Effect of maternal HIV infection, BMI and NOx air pollution exposure on birth outcomes in South African pregnant women genotyped for the p53 Pro72Arg (rs1042522).

Tumour suppressor protein, p53, plays a role in modulating innate immune responses, DNA repair, cell cycle arrest, senescence and apoptosis. Maternal nitrogen oxide (NOx) air pollution exposure, body mass index (BMI), human immunodeficiency virus (HIV) infection and p53 Pro72Arg (rs1042522) affect foetal growth. We investigated whether the aforementioned factors influence birth outcomes in a South African population. Pregnant women (n = 300; HIV -ve = 194 and HIV +ve = 106) were genotyped for the p53 rs1042522 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and further stratified based on HIV status, infants' birthweight (BW; NBW: normal BW [>2,500 g] and LBW: low BW [<2,500 g]) and gestational age (GA; NGA: normal GA [>37 weeks] and PTB: preterm birth [≤37 weeks]). A land use regression model was developed to characterize maternal NOx exposure. Pearson's correlation and multivariate regression analysis statistical tests were used to determine the effect of rs1042522 genotyped pregnant women's BMI and NOx exposure on maternal blood pressure and haemoglobin and iron levels, and infants' anthropometric measurements and Appearance Pulse Grimace Activity and Respiration (APGAR) scores. The prevalence of LBW and PTB was 14.7% and 18.7%, respectively. The LBW group had a higher frequency of the variant Arg-allele versus NBW group (47.7% vs. 31.4%, p = .0046, OR = 2.0, 95% CI = 1.26-3.17). No association was observed between NGA and PTB groups. A significant association between BMI and systolic blood pressure (r = .50, p = .00; B = 0.76, p = .002) and birth length (r = -.28, p = .01; B = -0.107, p = .011), and NOx and birth length (r = -.26, p = .08; B = -0.191, p = .046) and birthweight (B = -8.87, p = .048) was observed in HIV-infected mothers with the variant Pro/Arg + Arg/Arg genotypes. Mothers from the LBW group with the variant genotypes displayed an association between NOx and diastolic blood pressure (r = .58, p = .04), blood iron levels (r = -.60, p = .04; B = -0.204, p = .004), APGAR scores at 1 min (r = -.86, p = .00; B = -0.101, p = .003) and 5 min (r = -.75, p = .01) and birth length (r = -.61, p = .04), and BMI and diastolic blood pressure (r = .72, p = .01). In the PTB group, maternal variant genotypes and NOx were associated with blood haemoglobin levels (B = -0.132, p = .045) and APGAR scores at 1 min (B = -0.161, p = .045) and 5 min (B = -0.147, p = .043). Maternal rs1042522 Arg-allele, HIV infection, BMI and NOx exposure collectively play a role in lowering blood iron levels, gestational hypertension and LBW outcomes.

MiR-146a G/C rs2910164 variation in South African Indian and Caucasian patients with psoriatic arthritis.

