‐1 exposed seronegative (HES), and 305 HIV‐1 seronegative (HSN) individuals. The subjects were genotyped for IL‐4 589 C/T promoter polymorphism and IL‐4 Rα I50V by polymerase chain reaction restriction fragment length polymorphism. The results showed that IL‐4 589 C/T was not associated with the risk of HIV infection and disease progression. However, the IL‐4Rα I50 allele and genotype was significantly increased in HSP compared to HSN and HSP and was associated with risk of HIV infection. The frequency of IL‐4Rα I50 allele in the HSP group was higher than in HSN (76.11 vs. 64.75%; P = 0.000; OR = 1.734) and HES (76.11% vs. 62.00%; P = 0.007; OR = 1.953). Homozygous IL‐4Rα I50I genotype was significantly increased in HSP group compared with HSN (58.88% vs. 44.26%; P = 0.002; OR = 1.804) and HES (58.88% vs. 42.00%; P = 0.038; OR = 1.978). The present study for the first time suggests an association of IL‐4Rα I50 allele with increased likelihood of HIV‐1 infection in North Indian population. Further studies are required to confirm these findings and understand the effect of IL‐4Rα polymorphism on the outcome of HIV‐1 infection. J. Med. Virol. 81:959–965, 2009. © 2009 Wiley‐Liss, Inc.     

The effect of gender and genetic polymorphisms on matrix metalloprotease (MMP) and tissue inhibitor (TIMP) plasma levels in different infectious and non‐infectious conditions

Matrix metalloproteases (MMPs) are increased in different infections due to their role in controlling immune responses and are regulated by tissue inhibitors (TIMPs). Different MMP promoter single nucleotide polymorphisms (SNPs) induce changes in MMP genes, mRNA and protein expression. Gender might also modify MMP plasma levels. In order to determine the weight of these variables on MMP secretion we studied MMP‐1, ‐2, ‐3, ‐8, ‐9, ‐10, ‐13 and TIMP‐1, ‐2, ‐4 plasma levels in 90 patients with severe bacterial sepsis, 102 with anti‐retroviral (ARV)‐treated HIV monoinfection, 111 with ARV‐treated HIV–hepatitis C virus (HCV) co‐infection and 86 non‐infected controls (45 stroke and 41 trauma patients). MMP‐1(‐1607 1G/2G), MMP‐3(‐1612 5A/6A), MMP‐8(‐799C/T), MMP‐9(‐1562 C/T) and MMP‐13(‐77A/G) SNPs were genotyped. MMP‐3 plasma levels were significantly higher in men than in women in each diagnostic group, and MMP‐3 SNP allele 6A carriers also had higher levels than allele 5A carriers, an effect that was magnified by sepsis. Independent predictors of higher MMP‐3 levels were male gender (P = 0·0001), MMP‐3(‐1612 5A/6A) SNP (P = 0·001), higher levels of TIMP‐4 (P = 0·004) and MMP‐8 (P = 0·006) and lower levels of MMP‐1 (P = 0·03) by multivariate analysis. No strong associations with gender or SNPs were observed for other MMPs or TIMPs. In conclusion, male gender and MMP‐3(‐1612 5A/6A) 6A allele carriage increased MMP‐3 plasma levels significantly, especially in patients with severe bacterial sepsis. This confounding gender effect needs to be addressed when evaluating MMP‐3 plasma levels in any infectious or non‐infectious condition.     

Effect of TLR10 (2322A/G, 720A/C,and 992T/A) polymorphisms on the pathogenesis of Crimean Congo hemorrhagic fever disease

