ANRIL polymorphisms (rs1333049 and rs3217992) in relation to plasma CRP levels among in-patients with CHD.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in long non-coding RNA ANRIL (antisense noncoding RNA in the INK4 locus) were shown to be associated with coronary heart disease (CHD). The biological background for this association is not fully understood. The primary aim of this study was to investigate whether two leading ANRIL SNPs, namely, rs133049 and rs3217992, were associated with plasma levels of C-reactive protein among a large cohort of in-patients with CHD (n = 933). MATERIAL AND METHODS: CHD was defined as previous or current detection of 50% stenosis of a main coronary artery. Severe periodontitis was diagnosed if proximal attachment loss of at least 5 mm was found in at least 30% of teeth. For genotyping rs1333049 we applied PCR using sequence-specific primers and for rs321799 restriction fragment length polymorphism analyses. C-reactive protein (CRP) plasma levels were determined using a particle-enhanced immunological turbidity test. In addition, interleukin (IL)-6, low-density lipoprotein (LDL), total cholesterol, high-density lipoprotein (HDL), triglycerides, and number of leukocytes were determined. RESULTS: Genotype CC of rs1333049 was significantly associated with both elevated CRP levels and decreased HDL concentrations after univariate (p = 0.028, p = 0.012) and multivariate analysis (p = 0.041, p = 0.023) stratified for age, gender, body mass index, smoking, diabetes, and severe periodontitis. Furthermore, severe periodontitis (p = 0.031), but not SNP rs3217992, was associated with CRP plasma concentrations. CONCLUSIONS: Among patients with CHD, ANRIL SNP rs1333049 is an independent risk indicator for both elevated CRP plasma levels and reduced HDL concentrations. ClinicalTrials.gov Identifier: NCT01045070.

PYCARD gene polymorphisms and susceptibility to periodontal and coronary heart diseases.

Numerous studies have established a link between gene variants within the inflammasome complex and the incidence of periodontitis and cardiovascular illness across various ethnic groups. This study investigated the association between PYCARD gene polymorphism and susceptibility to periodontal disease and coronary heart disease (CHD) and their correlation with clinical periodontal indices. A total of 120 participants were enrolled, categorized into four groups: 30 healthy controls (C), 30 patients with generalized periodontitis (P), 30 patients with atherosclerotic CHD but clinically healthy periodontium (AS-C), and 30 patients with both atherosclerotic CHD and generalized periodontitis (AS-P). We recorded demographic data, collected blood samples, and measured periodontal indices, including plaque index, clinical attachment loss, bleeding on probing, and pocket depth. The genomic variant of the PYCARD gene was analyzed using a conventional polymerase reaction. A significant prevalence of T and G allele mutations and a higher distribution of CT and TT genotypes in PYCARD C/T (rs8056505) and the AG genotype in PYCARD A/G (rs372507365) were observed in groups P, AS-P, and AS-C. These single nucleotide polymorphisms (SNPs) were also positively correlated with the severity of clinical periodontitis indices. Our findings suggest that the increased frequency of T and G alleles and the distribution of CT, TT, and AG genotypes in PYCARD SNPs are significantly associated with an elevated risk for periodontal disease and CHD. These SNPs may participate in the pathogenesis of these conditions. The study reinforces the potential role of these genetic markers as risk factors for both diseases in the Iraqi population.

Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.

Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD) and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33-2.94; P = 6.9 x 10(-4)) for generalized aggressive periodontitis, and 1.72 (1.06-2.76; P = 2.6 x 10(-2)) for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases.

Relationship between professional dental care in childhood and coronary heart disease in adulthood in a single urban dental clinic.

PURPOSE: A growing body of evidence supports an association between coronary heart disease (CHD) and dental diseases, particularly periodontitis (PD). The present study was designed to assess the relationship between childhood dental care and adult CHD in a single community dental clinic. MATERIALS AND METHODS: Consecutive patients (n = 223) at a single urban U.S. dental clinic were asked to complete a questionnaire regarding the details of their childhood and present dental care as well as CHD and PD diagnoses. RESULTS: A significantly greater proportion of patients who reported a lack of prophylactic dental care in childhood also reported a present diagnosis of CHD (54.2% vs 23.6%, P < 0.001). In a multivariate logistic regression model including the traditional CHD risk factors of smoking, family history, age and sex, the relationship between dental care in childhood and reduced CHD remained significant (OR = 0.318, 95% CI = 0.159-0.635, P = 0.001). This association cannot be explained wholly by a mechanism involving the development of PD in patients with poor childhood dental care, as PD was not significantly associated with CHD in the multivariate model (OR = 1.646, 95% CI = 0.836-3.239, P = 0.149). CONCLUSIONS: In our single dental clinic assessment, adequate childhood professional dental prophylactic care was associated with reduced CHD in adulthood, an association independent of traditional risk factors. Further studies are required to better define the magnitude of this association.