BACKGROUND: Psoriasis and psoriatic arthritis (PsA) are inflammatory associated autoimmune disorders. MicroRNA (miR)-146a plays a crucial role in regulating inflammation. A single nucleotide polymorphism in the miR-146a gene (rs2910164), aberrantly alters its gene expression and linked with the pathogenesis of several disorders, including psoriasis and PsA. In South Africa, psoriasis and PsA are extremely rare in the indigenous African population and most common in both the Indian and Caucasian population. The aim of this study was to investigate whether the miR-146a rs2910164 contributes towards psoriasis and PsA development in South African Indian and Caucasian patients. METHODS: South African Indian (n = 84) and Caucasian (n = 32) PsA patients (total n = 116) and healthy control subjects (Indian: n = 62 and Caucasian: n = 38; total n = 100) were recruited in the study. DNA was extracted from whole blood taken from all subjects, and genotyped for the miR-146a rs2910164 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for laboratory parameters were obtained from pathology reports. The consulting rheumatologist collected all other clinical data. RESULTS: Unstratified data (Caucasians + Indians): A significant decrease in C-reactive protein (CRP) levels in PsA patients was observed (CRP monitored at inclusion vs. after 6 months of treatment) (18.95 ± 2.81 mg/L vs. 9.68 ± 1.32 mg/L, p = 0.0011). The miR-146a rs2910164 variant C-allele frequency in PsA patients was significantly higher vs. healthy controls (35.78% vs. 26% respectively, p = 0.0295, OR = 1.59 95% CI 1.05-2.40). Stratified data (Indians): The variant C-allele frequency in Indian PsA patients was significantly higher vs. healthy Indian controls (35.71% vs. 22.58%, p = 0.0200, OR = 1.91 95% CI 1.13-3.22). Stratified data (Caucasians): The variant C-allele frequency distribution between Caucasian PsA patients and healthy Caucasian controls was similar. CONCLUSION: The rs2910164 variant C-allele may play a role in the progression of PsA in the South African Indian population. The main limitation in this study was the small sample size in the case-control cohorts, with a low overall statistical power (post-hoc power analysis = 19%).

The Effect of Nitric Oxide Pollution on Oxidative Stress in Pregnant Women Living in Durban, South Africa.

The purpose of the study was to evaluate the effect nitric oxide (NO x ) pollution had on maternal serum 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) levels and neonatal outcomes in pregnant women living in Durban, South Africa (SA). Women, in their third trimester with singleton pregnancies, were recruited from the heavily industrialised south (n = 225) and less industrialised north (n = 152). Biomarker levels of serum 8-OHdG concentrations were analysed, and the women were genotyped for glutathione-S-transferases pi 1 (GSTP1) and glutathione-S-transferases mu 1 (GSTM1) polymorphisms. The level of NO x pollution in the two regions was determined by using land use regression modelling. The serum 8-OHdG was shown to correlate significantly with NO x levels; this relationship was strengthened in the south (p < 0.05). This relationship was still observed after adjusting for maternal characteristics. GSTP1 was significantly associated with the south region, where the variant (AG+GG) genotype was associated with increased 8-OHdG levels as a result of NO x exposure (p < 0.05). GSTM1 null genotype was associated with a positive correlation between NO x and 8-OHdG levels (p < 0.05). NO x levels were found marginally to reduce gestational age (p < 0.05) with mothers carrying male neonates. Variant GSTP1 and living in the north were factors that contributed to gestational age reduction (p < 0.05). Our study demonstrated that NO x exposure resulted in increased 8-OHdG levels in pregnant women living in Durban, SA, which led to gestational age reduction. The GSTP1 variant increased susceptibility of individuals to harmful effects of NO x .

MicroRNA-146a rs2910164 is associated with severe preeclampsia in Black South African women on HAART.

BACKGROUND: South African (SA) Black women have a high prevalence of preeclampsia and HIV, both conditions associated with increased inflammation. miR-146a is an inflammatory-associated miR and a common single nucleotide polymorphism (rs2910164) has been associated with several disease conditions. To date, this SNP has not been investigated in SA Black women. We therefore aimed to investigate the miR-146a G > C SNP in SA Blacks with preeclampsia, and further examine possible association among preeclamptic (PE) women with HIV infection on HAART. METHODS: This hospital-based, case-control study included 95 normotensive and 98 PE Black SA women (aged 16-46 years old). Patients and controls were genotyped by PCR-RFLP. Using a Cytometric Bead Array assay, serum cytokine levels (including Th1- and Th2-related cytokines) were determined in 4 groups of pregnant women, viz: normotensive, HIV infected, PE + HIV infected, and PE women. RESULTS: There was no significant association between the miR-146a polymorphism and PE susceptibility in our data. However, in the subgroup analyses, the variant genotypes (GC/CC) were significantly associated with lower severe PE risk (p = 0.0497), more especially in the presence of HIV and HAART (p = 0.017). In the normotensive group, the variant genotypes were associated with lower IL-2 in both the total normotensive group (269 ± 1.26 (36) vs 273 ± 1.31 (23); p = 0.035) and the PE HIV+ sub-group 265 ± 1.54 (19) vs 271 ± 1.38 (11); p = 0.008). CONCLUSIONS: Our study suggests that miR-146a rs2910164 polymorphism might not be associated with PE susceptibility, cytokines or related features. However, the miR-146a GC/CC genotype might reduce susceptibility to severe PE, which might be further influenced by the presence of co-morbid HIV infection among pregnant women on HAART. This variant genotype may also be associated with reduced circulating IL-2 levels and thus reduced pro-inflammatory response in normotensive women, which may be further influenced by the presence of HIV infection and HAART.