Crimean Congo hemorrhagic fever (CCHF) is a tick‐borne disease caused by the Crimean Congo hemorrhagic fever virus (CCHFV). Toll‐like receptors (TLRs) are type 1 transmembrane proteins of immune cells that play a critical role in innate and adaptive immunity. The present study first time aims to investigate the relation between TLR10 gene polymorphisms (720A/C, 992T/A, and 2322A/G), severity/non‐severity, fatality/non‐fatality, and CCFH disease by using PCR‐RFLP assay in a Turkish population. TLR10 720A/C polymorphism was determined to be statistically significant both genotype and allele frequency (P = 0,011, P = 0.015, respectively). TLR10 992T/A polymorphism was found statistically significant relationships between patient and control (P = 0.026) and individual with AA genotype have approximately three times greater risk than TT genotype (OR = 2.93). There was not a significant difference in 2322A/G genotype distribution (P = 0.152). There were also statistically significant associations between both TLR10 992T/A and 2322A/G polymorphism and patient mortality (P = 0.001 and P = 0.008, respectively). We have not found statistically any linkage among TLR10 haplotype, but individual AAA and GAT haplotype have higher risk than individual AAT haplotype (OR = 3.22, OR = 1.93, respectively). Consequently, this study shows that pathogenesis of CCHF disease is associated with the TLR10 720A/C and 992T/A polymorphisms. There is a statistically significant association in fatal/non‐fatal patients with TLR10 720A/C and 992T/A. The TLR10 992AA genotype might increase and TLR10 720CC genotype might decrease susceptibility to pathogenesis of CCHF disease. TLR 10 polymorphisms may be also an important biomarker for CCHF susceptibility and fatality rate.     

The association of interferon‐gamma,interleukin‐4 and interleukin‐17 single‐nucleotide polymorphisms with susceptibility to tuberculosis

Susceptibility to tuberculosis and progression of the disease depend on interactions between the bacterial agent, host immune system, and environmental and genetic factors. In this case‐controlled study, we aimed to determine the role of single‐nucleotide polymorphisms of interferon‐gamma, interleukin‐4 and interleukin‐17 in susceptibility to tuberculosis. Genomic DNA was extracted from peripheral blood samples of patients and controls. The association of single‐nucleotide polymorphisms in interleukin‐4 (?590C/T), interleukin‐17 (?152A/G) and interferon‐gamma (+874T/A) was investigated by polymerase chain reaction (PCR)‐restriction fragment length polymorphism and amplification refractory mutation system‐PCR. A total of 76 tuberculosis patients and 119 healthy individuals were included in this study. The interferon‐gamma (+874T/A) TA genotype was significantly associated with susceptibility to tuberculosis in patients compared to controls (OR = 1.76; 95%CI = 0.84–3.71; p = 0.007), while the interferon‐gamma (+874T/A) TT genotype (OR = 0.51; 95%CI = 0.19–1.36; p = 0.007) had protective effects against tuberculosis and was related to a low risk of tuberculosis development. The difference between allelic and genotypic frequencies of interleukin‐4 (?590C/T) between patients and controls was not significant (p = 0.46). Multivariate logistic regression analysis revealed that the interleukin‐17 (?152A/G) AG genotype (OR = 2.27; 95%CI = 1.19–4.34; p = 0.03) and AA genotype (OR = 1.03; 95%CI = 0.43–2.44; p = 0.03) were significantly different between patients and controls. In conclusion, single‐nucleotide mutations in different cytokine genes may have protective effects or increase the risk of tuberculosis.     

Association between the Interleukin‐6 Gene −572 C/G Polymorphism and the Risk of Type 2 Diabetes Mellitus: A Meta‐Analysis of 11,681 Subjects

The association between the interleukin‐6 (IL‐6) gene ?572 C/G (rs1800796) polymorphism and type 2 diabetes mellitus (T2DM) risk remains controversial. Thus, we performed this meta‐analysis by searching PubMed, Embase, Web of Science, CBMdisc and CNKI databases until January 30, 2012. In addition, hand searching of the references of identified articles was performed. A total of 10 case–control studies including 11,681 subjects were selected to evaluate the possible association. Our results showed evidence for significant association between the IL‐6 gene ?572 C/G polymorphism and T2DM risk (for G allele vs. C allele: odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09–1.52, P = 0.002, P = 0.008 after Bonferroni testing; for G/G vs. C/C: OR = 1.89, 95% CI = 1.51–2.37, P < 0.00001, P < 0.00004 after Bonferroni testing; for GG vs. G/C + C/C: OR = 1.75, 95% CI = 1.20–2.56, P = 0.004, P = 0.016 after Bonferroni testing; for G/G + G/C vs. C/C: OR = 1.32, 95% CI = 1.11–1.57, P = 0.001, P = 0.004 after Bonferroni testing). In addition, similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta‐analysis suggests a significant association between the IL‐6 gene ?572 G allele and increased risk of T2DM.     

