Genetic variability and the risk of myocardial infarction in Poles under 45 years of age

Introduction

Myocardial infarction is caused by the obstruction of an artery in places of atherosclerosis plaque rupture. Endothelial cells during their activation express chemoattractant and adhesion molecules whereas infiltrating inflammatory cells produce enzymes, predisposing a lesion to rupture.

Material and methods

We investigated the correlation between polymorphisms in the human genes E-selectin (Ser128Arg), ICAM1 (K469E), OLR1 (K167N), MMP1 (1G/2G) and MMP3 (−1612 5A/6A) and the risk of MI in young Poles under 45 years. There was no significant difference in the frequency of single nucleotide polymorphism (SNP) of the studied genes E-selectin (Ser128Arg), ICAM1 (K469E), OLR1 (K167N) and MMP3 (−1612 5A/6A) between patients with MI and controls.

Results

The analysis of the association of the 1G2G polymorphism with the risk of myocardial infarction indicated an odds ratio (OR) of 5.68 (95% confidence interval [95% CI] 2.60 to 12.36). Other factors associated with myocardial infarction were: smoking (OR 4.12; 95% CI 1.63–10.44), male sex (OR 16.02; 95% CI 5.90–43.46), hypercholesterolaemia (OR 2.74; 95% CI 1.29–5.83) and arterial hypertension (OR 4.56; 95% CI 1.66–14.47).

Conclusions

We found that only MMP1 1G/2G polymorphism is associated with myocardial infarction in the Polish population of individuals younger than 45 years. Clinical factors seemed to play a greater role in the analysed group.     

Polymorphisms in thrombospondin genes and myocardial infarction: a case-control study and a meta-analysis of available evidence

A role of thrombospondins (TSPs) in atherosclerosis and thrombosis was suggested by associations of single nucleotide polymorphisms in the genes coding for TSP-1 (rs2228262; Asn700Ser), TSP-2 (rs8089; 3' untranslated region), and TSP-4 (rs1866389; Ala387Pro) with myocardial infarction (MI). However, these findings were not consistently confirmed in replication studies. We determined the genotypes related to these polymorphisms in a large case-control sample of MI and performed a meta-analysis of data obtained in the present sample and available from prior studies that included Europeans or Americans of European origin. In the population examined here, the carriers of the minor allele of the polymorphism in the TSP-2 gene (GG and TG genotypes) had a mildly statistically significant higher risk of MI than the homozygous carriers of the major allele (TT genotype) [adjusted odds ratio (OR) 1.19; 95% confidence interval (CI), 1.02 to 1.39]. In similar comparisons, no associations of the polymorphisms in the TSP-1 (adjusted OR 1.12; 95% CI, 0.93 to 1.35) and TSP-4 (adjusted OR 0.99; 95% CI, 0.85 to 1.16) genes with MI were observed. The meta-analysis included 6388 (TSP-1), 4930 (TSP-2), and 6978 (TSP-4) cases. None of the polymorphisms was found to be linked with the risk of MI. Thus, despite associations in certain individual studies, the synthesis of available evidence did not suggest that the TSP polymorphisms included in this study were associated with MI.     

Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness--the ECTIM, AXA, EVA and GENIC Studies

The TNFRSF1A gene was screened for polymorphisms in 95 subjects with premature myocardial infarction (MI), who also had one parent who had an MI. A total of 10 polymorphisms were found: three in the promoter region, two in exons and five in introns. All polymorphisms were genotyped in ECTIM, a case-control study of MI (1815 subjects). The nonsynonymous 92Q allele was found in 1.8, 1.0 and 1.7% of controls from Strasbourg, Belfast and Glasgow - respectively; in cases: 4.2, 2.2 and 3.2%. The population-adjusted odds ratio (OR) for MI associated with allele Q carrying was 2.15 (95% CI: 1.09-4.23). To check its possible implication in atherosclerosis, this polymorphism was then genotyped in the AXA Study (ultrasound examinations of carotid and femoral arteries in the context of an employment medical examination, 733 subjects), the EVA Study (ultrasound examinations of carotid arteries in a study of cognitive and vascular ageing, 1092 subjects) and the GENIC Study (on brain infarction (BI), 912 subjects). In the AXA Study, among smokers, carrying the 92Q allele was positively associated with the presence of a carotid plaque (OR 5.07; 95% CI: 1.64-15.63) and with a thickening of the carotid intima-media thickness (IMT) (0.59 (0.11) vs 0.54 (0.11), P=0.045). In the EVA Study, carriers of allele 92Q had an increased mean carotid IMT (0.70 (0.09) vs 0.67 (0.13), P=0.02). No significant association of the 92Q allele was found with BI in the GENIC Study. Overall, these results may suggest that carriers of the 92Q allele may be at increased risk of atherosclerosis.     