microRNA-27a rs895819 is associated with obesity in HIV infected preeclamptic Black South African women on HAART.

BACKGROUND: Preeclampsia (PE) and HIV/AIDS present a major health challenge globally. South Africa has the highest disease burden of both HIV/AIDS and PE in the world. Despite extensive research, the pathophysiology of these conditions is not completely understood, however a genetic predisposition in women may affect susceptibility. MiRNA-27a regulates adipogenesis and glucose metabolism. A single nucleotide polymorphism (SNP) in miRNA-27a (rs895819T > C) has shown to have disparate effects in various populations. This study investigated the frequency of rs895819 in pregnant normotensive and preeclamptic Black South African (SA) women. METHODS: Enrollment into the study included: normotensive (n = 95; 45 HIV+; 80 analysed for rs895819T > C, age range: 16-46 years) and PE patients (n = 98; 45 HIV+; 56 analysed for rs895819T > C), age range: 16-42 years). DNA was isolated from peripheral blood mononuclear cells (PBMC). Genotyping of miRNA-27a rs895819 was detected using a TaqMan® SNP Genotyping assay. RESULTS: We did not find a significant association of miR-27a polymorphism with PE susceptibility in our data. However, in the subgroup analysis (based in HIV status), the variant genotypes (TC/CC) were associated with higher body mass index (BMI) among PE women (32.57 vs. 29.25, p = 0.064), significantly in the presence of HIV infection (33.47 vs. 27.8, p = 0.005). CONCLUSION: The results of this study suggests that miR-27a rs895819 may not be associated with PE susceptibility; however, the miR-27a TC/CC genotype increases susceptibility to elevated BMI in PE, which may be significantly influenced by co-morbid HIV infection among pregnant women on HAART.

Neonatal bronchoscopy: Role in respiratory disease of the newborn-A 7 year experience.

BACKGROUND: Bronchoalveolar lavage (BAL) is a standardized method to obtain specimen samples from the airway lumen of the respiratory system. BAL is used to diagnose lung infection and infection markers in neonates. OBJECTIVES: The aim was to evaluate the utility of flexible fiberoptic bronchoscopy in term and preterm neonates and to evaluate the use of BAL obtained by bronchoscopy in neonatal lung disease. METHODS: A retrospective analysis of Neonatal Intensive Care Unit (NICU) babies, during a 7-year period was conducted on 599 neonates who underwent the BAL procedure. Characteristics of the patients, indications, complications, and results of the procedure were recorded. RESULTS: The main indications were nosocomial pneumonia (140) and unilateral lung disease (74). A normal finding was most prevalent (201), followed by tracheitis (65). Microbiology on BAL fluid was positive in 33% of bronchoscopies (195/599); most common organisms isolated were Acinetobacter, Klebsiella, and Pseudomonas. CONCLUSIONS: Neonatal bronchoscopy can serve as an important diagnostic and therapeutic tool in the management of neonatal lung disease, BAL specimen microbiology from bronchoscopy directs clinical decision making in the management of neonatal lung infection. Individual common markers of infection have poor correlation to BAL. A combination of the markers, however, improves correlation with BAL but their utility in clinical management of lung infection is subject to caution. A negative BAL may shift management emphasis on minimizing lung injury especially in neonates who are ventilator dependent; BAL has the potential to critically affect the management of babies with significant lung disease especially when ventilator dependent.