Comprehensive analysis of HIV Gag‐specific IFN‐γ response in HIV‐1‐ and HIV‐2‐infected asymptomatic patients from a clinical cohort in The Gambia

Majority of HIV‐2‐infected individuals meet the criteria of long‐term non‐progressors. This has been linked to superior qualitative HIV‐2‐specific cellular immune responses that correlate with viral control. However, it is unknown whether this is due to frequent targeting of immunodominant Gag epitopes in HIV‐2 than HIV‐1 infection. We describe a comprehensive comparison of the magnitude, breadth and frequency of Gag responses and the degree of cross‐recognition of frequently targeted, immunodominant Gag peptides in a cross‐sectional study of asymptomatic HIV‐1‐ and HIV‐2‐infected individuals. Fresh PBMC from 20 HIV‐1‐ and 20 HIV‐2‐infected patients with similar CD4⁺ T‐cell counts (p=0.36) were stimulated with pools of HIV‐1 and/or HIV‐2 Gag peptides in an IFN‐γ ELISPOT assay. We found no difference in the cumulative magnitude of IFN‐γ responses (p=0.75) despite significantly lower plasma viral loads in HIV‐2‐infected people (p<0.0001). However, Gag211–290 was targeted with significantly higher magnitude in HIV‐2‐infected subjects (p=0.03) although this did not correlate with viral control. There was no difference in frequently targeted Gag peptides, the breadth, immunodominance or cross‐recognition of Gag peptide pools between the two infections. This suggests that other factors may control viral replication in HIV‐2 infection.     

Association of the IL‐10 receptor A536G (S138G) loss‐of‐function variant with multiple sclerosis in Tunisian patients

Interleukin‐10 (IL‐10), a potent anti‐inflammatory T‐cell cytokine, has been shown to be a regulatory cytokine that is associated with disease remission in multiple sclerosis (MS) and exerts its activity through its cognate cell surface receptor complex, IL‐10 receptor 1 (IL‐10R1) and IL‐10R2. The purpose of this study was to investigate the IL‐10R1 S138G loss‐of‐function polymorphism (A536G: rs3135932) for possible influence on susceptibility and outcome of MS in Tunisian patients. A total of 103 Tunisian MS patients and 160 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL‐10R1 gene by multiplex allele‐specific polymerase chain reaction. Associations between G allele [odds ratio (OR) = 5.57; 95% confidence intervals (CI) = 3.26–9.54; p = 10^?7], GG genotypes [OR = 10.41; 95% CI = 2.28–47.58; p = 0.0007] and AG genotype [OR = 4.14; 95% CI = 2.16–7.93; p = 0.000016] with the risk development of MS were found. In contrast, the AA genotype seemed to be associated with protection against MS [OR = 0.17; 95% CI = 0.09–0.30; p = 10^?7]. No association was found between S138G SNP and clinical features or disease activity of MS patients. In conclusion, our results suggest that S138G loss‐of‐function polymorphism of the IL‐10R1 may be important risk factor in increasing susceptibility to MS.     

Dimorphic HLA‐B signal peptides differentially influence HLA‐E‐ and natural killer cell‐mediated cytolysis of HIV‐1‐infected target cells

As a mechanism of self‐protection, signal peptides cleaved from human leukocyte antigen (HLA) class I products bind to HLA‐E before the complex interacts with the natural killer (NK) cell receptor CD94/NKG2A to inhibit NK‐mediated cell lysis. Two types of the signal peptides differ in their position 2 (P2) anchor residue, with P2‐methionine (P2‐M) having higher HLA‐E binding affinity than P2‐threonine (P2‐T). All HLA‐A and HLA‐C molecules carry P2‐M, whereas HLA‐B products have either P2‐M or P2‐T. Epidemiological evidence suggests that P2‐M is unfavourable in the context of HIV‐1 infection, being associated with accelerated acquisition of HIV‐1 infection in two African cohorts. To begin elucidating the functional mechanism, we studied NK‐mediated killing of CD4⁺ T cells and monocyte‐derived macrophages infected with two laboratory‐adapted HIV‐1 strains and two transmitted/founder (T/F) viruses. In the presence of target cells derived from individuals with the three HLA‐B P2 genotypes (M/M, M/T and T/T), NK‐mediated cytolysis was elevated consistently for P2‐T in a dose‐dependent manner for all cell and virus combinations tested (P = 0·008–0·03). Treatment of target cells with an anti‐HLA‐E monoclonal antibody restored NK‐mediated cytolysis of cells expressing P2‐M. Observations on cell lysis were also substantiated by measurements of HIV‐1 p24 antigen in the culture supernatants. Overall, our experiments indicate that the anti‐HIV‐1 function mediated by NK cells is compromised by P2‐M, corroborating the association of HLA‐B genotype encoding P2‐M with accelerated HIV‐1 acquisition.     