Association of the lymphotoxin-alpha gene Thr26Asn polymorphism with severity of coronary atherosclerosis

A recent large-scale, genome-wide association study of single nucleotide polymorphisms showed a strong association between susceptibility to myocardial infarction and the Thr26Asn polymorphism in the lymphotoxin-alpha (LTA) gene. In the present study, we investigated whether the LTA Thr26Asn polymorphism was associated with the extent of coronary atherosclerosis in a large cohort (n=1082) of well-documented coronary artery disease patients. Thr26Asn genotypes showed a significant different distribution in male patients, when stratified according to the number of diseased coronary arteries, with an odds ratio of 1.98 (95% CI 1.22-3.22) for multiple-vessel disease in patients of the Asn/Asn genotype, compared with patients of the Thr/Thr or Thr/Asn genotype (P=0.006). Thus, further to the recent finding that LTA gene variation is associated with susceptibility to coronary heart disease, the present study provides evidence of an association between LTA genotype and the extent of coronary atherosclerosis.     

The intercellular adhesion molecule-1 (ICAM-1) gene polymorphism K469E in end-stage renal disease patients with cardiovascular disease

The intercellular adhesion molecule-1 (ICAM-1) mediates interaction of activated endothelial cells with leukocytes. It plays an important role in the pathogenesis of atherosclerosis. A functionally important polymorphism of the ICAM-1 gene, K469E, has been described. We investigated whether this polymorphism influences the risk of CVD in end-stage renal disease (ESRD) patients. The groups of 1016 ESRD patients and 824 healthy individuals were genotyped by PCR and allele specific oligonucleotide technique. The T allele of the K469E polymorphism was significantly more frequent in ESRD CVD+ patients than CVD- and controls (OR 2.26, 95% CI 1.87-2.72 and 1.82, 95% CI 1.55-2.11, respectively). The TT genotype was also more frequent in CVD+ patients (OR 9.90, 95% CI 6.17-15.88 vs. CVD- subgroup). When patients were stratified according to clinical outcome of CVD, there was a tendency towards higher frequencies of the T allele and TT genotype in patients with myocardial infarction (OR for T allele 1, 57, 95% CI 1.12-2.18 vs. patients without MI). In the multivariate regression analysis the carrier status of T allele of K469E was an independent risk factor of susceptibility to CVD. Our data suggest that the ICAM-1 K469E polymorphism is associated with CVD in ESRD patients.     

基质金属蛋白酶9基因-1562C/T多态性与新疆维吾尔族心肌梗死的相关性研究

目的 探讨新疆维吾尔族人群基质金属蛋白酶9(matrix metalloproteinase 9,MMP9)基因启动子区-1562C/T多态性与心肌梗死(myocardialinfarction,MI)发病的相关性.方法 选择经皮冠状动脉造影检查确诊的维吾尔族心肌梗死患者347例(MI组),以同期冠脉造影阴性、排除冠心病诊断的403例维吾尔族患者为对照组.采用聚合酶链反应-限制性片段长度多态性方法对所有纳入对象MMP9基因-1562C/T多态性进行分析,比较两组间MMP9基因多态性频率分布的差异,并结合造影情况,探讨MMP9基因多态性与MI发病及冠脉狭窄程度的关系.结果 MI组CT+TT基因型频率(27.67%)明显高于对照组(14.14%),两组差异具有统计学意义(χ2=20.99,P＜0.01),T等位基因频率在MI组和对照组分别为15.71%、7.56%(χ2=24.57,P＜0.01).Logistic回归分析显示,携带-1562T等位基因的个体发生MI的风险大约升高2倍(OR=2.009,95%CI:1.250～3.230);携带T等位基因合并糖尿病的个体发生MI的风险明显升高(OR=3.714,95%CI:1.299～10.773).MMP9基因-1562C/T多态性分布与MI冠脉狭窄程度差异无统计学意义.结论 MMP9基因-1562C/T多态性可能与新疆维吾尔族人群MI茇病具有相关性;-1562T等位基因可能是MI遗传易感性的基因标记之一;-1562T等位基因与糖尿病在MI发生中具有协同作用.MMP9基因-1562C/T多态性与MI冠脉狭窄程度无关.