OGG1 Ser326Cys polymorphism, HIV, obesity and air pollution exposure influences adverse birth outcome susceptibility, within South African Women.

The global HIV and obesity epidemics are major public health concerns; particularly as both are associated with increased risk of adverse birth outcomes. Despite extensive research, their combined effect, in terms of birth outcomes, has not been investigated. A single-nucleotide polymorphism (SNP) within 8-oxoguanine glycosylase 1 (OGG1) (Ser326Cys) has been suggested to affect body mass indices and therefore could predispose South African (SA) women to adverse effects of obesity. This study investigated the associations of OGG1 Ser326Cys SNP in relation to HIV and obesity on the susceptibility of low-birthweight (LBW) and pre-term birth (PTB) in SA women exposed to ambient air-pollution living in Durban. In our study population, the OGG1 SNP was associated with HIV and obesity. Wild-type (CC)-carrying patients had increased susceptibility for HIV-associated LBW and PTB. Co-morbid HIV and obese patients delivered neonates with decreased birthweights. Living within the heavily-polluted south-Durban and carrying the CC-genotype increased the risk for PTB within our study population.

The Tyr113His T/C rs1051740 and 'very slow' phenotype of the EPHX1 gene alters miR-26b-5p and miR-1207-5p expression in pregnancy.

BACKGROUND: Environmental insults and microsomal epoxide hydrolase 1 (EPHX1) single nucleotide polymorphisms (SNPs), Tyr113His T/C rs1051740 and His139Arg A/G rs2234922, aberrantly alters microRNA (miR) expression and are linked to low birthweights (LBW). OBJECTIVES: To investigate the interplay between pollution, EPHX1 SNPs and miRs during pregnancy and associated LBW outcomes. METHODS: South African pregnant women (n=241) were recruited in the MACE birth cohort study in Durban, a city with high levels of industry and traffic related pollutants. EPHX1 SNPs were genotyped using PCR-RFLP and grouped into their respective phenotypes, i.e. normal (N), slow (S), very slow (VS) and fast (F). EPHX1, miR-26b-5p, miR-193b-3p and miR-1207-5p expression were determined using quantitative PCR. RESULTS: Mothers with the Tyr113His SNP had low iron levels [TT vs. TC+CC: mean difference (MD)=0.67g/dl; p=0.0167], LBW [TT vs. TC+CC: MD=189.30g; p=0.0067], and low EPHX1 expression; p<0.0001. miR-26b-5p and miR-1207-5p expression were significantly higher in the CC genotypes compared to TT+TC groups; p<0.0001. The opposite trend occurred for miR-193b-3p; p=0.0045. Mothers with the VS phenotype had low iron levels [N vs. VS and VS vs. F: MD=2.03 and -1.96g/dl; p=0.0021, respectively], decreased gestational age [VS vs. F: MD=-2.14weeks; p=0.0051, respectively], and LBW [N vs. VS, VS vs. F and S vs. VS: MD=1000, -940.30 and 968.80g; p<0.0001, respectively]; F phenotype had the highest EPHX1 expression [N vs. F, VS vs. F and S vs. F: MD=-1.067, -1.854 and -1.379; p=0.0002, respectively]; and N phenotype had low miR-26b-5p [N vs. VS: MD=-0.6100; p=0.0159] and miR-1207-5p [N vs. VS and VS vs. F: MD=-0.834 and 1.103; p=0.0007, respectively] expression. miR-193b-3p expression between phenotypes remained unchanged. CONCLUSION: The Tyr113His T/C variant of rs1051740 and VS phenotype alters EPHX1, miR-26b-5p and miR-1207-5p expression, and contributes towards low blood iron levels and LBW.

Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia.

INTRODUCTION: Preeclampsia and HIV/AIDS are inflammatory conditions that contribute significantly to adverse maternal and foetal outcomes. The immune reconstitution effects of HAART on inflammatory mediators has not been adequately studied in pregnancy and may impact on the inflammatory cytokine network in women with co-morbid preeclampsia. Our study evaluated changes in pro-inflammatory cytokines IL-2, TNF-α, IFN-γ and IL-6 in HIV infected preeclamptic women on HAART. METHODS: A prospective experimental study was conducted at Prince Mshiyeni Memorial Hospital between July 2013 and September 2014. One hundred and ninety three pregnant women were recruited into 4 groups: uninfected normotensive (50; 26%), infected normotensive (45; 23%), uninfected preeclamptic (53; 28%) and infected preeclamptic women (45; 23%). Serum levels of cytokines TNF-α, IFN- γ, IL-2 and IL-6 were determined using commercially available kits and a Cytometric Bead Array (CBA). Comparative data was recorded and analysed descriptively. RESULTS: In the control groups (normotensive), significantly lower values were found in IL-2 (p = 0.010), TNF-α (p = 0.045), and IL-6 (p = 0.005); and a non-significant decrease was observed in IFN-γ (p = 0.345) in HIV infected women on HAART compared to uninfected controls. In the experimental group (preeclamptic) women, significantly reduced levels were observed in IL-2 and TNF-α (p = 0.001; p = 0.000) and non-significant decreases were observed in IFN-γ and IL-6 (p = 0.023; p = 0.086) in HIV infected women on HAART compared with uninfected preeclamptic women. Non-significant differences were observed between uninfected preeclamptic and normotensive women. CONCLUSION: In uncomplicated/normotensive pregnancies, HIV/HAART is associated with significant decreases in IL-2, TNF-α and IL-6, and in preeclamptic women significant decreases in IL-2 and TNF-α were observed. These findings suggest that HIV/HAART impacts on pro-inflammatory cytokines in women with co-morbid preeclampsia. This provides a platform for further research on immune reconstitution effects of HAART during pregnancy, and the development of potential immune modulation therapies for the management of preeclampsia.

The Arg72 variant of the p53 functional polymorphism (rs1042522) is associated with coronary artery disease in young South Africans of Indian ancestry.

BACKGROUND AND AIM: Tumor protein p53 (p53), classically referred to as a tumor suppressor gene, is involved in cell cycle regulation and may be related to atherosclerosis by affecting smooth muscle cell proliferation, a feature of atherogenesis. A polymorphism at codon 72 (rs1042522) results in functional variability and hence plays a role in the pathophysiology of coronary artery disease (CAD). This polymorphism has been well established for its role in cancer and has only recently been investigated in CAD. Limited data is available on South Africans (SA) of Indian ancestry. We examined associations of this polymorphism and clinical markers in a cohort of young SA Indian CAD patients. METHODS: A total of 284 subjects were recruited into this study which included 100 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45years), 100 age- and sex-matched Indian controls and 84 age- and sex-matched Black controls. Polymorphic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for clinical markers were obtained from pathology reports. RESULTS: Genotype distribution differed significantly between CAD patients and Indian controls (Pro/Pro, Pro/Arg, Arg/Arg: 24%, 48%, 28% vs. 30%, 61%, 9% respectively, p=0.0025). There was a significant genotype distribution between Indian and Black controls (Pro/Pro, Pro/Arg, Arg/Arg: 30%, 61%, 9% vs. 45.2% 40.5%, 14.3% respectively, p=0.0212). A significantly higher frequency of the p53 Arg72 allele was found in CAD patients compared to controls (52% vs. 39.5% respectively, p=0.0159). The variant allele was slightly higher in Indian controls (39.5%) compared to Black controls (34.5%), but this did not reach statistical significance (p=0.3324). The levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin and %HbA1c were not significantly influenced by the p53 genotypic variants. CONCLUSION: Although the p53 codon 72 SNP is not associated with clinical markers of disease in CAD, the higher frequency of the variant allele in SA Indians may be a contributing factor for this population having an increased risk of developing premature CAD.