Association of IFNλ4 rs12979860 polymorphism with the acquisition of HCV and HIV infections among people who inject drugs

We investigated the presence of a single‐nucleotide polymorphism designated rs12979860 in the interferon λ4 (IFNλ4) gene among 345 people who inject drugs (PWID) and 495 blood donors to evaluate associations between the rs12979860 genotypes and human immunodeficiency virus/hepatitis C virus (HIV/HCV). The rs12979860 TT genotype was over‐represented among HIV+ PWID than HIV? PWID and blood donors (16% vs 8% and 10%, P = 0.03, respectively). PWID with TT genotype had approximately twice the probability of being HIV+ (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.11 to 4.33) than PWID without TT. Every additional year of intravenous drug use (IVDU) decreased the OR 1.16 times (OR, 0.86; 95% CI, 0.75 to 0.98). This suggests that rs12979860 TT increases susceptibility to HIV and this impact decreases with increasing duration of IVDU.     

Tumor Necrosis Factor and Interleukin‐6 Gene Polymorphisms and Endometriosis Risk in Asians: A Systematic Review and Meta‐Analysis

A relationship between endometriosis and tumor necrosis factor (TNF‐α) and interleukin‐6 (IL‐6) gene polymorphisms has been raised for Asians. However, this topic is controversial. This study was a meta‐analysis to explore whether TNF‐α/IL‐6 gene polymorphisms were associated with a risk of endometriosis in Asians. By searching PubMed, HuGENet, and China National Knowledge Infrastructure (CNKI) databases, 17 studies were identified and included (3372 cases and 4008 controls). The odds ratio (OR) with 95% confidence interval (CI) was used to assess the association between TNF‐α/IL‐6 gene polymorphisms and endometriosis risk. An association of TNF‐α gene ‐1031T/C polymorphism with endometriosis was found (TT + TC vs. CC: OR 0.50, 95% CI 0.30–0.82, I² = 37.1%, P = 0.20; TT vs. CC: OR 0.50, 95% CI 0.30–0.82, I² = 43.0%, P = 0.173; TC vs. CC: OR 0.49, 95% CI 0.29–0.83, I² = 10.6%, P = 0.327). In addition, TNF‐α‐238A/G and IL‐6 ‐174C/G gene polymorphisms were also likely to be associated with endometriosis in Asians. For the TNF‐α‐238A/G gene polymorphism, the OR was 1.577 (95% CI: 1.01–2.48). For the IL‐6 ‐174C/G gene polymorphism, the OR was 1.554 (95% CI: 1.04–2.31). No associations were detected between the TNF‐α‐308A/G and IL‐6 ‐634C/G polymorphisms and susceptibility to endometriosis. Our results indicate that the TNF‐α gene ‐1031T/C polymorphism can reduce the risk of endometriosis, but for Asians, TNF‐α‐238A/G and IL‐6 ‐174C/G gene polymorphisms may be a risk factor for endometriosis. No association was found for the TNF‐α‐308A/G and IL‐6 ‐634C/G gene polymorphisms.     

Association of the Vascular Endothelial Growth Factor Gene Polymorphisms (–460C/T, +405G/C and +936T/C) with Endometriosis: A Meta‐Analysis

Published data on the association between the vascular endothelial growth factor (VEGF) gene –460C/T (rs833061), +405G/C (rs2010963), +936T/C (rs3025039) polymorphisms and endometriosis risk are inconclusive. Eleven eligible case‐control studies including 2690 cases and 2803 controls were included in this meta‐analysis through searching the databases of PubMed and CBMdisc (up to August 1, 2011). In the overall analysis, no significant association between the –460C/T and +405G/C polymorphisms and risk of endometriosis was observed. However, significant associations were observed between endometriosis risk and VEGF+936T polymorphism with summarized odds ratio of 1.19 (95%CI, 1.02–1.37), 1.18 (95%CI, 1.03–1.37), 1.15 (95%CI, 1.01–1.30) for CT versus CC genotype, dominant mode (CT/TT vs. CC) and allele comparison (T vs. C), respectively. Furthermore, stratified analysis showed that significantly strong association between +936T/C polymorphism and endometriosis was present only in stage III–IV (OR = 1.32 for dominant mode; OR = 1.30 for T vs. C), but not in stage I–II. However, no significantly increased risk of endometriosis was found in any of the genetic models in Asians or in Caucasians. This meta‐analysis supports that VEGF+936T/C polymorphism is capable of causing endometriosis susceptibility.     