Abstract：

Objective To investigate the association between matrix metalloproteinase 9 gene (MMP9)- 1562C/T polymorphism and myocardial infarction (MI) in Uighur population of Xinjiang.Methods A total of 347 patients with MI evidenced by coronary arteriography, and 403 controls free from coronary artery disease with normal angiograms were recruited for the study. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) was used to detect the -1562C/T functional promoter polymorphism of the MMP9 gene. The relationship between the polymorphism and the severity of coronary arterial stenosis was analyzed. Results The results showed that the frequency of CT and TT genotypes in patients with MI (27. 67%) was significantly higher than that in controls (14. 14%). The frequencies of the - 1562T allele were 15. 71% and 7. 56% in the MI group and the control group respectively (2 = 24.57, P＜0.01). Logistic regression analysis indicated that the T allele carriers (CT+TT) had significantly increased risk of MI compared with the CC carriers (OR=2. 009, 95%CI: 1. 250-3. 230). Individuals carrying the -1562T allele with diabetes mellitus were at an increased risk of MI (OR=3. 714, 95% CI: 1. 299-10. 773). The frequencies of CT and TT genotypes were not significantly different among MI patients with one, two and three or more significantly diseased vessels (χ2 =0. 491, P=0. 782). Conclusion The - 1562C/T polymorphism in the MMP9 gene promoter is associated with the susceptibility to MI in the Uighur population of Xinjiang. The T allele might be a risk factor of MI. And there was a coordinated effect between the -1562T allele and diabetes mellitus in the development of MI.The -1562C/T polymorphism may not be a predictor of the severity of coronary atherosclerosis.     

Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes

BACKGROUND: Two common polymorphisms of the beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu ) have been extensively studied for their possible association with asthma-related phenotypes, but the results of individual studies have been inconclusive. OBJECTIVE: We aimed to integrate quantitatively the available evidence on the association of the Arg16Gly and the Gln27Glu polymorphisms with asthma, nocturnal asthma, asthma severity, and bronchial hyperresponsiveness. METHODS: Meta-analysis of case-control and cohort studies using random effects models. RESULTS: A total of 28 studies were included in the meta-analysis. The summary estimates suggested that neither the Gly16 nor the Glu27 allele contributes to asthma susceptibility overall (odds ratio [OR], 1.01; 95% CI, 0.90-1.13; and OR, 0.95; 95% CI, 0.83-1.09, respectively) or to bronchial hyperresponsiveness (OR, 0.90; 95% CI, 0.77-1.05; and OR, 1.07; 95% CI, 0.94-1.22, respectively). There was a strong association of Gly16 with nocturnal asthma (OR, 2.20; 95% CI, 1.56-3.11) and a less strong association with severe or moderate rather than milder asthma (OR, 1.42; 95% CI, 1.04-1.94). No such effects were seen for the Glu27 allele (OR, 1.02; 95% CI, 0.74-1.40; and OR, 0.82; 95% CI, 0.59-1.14, respectively). Moreover, there was evidence that Gly16 homozygotes had a much higher risk for nocturnal asthma (OR, 5.15; 95% CI, 2.44-10.84) and asthma severity (OR, 2.84; 95% CI, 1.62-4.96) than the Arg16 homozygotes. CONCLUSION: The Gly16 allele of the beta2-adrenergic receptor gene predisposes to nocturnal asthma, and this may also explain the association with asthma severity. Neither polymorphism modulates the risk for bronchial hyperresponsiveness or mild asthma.     