Sirtuin 1 rs1467568 and rs7895833 in South African Indians with early-onset coronary artery disease.

BACKGROUND: Sirtuin 1 (SIRT1), a class III histone deacetylase, has been identified as a candidate molecule affecting the epigenetic mechanisms of cardiovascular disease (CVD). Previous studies have shown that some SIRT1 single-nucleotide polymorphisms (SNPs) are associated with body mass index, diabetes, blood pressure, cholesterol metabolism and coronary artery calcification. We investigated two A>G SIRT1 SNPs, rs1467568 and rs7895833, in young South African (SA) Indians with coronary artery disease (CAD) and compared them to Indian and black controls. METHODS: For rs1467568, a total of 287 subjects were recruited into this study (104 CAD patients, 99 age-, gender- and race-matched controls, and 84 age- and gender-matched black controls). For rs7895833, a total of 281 subjects were recruited into this study (100 CAD patients, 99 age-, gender- and race-matched controls, and 82 age- and gender-matched black controls). All patients were male, of Indian ethnicity, stable CAD confirmed on angiography, mean age 37.5 years; range 24-45. All subjects were genotyped using TaqMan SNP genotyping assays. RESULTS: The variant allele for both SNPs was found at a higher frequency in the total Indian group compared to the total black population (rs1467568: 41 vs 18.5%, respectively, p < 0.0001, OR = 3.190, 95% CI: 2.058-40943; and rs7895833: 41 vs 22%, respectively, p < 0.0001, OR = 2.466, 95% CI: 1.620- 3.755). Indian controls presented with a higher frequency for both SNPs compared to black controls (rs1467568: 40 vs 18.5%, respectively, p < 0.0001, OR = 2.996, 95% CI: 1.850- 4.853; and rs7895833: 41 vs 22%, respectively, p < 0.0001, OR = 2.513, 95% CI: 1.578-4.004). No difference was seen in the distribution of both SNPs between CAD patients and either control group. We did not observe any association between the SNPs and clinical parameters in CAD patients and controls. CONCLUSION: Both SNP variant alleles occurred more frequently in SA Indians than in SA blacks. A larger study group and further analysis is required to assess whether these SIRT1 SNPs may serve as risk factors that contribute to Indians developing early-onset CAD.

Methylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary artery disease in young South African Indians.

Methylenetetrahydrofolate reductase (MTHFR) reduces 5',10'-methylenetetrahydrofolate to 5'-methyltetrahydrofolate, and is involved in remethylation of homocysteine to methionine, two important reactions involved in folate metabolism and methylation pathways. The common MTHFR C677T single nucleotide polymorphism (SNP) (rs1801133) has been associated with raised levels of homocysteine, a well known risk factor for coronary artery disease (CAD). CAD is a major cause of mortality worldwide. The age of onset of this chronic disorder is on the decline, particularly in the Indian population. Indians in South Africa (SA) have a higher prevalence of premature CAD compared to Black South Africans. The MTHFR C677T SNP has not been investigated in the SA Indian population. The present study therefore investigated the MTHFR C677T SNP in young SA Indian males with CAD compared to young Indian and Black male controls. A total of 290 subjects were recruited into this study which included 106 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45 years), 100 Indian male controls (mean age 37.5, range 28-45 years), and 84 Black male controls (mean age 36.4, range 25-45). Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) was used to genotype CAD patients and healthy controls. Data for clinical markers were obtained from pathology reports. There was a significant association between the 677 MTHFR variant (T) allele and CAD patients compared to the healthy Indian controls (p=0.0353, OR=2.105 95% CI 1.077-4.114). Indian controls presented with a higher frequency of the variant allele compared to Black controls (7% vs. 2% respectively, p=0.0515 OR=3.086 95% CI 0.9958-9.564). The MTHFR C677T SNP did not influence levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin, HbA1c or hsCRP. The higher frequency of the MTHFR 677 variant allele in South African Indians may be a contributing factor to the higher risk profile for the development of premature CAD in Indians.

miR-146a polymorphism influences levels of miR-146a, IRAK-1, and TRAF-6 in young patients with coronary artery disease.