Association of Monocyte Chemoattractant Protein‐1 (MCP‐1)‐2518A>G Polymorphism with Susceptibility to Coronary Artery Disease: A Meta‐Analysis

We attempted to systematically elucidate the association between monocyte chemoattractant protein‐1 (MCP‐1) ‐2518A>G polymorphism and risk of coronary artery disease (CAD). Eligible studies were identified through PubMed, EBSCO, and Web of Science Databases. The magnitude of MCP‐1 polymorphism effect and its possible mode of action on CAD were estimated. The odds ratio (OR) with 95% confidence intervals (CI) were pooled in a specific genetic model to assess the association. A total of 21 studies were involved. There was significant gene effect on CAD risk in the overall population (likelihood ratio test: p < 0.0001). Patients with GG and AG genotypes had 1.435 (95% CI: 1.183–1.740) and 1.087 (95% CI: 1.008–1.172) times higher risk of CAD than those with AA genotype. These gene effects suggested a recessive model to be appropriate. The pooled OR was 1.362 (95% CI: 1.137–1.631; p_uncorrected = 0.001, p_FDR = 0.005) in the recessive model. In the ethnicity‐stratified analysis, significant association was observed in the Caucasian population (OR = 1.492; 95% CI: 1.106–2.014; p_uncorrected = 0.009, p_FDR = 0.015), whereas no statistical significant association was detected in the Asian population (adjusted p = 0.124). The results suggested that MCP‐1 ‐2518A>G polymorphism may be associated with susceptibility to CAD, especially in Caucasians.     

Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus‐infected children

Single nucleotide polymorphisms (SNPs) in immune‐related genes have been shown to play a role in driving the development of the severe phenotypes of dengue virus (DENV) infection. We assessed the association between IFNL3 gene SNP (rs12979860) and dengue clinical outcomes in children. Patients with dengue‐related symptoms (aged 1–15 years) admitted at a public hospital in Northeast Brazil were invited to participate. The association between rs12979860 polymorphism and dengue classification and clinical signs and symptoms were analysed. A total of 206 DENV‐infected children were included: 53.4% of the infections were classified as severe dengue. The T allele carriers had higher risk of developing severe dengue when compared to CC genotype carriers (OR: 1.81; 95% CI: 0.98–3.32 p = .054). The T allele carriers also showed longer fever episodes when compared to patients with the CC genotype (OR: 1.90; 95%CI: 1.07–3.38; p = .027). On the other hand, the ones carrying the CT/TT genotype had 70% lower chance of developing thrombocytopenia when compared to those with the CC genotype (OR: 0.30; 95%CI: 0.08–0.88; p = .042). Our findings demonstrated that the T allele carriers of the IFNL3 gene had higher risk of developing severe dengue, suggesting a link between IFN‐λ expression and DENV immunopathogenesis.     

A protective polymorphism in MMP16, improved blood gas levels,and chronic obstructive pulmonary diseases: Family and two population‐based studies

The aberrant expression of matrix metalloproteinases (MMPs) is known to contribute to the pathogenesis of airway remodeling and alveolar disruption in chronic obstructive pulmonary disease (COPD). In the discovery stage, 11 COPD from five families were subjected to whole‐genome sequencing, and 21 common polymorphisms in MMPs and TIMPs were identified. These polymorphisms were genotyped in two subsequent verification studies. Of these polymorphisms, c.2392G>A (rs2664370T>C) and c.4158C>A (rs2664369T>G) in MMP16 remained significantly different. Functionally, we found that MMP16 expression was significantly increased in peripheral blood monocytes (PBMCs) from COPD and in cigarette smoke extract‐treated 16HBE cells compared with controls. This was also shown by bioinformatics analysis. COPD carrying rs2664370CC showed decreased levels of MMP16 in the plasma and in PBMCs compared with those carrying CT and TT. Treatment with hsa‐miR‐576‐5p mimics led to a greater reduction in luciferase reporter activity in cells transfected with rs2664370CC. Moreover, blood levels of base excess, PCO₂, and PO₂ in COPD with rs2664370CC were significantly lower than those with rs2664370CT+TT. Taken together, these results demonstrate that the rs2664370T>C polymorphism in MMP16 protects against the risk of COPD, likely by favoring interaction with hsa‐miR‐576‐5p, leading to reduced MMP16 expression and improved blood gas levels.     