Association between the Interleukin 10-1082G>A polymorphism and coronary heart disease risk in a Caucasian population: a meta-analysis

Interleukin-10 (IL-10) is a cytokine with anti-inflammatory and B-cell-stimulating activity. IL-10 is expressed in human atherosclerotic plaques and studies have shown the involvement of IL-10 in the atherosclerotic process. The IL-10-1082G/A polymorphism is one of the most commonly studied polymorphisms in this gene because of its association with coronary heart disease (CHD) risks, but previous results have been conflicting. We performed a meta-analysis using six eligible case-control studies (including 14 data sets) with a total of 5006 patients and 3968 controls to summarize the existing data on the association between the IL-10-1082G/A polymorphism and CHD risk. Compared with the common IL-10-1082G/A GG genotype, the carriers of variant genotypes (IL-10-1082GA/AA) had a 1.12-fold elevated risk of CHD (95% CI = 1.01-1.23, P = 0.03) under the dominant genetic model, as estimated using a random effect model. The effect of the IL-10-1082G/A polymorphism was further evaluated using stratification analysis. In the three disease of artery studies, with the variant genotypes had a not obvious increased risk of disease of artery (OR = 1.19, 95% CI = 0.98-1.44, P = 0.08) as estimated using a fixed effect model. Similar results were found in the nine myocardial infarction studies (OR = 1.13, 95% CI = 1.00-1.27, P = 0.05). It was also demonstrated that the increased risk of CHD associated with IL-10-1082G/A variant genotypes was more pronounced in Caucasians (OR = 1.12, 95% CI = 1.01-1.23, P = 0.03). Our meta-analysis suggests that the IL-10-1082G/A polymorphism genotypes (GA+AA) might be associated with an increased risk of CHD, especially in Caucasians.     

Does occupational gender segregation influence the association of effort-reward imbalance with myocardial infarction in the SHEEP study?

The objective of this study was to investigate whether occupational gender segregation moderates the association between job stress in terms of effort-reward imbalance and the risk of myocardial infarction. This analysis was conducted in 1,381 cases and 1,697 referents of the Swedish SHEEP case control study aged 45-70 years. Information on myocardial infarction and biological coronary risk factors (e.g. hypertension, blood lipids) was achieved from clinical screenings. Information on socio-demographic variables, effort-reward imbalance, behavioral coronary risk factors (e.g., smoking), and additional coronary risk factors (e.g., diabetes, family history of coronary heart disease) was derived from well-tested standardized questionnaires. After adjustment for confounders the strongest association between overcommitment (the intrinsic component of effort-reward imbalance) and risk of belonging to the myocardial infarction group was found among women in male-dominated jobs (odds ratio [OR] = 2.71, 95% CI = 1.13-6.52) as compared to the remaining group (OR = 1.52, 95% CI = 1.01-2.31). Moreover, a significant interaction between pronounced overcommitment and male domination in relation to myocardial infarction was observed among women (OR = 2.44, 95% CI = 1.05-5.67). In men, an association between the ratio of effort and reward (the extrinsic component of the model) and risk of myocardial infarction was found for the majority, that is the group not working in women-dominated jobs (OR = 1.39, 95% CI = 1.04-1.86). Despite methodological limitations, this study gives preliminary evidence of a moderating effect of occupational gender segregation on the association of effort-reward imbalance (i.e., the intrinsic model component overcommitment) with acute myocardial infarction risk among women, but not among men.     

Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans

Single-nucleotide polymorphisms within the BAT1-NFKBIL1-LTA genomic region (6p21.3) and the LGALS2 gene (22q13.1), encoding a regulator for lymphotoxin-alpha, the product of the LTA gene, have been reported to be linked with the risk of myocardial infarction in Japanese. We employed nine polymorphisms from the BAT1-NFKBIL1-LTA region and one polymorphism from the LGALS2 gene, and investigated whether such associations were also present in Europeans. The study included 3657 patients with myocardial infarction and 1211 control individuals with angiographically normal coronary arteries. Minor homozygous genotypes of polymorphisms in BAT1 (rs2239527, -23C/G), NFKBIL1 (rs2071592, -63T/A) and LTA (rs1800683, -162G/A; rs909253, 252G/A; rs1041981, Thr26Asn) were associated with moderately protective effects against myocardial infarction (P 相似文献   

Association between survivin -31G > C promoter polymorphism and cancer risk: a meta-analysis

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin -31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin -31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin -31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations.     

Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD)

Molecular genetic investigations of attention deficit hyperactivity disorder (ADHD) have found associations with a variable number of tandem repeat (VNTR) situated in the 3'-untranslated region of dopamine transporter gene (DAT1), a VNTR in exon 3 of dopamine receptor 4 gene (DRD4) and a microsatellite polymorphism located at 18.5 kb from the 5' end of dopamine receptor 5 gene (DRD5). A number of independent studies have attempted to replicate these findings but the results have been mixed, possibly reflecting inadequate statistical power and the use of different populations and methodologies. In an attempt to clarify this inconsistency, we have combined all the published studies of European and Asian populations up to October 2005 in a meta-analysis to give a comprehensive picture of the role of the three dopamine-related genes using multiple research methods and models. The DRD4 7-repeat (OR=1.34, 95% CI 1.23-1.45, P= 2 x 10(-12)) and 5-repeat (OR=1.68, 95% CI 1.17-2.41, P=0.005) alleles as well as the DRD5 148-bp allele (OR=1.34, 95% CI 1.21-1.49, P= 8 x 10(-8)) confer increased risk of ADHD, whereas the DRD4 4-repeat (OR=0.90, 95% CI 0.84-0.97, P=0.004) and DRD5 136-bp (OR=0.57, 95% CI 0.34-0.96, P=0.022) alleles have protective effects. In contrast, we found no compelling evidence for association with the 480-bp allele of DAT (OR=1.04, 95% CI 0.98-1.11, P=0.20). No significant publication bias was detected in current studies. In conclusion, there is a statistically significant association between ADHD and dopamine system genes, especially DRD4 and DRD5. These findings strongly implicate the involvement of brain dopamine systems in the pathogenesis of ADHD.     

Association between the CD14−260C>T gene polymorphism and susceptibility to myocardial infarction: Evidence from case−control studies

Numerous published studies have investigated the relationship between the CD14?260C>T (rs2569190) polymorphism and the risk of myocardial infarction (MI). However, the results are still conflicting and inconclusive. Potentially eligible published articles were searched in four databases including PubMed, Web of Science, EMBASE and Chinese Biomedical Database (CBM). The odds ratio (OR) with its 95% confidence interval (CI) was used to estimate the strength of the associations. Thirteen papers including 17 case–control studies were included, reporting a total of 6,443 MI patients and 6,315 controls. A significant increase in overall MI susceptibility was identified in the homozygote model. In the subgroup analysis, with respect to the type of MI, a significantly increasing acute MI susceptibility was found in the homozygote model. In the subgroup analysis for ethnicity, a significant increased susceptibility was found in Asian populations in allele, homozygote, recessive and dominant models. However, no significant association was found among Caucasian populations. In conclusion, there may be a moderate association between the CD14?260C>T polymorphism and acute MI susceptibility. This association may be different between ethnicities with the CD14?260C>T polymorphism being a risk factor for myocardial infarction in Asian populations.     

Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction.

We sought to evaluate the underlying coronary pathology of fatal postoperative myocardial infarction (MI). It has been hypothesized that most MIs following noncardiac surgery occur in the setting of increased oxygen demand that exceeds coronary blood supply. However, most MIs not associated with surgery are caused by plaque rupture and intracoronary thrombosis. In a retrospective cohort study, we reviewed 1841 consecutive autopsy records from 1981 to 1995 at two institutions and identified 26 cases of postoperative MI with coronary arteries available. Plaque rupture was present in 12 cases (46%, 95% confidence interval [CI] 27%-67%). Of the 9 (35%) patients with intracoronary thrombus, 5 (56%; 19% of entire group) had total occlusion. Thrombus occurred on a >50% stenosis (by cross-sectional area) in a total of 33% (95% CI 16%-55%) of patients. The only statistically significant difference in clinical variables between patients with and without plaque rupture was longer interval from surgery to death in patients with plaque rupture (7.8+/-4.4 days versus 4.4+/-4.8 days; p = 0.047). In this autopsy series, coronary plaque rupture was associated with almost half of fatal postoperative MI cases. Strategies aimed at reducing triggers of plaque rupture with coronary occlusion might reduce postoperative MI fatality.     