Modulation of nuclear factor KappaB (NF-κB) activation may play a role in regulating inflammatory conditions associated with coronary artery disease (CAD). MicroRNA-146a (miR-146a) primarily targets interleukin-1 receptor-associated kinase 1 (IRAK-1) and tumour necrosis factor receptor associated factor 6 (TRAF-6), which results in inhibition of NF-κB via the TLR pathway. This study investigated the influence of the miR-146a GC rs2910164 on miR-146a expression in young South African Indians with CAD. CAD patients and controls were genotyped by PCR-RFLP and miRNA-146a levels were measured by qPCR. IRAK-1, TRAF-6 and NF-κB expression was determined by Western blot. No differences in genotypic frequency was found (GG: 45 vs. 47%, GC: 46 vs. 41%, CC: 9 vs. 12%) in controls and patients respectively (odds ratio = 1.025; 95% confidence interval 0.6782-1.550; p = 0.9164). Significantly higher levels of miR-146a was associated with CAD patients with the CC genotype (6.25-fold increase relative to controls and patients with the wildtype variant, p < 0.0001). Significantly lower levels of IRAK-1 (0.38 ± 0.02; p = 0.0072) and TRAF-6 (0.44 ± 0.02; p = 0.0146) was found in CAD patients with the CC genotype. The lowest levels of NF-κB and C-reactive protein were found in patients with the homozygous C allele compared to the heterozygous GC and wildtype variants. We propose a role for miR-146a in TLR signalling through a negative feedback mechanism involving the attenuation of NF-κB by down-regulation of IRAK-1 and TRAF-6. Our observations implicate miR-146a as a target for lowering inflammation in CAD patients.

The interleukin-6 -147 g/c polymorphism is associated with increased risk of coronary artery disease in young South African Indian men.

BACKGROUND: Interleukin-6 (IL-6) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases such as coronary artery disease (CAD). The -174 IL-6 G/C promoter polymorphism influences mRNA levels and protein expression and is implicated in CAD. The Indian population in South Africa, unlike the black community, has a high prevalence of premature CAD. This polymorphism has not been fully explored in this population. The present study assessed the -174 IL-6 G/C polymorphism in young Indian patients with angiographically documented CAD and compared them with age- and gender-matched Indian and black control subjects. METHODS: Polymorphic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism, and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The -174 IL-6 C allele was found with a higher frequency (23%) in the total Indian group compared to 2% in the black participants [P<0.0001, odds ratio (OR)=0.05, 95% confidence interval (CI) 0.018-0.14). The difference in frequency was more pronounced when Indian controls were compared to black controls (29% vs. 2%, respectively) (P<0.0001, OR=0.05, 95% CI 0.02-0.17). A significant association between the -174 IL-6 G allele and CAD was found in Indian patients compared to Indian controls (84% in cases vs. 71% in Indian controls; P=0.043, OR=0.47 95% CI 0.23-0.95). Levels of IL-6 in circulation were higher in black controls (6.62±0.63 pg/mL) compared to Indian controls (2.51±0.57 pg/mL) and CAD patients (1.46±0.36 pg/mL) (P<0.0001). Levels of IL-6 were higher in all groups with homozygous -174 IL-6 C alleles, but only significant in the healthy Indian control group (GG 3.73±0.94 pg/mL vs. GC/CC 0.89±0.5 pg/mL, P=0.0001). CONCLUSION: The presence of the IL-6 -174 G allele influences levels of IL-6 and increases the risk of CAD in South African Indians.