Association of a Tgf‐B1‐509c/T Polymorphism with Gastric Cancer Risk: A Meta‐Analysis

Published data on the association between the transforming growth factor B1 (TGF‐B1) gene 509C/T polymorphism and gastric cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta‐analysis of the TGFB1‐509C/T polymorphism (with 2130 cases and 2374 controls) from seven published case‐control studies was performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, the dominant model, and the recessive model. In the overall analysis, the T allele was significantly associated with susceptibility to gastric cancer in the recessive model (TT vs. CC+CT) (TT vs. CC+CT: OR = 1.35, 95% CI: 1.10–1.66, P = 0.10 for heterogeneity) when all the included studies were pooled into the meta‐analysis. In the stratified analysis by country, the T allele was also found to be significantly associated with increased gastric cancer risk in the recessive model (TT vs. CC+CT) in Chinese studies and in T versus C in the Indian study. In conclusion, this meta‐analysis supports the TGFB1‐509T polymorphism as a susceptibility factor for gastric cancer.     

The 894G>T variant in the endothelial nitric oxide synthase gene and spina bifida risk

The 894G>T single nucleotide polymorphism (SNP) in the endothelial NOS (NOS3) gene, has recently been associated with embryonic spina bifida risk. In this study, a possible association between the NOS3 894G>T SNP and spina bifida risk in both mothers and children in a Dutch population was examined using both a case-control design and a transmission disequilibrium test (TDT). Possible interactions between the NOS3 894G>T SNP and the MTHFR 677C>T SNP, elevated plasma homocysteine, and decreased plasma folate concentrations were also studied. The NOS3 894TT genotype did not increase spina bifida risk in mothers or children (OR 1.50, 95%CI 0.71–3.19 and OR 1.78, 95%CI 0.75–4.25, respectively). The TDT demonstrated no preferential transmission of the NOS3 894T allele (Χ ² = 0.06, P = 0.81). In combination with the MTHFR 677TT genotype or elevated plasma homocysteine concentrations, the NOS3 894GT/TT genotype increased maternal spina bifida risk (OR 4.52, 95%CI 1.55–13.22 and OR 3.38, 95%CI 1.46–7.84, respectively). In our study population, the NOS3 894GT/TT genotype might be a risk factor for having a spina bifida affected child in mothers who already have an impaired homocysteine metabolism.     

Homeostatic chemokines CCL19 and CCL21 promote inflammation in human immunodeficiency virus‐infected patients with ongoing viral replication

CCL19 and CCL21 and their receptor CCR7 are expressed constitutively within lymphoid organs, regulating lymphocyte homing. Recent studies suggest that these chemokines may have inflammatory properties. We hypothesized a role of CCL19/CCL21 in human immunodeficiency virus (HIV) infection by promoting inflammation. We examined the expression of CCL19 and CCL21 in mononuclear cells from peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) in HIV‐infected patients before and during highly active anti‐retroviral therapy (HAART). We also examined the ability of CCL19/CCL21 to promote inflammatory responses in these patients. PBMC from untreated HIV‐infected patients (n = 29) released enhanced levels of CCL19 spontaneously compared with cells from controls (n = 20), particularly in those with symptomatic disease (n = 15, P < 0·01 versus controls). During HAART (n = 9), there was a decrease in the spontaneous CCL19 release and an increase in the phytohaemagglutinin‐stimulated CCL19 release in both PBMC (P < 0·01) and BMMC (P < 0·05). In patients with enhanced HIV replication there was an increased proportion of inflammatory CD8⁺CCR7^‐CD45RA^‐ T cells in peripheral blood [P < 0·01 and P < 0·05 versus controls, untreated (n = 9) and treatment failure (n = 8), respectively]. In vitro, CCL19/CCL21 promoted an inflammatory response in PBMC when accompanied by high viral load, irrespective of HAART. The HIV‐tat protein significantly boosted the inflammatory effect of CCL19/CCL21 in PBMC. These findings link a dysregulated CCL19/CCL21/CCR7 system in HIV‐infected patients to persistent inflammation and HIV replication, not only in untreated HIV infection, but also in treatment failure during HAART.