Functional polymorphisms and haplotypes in the promoter of the MMP2 gene are associated with risk of nasopharyngeal carcinoma

Matrix metalloproteinases (MMPs) play important roles in cancer initiation and development. Several polymorphisms in the promoters of a number of MMP genes, which can affect the respective MMP production in an allele-specific manner, have been well characterized. We examined whether these functional polymorphisms were related to the risk of nasopharyngeal carcinoma (NPC) in Chinese populations. Eight polymorphisms in the promoter of MMP1, MMP2, MMP3, MMP7, MMP9, MMP12, and MMP13 were genotyped in two independent case-control populations; one is from Guangxi province (593 patients with NPC and 480 controls), and the other is from Guangdong province (239 patients and 286 controls). We observed significantly increased susceptibility to NPC for the MMP2 -1306CC (rs243865:C>T) (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.30-3.10) and -735CC (rs2285053:C>T) (OR = 1.56, 95% CI = 1.17-2.09) genotype carriers compared with noncarriers in the Guangxi population. This association was confirmed in the Guangdong population (for -1306CC: OR = 2.19, 95% CI = 1.21-3.96; for -735CC: OR = 1.60, 95% CI = 1.13-2.28). The C(-1306)-C(-735) haplotype was also significantly associated with increased susceptibility to NPC in both the Guangxi (OR = 1.64, 95% CI = 1.35-1.99) and Guangdong population (OR = 1.68, 95% CI = 1.29-2.19). Furthermore, stratified analysis indicated that the increased susceptibility to NPC related to the -1306CC and -735CC genotype and the C(-1306)-C(-735) haplotype was more pronounced in heavier smokers. Our findings suggest that the genetic polymorphisms or haplotype in the MMP2 promoter may play a role in mediating the susceptibility to NPC in Chinese populations.     

Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture

Intimal thickening, the accumulation of cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation, especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction.     

CD14 C-260T gene polymorphism and ischemic heart disease susceptibility: A HuGE review and meta-analysis

The CD14 gene C-260T polymorphism has been reported to be associated with ischemic heart disease, but results were conflicting. To evaluate the role of the CD14 C-260T polymorphism in ischemic heart disease, we performed meta-analyses of all available data. Comprehensive searches for studies on the association between the genotypes (CC, CT, TT) distributions and ischemic heart disease risk were performed. Patients with acute coronary syndrome, prior myocardial infarction, stable angina pectoris, or angiographic coronary artery stenosis were included. Potential sources of heterogeneity were explored by meta-regression. Analyses were performed under European, East Asian, and Indian studies, respectively. Data were available for 19 studies involving 11,813 cases and 6,196 controls. The summary odds ratio under the recessive model was 1.53 (95% confidence interval: 1.20–1.96) for East Asian studies published in English language journals on overall ischemic heart disease. Pooled odds ratios under the codominant model were about 1.81 (95% confidence interval: 1.36–2.40) and 1.70 (95% confidence interval: 1.26–2.29) for Chinese studies on overall ischemic heart disease and other ischemic heart disease (angina pectoris and angiographic coronary artery stenosis), respectively. No significant association was found in a European population, an Indian population, or the vulnerable plaque ischemic heart disease (acute coronary syndrome and prior myocardial infarction) subgroup of an East Asian population. It is probable that T allele and TT genotype are associated with ischemic heart disease in the East Asian population but not in the European or Indian populations. Further studies are warranted to assess these associations in greater details, especially in East Asian and Indian populations.     

Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects

Folate supplementation appears to reduce the risk for neural tube defects (NTDs). Methylenetetrahydrofolate reductase (MTHFR) is a candidate gene in the folate metabolism pathway that has been extensively studied in different human populations. We examined the risk associated with having the thermolabile variant (TT) of MTHFR in a study of 175 American Caucasians with NTDs and their families. We found a significant association in patients compared with 195 unrelated controls [odds ratio (OR) = 2.13, 95% confidence interval (95% CI) = 1.11-4.09)], but not in mothers (OR = 1.29, 95% CI = 0.622-2.67) or in fathers (OR = 1.45, 95% CI = 0.681-3.09). We found no evidence for unequal transmission from parents to an affected child (p > 0.10). We failed to find a previously reported association for a combined haplotype for MTHFR and cystathionine beta-synthase, except in subjects with NTDs compared with 559 pooled controls (OR = 2.87, 95% CI = 1.03-8.03). We found no evidence for an association for a novel CA-repeat polymorphism identified in a gene closely linked to MTHFR (p > 0.10). Our studies continue to suggest that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families.     

Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: A meta-analysis

Abstract

Published data on the association between the IFIH1 rs1990760 polymorphism and multiple autoimmune diseases are controversial and inconclusive. To more precisely estimate the association between the IFIH1 rs1990760 polymorphism and susceptibility to autoimmune diseases, a meta-analysis was conducted. Studies examining the association of the IFIH1 rs1990760 polymorphism with autoimmune diseases were exhaustively searched using PubMed, Web of Science and a review of the references. A total of 19 studies with 26 comparisons including 8 type 1 diabetes (T1D), 5 systemic lupus erythematosus (SLE), 5 Graves’ disease (GD), 2 multiple scleorosis (MS), 2 rheumatoid arthritis (RA), 2 Hashimoto's thyroiditis (HT), 2 autoimmune Addison’s disease (AAD) were available for this meta-analysis. Meta-analysis was performed for genotype T/T?+?T/C (dominant model), genotype T/T (recessive model) and T-allele in fixed or random-effects models. The overall odds ratios (ORs) and 95% confidence intervals (CIs) for T-allele were T1D (OR?=?1.184, 95% CI?=?1.142–1.229), SLE (OR?=?1.143, 95% CI?=?1.073–1.217), MS (OR?=?1.181, 95% CI?=?1.062–1.313) and RA (OR?=?1.115, 95% CI?=?1.004–1.239), respectively. For T1D and SLE, significant association was observed in the population of European ancestry, but not in the Asian population. This meta-analysis demonstrates that the IFIH1 rs1990760 T-allele confers susceptibility to T1D, SLE, MS and RA and suggests that the IFIH1 rs1990760 polymorphism might have no effect on GD and AAD. Our result provides further evidence for the notion of common gene underlying multiple autoimmune diseases.     

The interleukin-10-1082 promoter polymorphism and cancer risk: a meta-analysis

Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic properties and play an important role in the pathogenesis of cancer. IL-10-1082A>G polymorphism is the most extensively studied polymorphism in the IL-10 gene in cancer susceptibility. To date, a number of case-control studies were conducted to investigate the association between IL-10-1082A>G polymorphism and cancer risk in humans. However, the association between the IL-10-1082A>G polymorphism and cancer risk is still ambiguous. In an effort to solve this controversy, we performed a meta-analysis based on 61 case-control studies, including 14,499 cancer cases and 16,967 controls. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. In the stratified analyses by specific cancer type, increased risk was found in lung cancer (OR = 3.16, 95% CI = 1.16-8.63 for GA versus AA; OR = 2.07, 95% CI = 1.16-3.70 for GG versus AA; OR = 3.17, 95% CI = 1.31-7.68 for GA/GG versus AA) and non-Hodgkin's lymphoma (OR = 1.18, 95% CI = 1.02-1.36 for GA versus AA; OR = 1.17, 95% CI = 1.02-1.35 for GA/GG versus AA). The meta-analysis also indicated that the variant genotypes were associated with a moderately increased risk in Asians in all genetic models (OR = 1.80, 95% CI = 1.17-2.76 for GA versus AA; OR = 3.32, 95% CI = 1.62-6.82 for GG versus AA; OR = 1.67, 95% CI = 1.07-2.60 for GA/GG versus AA; OR= 2.93, 95% CI = 1.43-6.03 for GG versus AA/GA). The meta-analysis suggested that the IL-10-1082A>G polymorphism was associated with increased risk of cancer in Asians and lung cancer and non-Hodgkin's lymphoma. To draw comprehensive and true conclusions, more researches with larger numbers of worldwide participants are needed to examine associations between IL-10-1082A>G polymorphism and cancer risk.