Family history of coronary heart disease, health care and health behaviors.

INTRODUCTION: Previous studies on health care and health behaviors in individuals with a family history of coronary heart disease (CHD) have produced contradictory results, and there is still no evidence that these individuals are more aware of their risk and have improved health behaviors and heath care. This study aims to evaluate health care and health behaviors according to family history of CHD. METHODS: Individuals randomly selected from the general population living in Porto, Portugal, aged ≥ 18 years (evaluation period: 1999-2003), and without prior history of chronic diseases (n=764), were evaluated by questionnaires on family and personal disease history, health care and health behaviors. A family history of CHD was defined as the occurrence of acute myocardial infarction or sudden death in at least one first-degree relative. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using unconditional logistic regression after stratification for age (18-39 vs. ≥ 40 years) and education (≤ 6 vs. >6 years schooling). RESULTS: Among men, 20% reported a family history of CHD, approximately the same proportion as in women (19.4%) (p=0.900). The proportion of subjects with a family history of CHD was significantly higher in older (≥ 40 vs. 18-39 years: 25.0% vs. 12.0%, p<0.001) and less educated individuals (>6 vs. ≤ 6 years: 27.0% vs. 17.1%, p=0.004). Overall, no significant associations were found between health care and behaviors and CHD family history. Only in younger individuals, after adjustment for education, was a significant positive association found between 1-2 dental visits and CHD family history (OR=2.92; 95% CI: 1.27-6.70). Younger subjects who smoked and consumed alcohol and caffeine also presented a higher probability of having CHD family history, but the associations were not statistically significant. DISCUSSION AND CONCLUSIONS: In this population without disease requiring regular medical care, individuals with CHD family history had similar care-seeking patterns and health behaviors to those without. These results suggest a lack of awareness of their increased risk and highlight the importance of developing measures to promote sustained and effective changes in risk factors in individuals with genetic susceptibility to CHD.

Association of genetically predicted blood sucrose with coronary heart disease and its risk factors in Mendelian randomization.

We assessed the associations of genetically instrumented blood sucrose with risk of coronary heart disease (CHD) and its risk factors (i.e., type 2 diabetes, adiposity, blood pressure, lipids, and glycaemic traits), using two-sample Mendelian randomization. We used blood fructose as a validation exposure. Dental caries was a positive control outcome. We selected genetic variants strongly (P < 5 × 10-6) associated with blood sucrose or fructose as instrumental variables and applied them to summary statistics from the largest available genome-wide association studies of the outcomes. Inverse-variance weighting was used as main analysis. Sensitivity analyses included weighted median, MR-Egger and MR-PRESSO. Genetically higher blood sucrose was positively associated with the control outcome, dental caries (odds ratio [OR] 1.04 per log10 transformed effect size [median-normalized standard deviation] increase, 95% confidence interval [CI] 1.002-1.08, P = 0.04), but this association did not withstand allowing for multiple testing. The estimate for blood fructose was in the same direction. Genetically instrumented blood sucrose was not clearly associated with CHD (OR 1.01, 95% CI 0.997-1.02, P = 0.14), nor with its risk factors. Findings were similar for blood fructose. Our study found some evidence of the expected detrimental effect of sucrose on dental caries but no effect on CHD. Given a small effect on CHD cannot be excluded, further investigation with stronger genetic predictors is required.

SAA and PLTP activity in plasma of periodontal patients before and after full-mouth tooth extraction.

OBJECTIVE: To assess whether treatment of advanced periodontal disease affects plasma levels of serum amyloid A (SAA) and phospholipid transfer protein (PLTP) activity. DESIGN: We measured the levels of SAA and PLTP activity in plasma of 66 patients with advanced periodontal disease before and after treatment by full-mouth tooth extraction (FME). RESULTS: At baseline, median SAA levels in our study population were within the normal range (2.7 microg ml(-1)) but SAA was elevated (>5 microg ml(-1)) in 18% of periodontitis patients. Three months after FME, SAA levels were significantly reduced (P = 0.04). SAA did not correlate with any of the periodontal disease parameters. PLTP activity was elevated in patients with periodontitis, compared to the PLTP activity reference group (age-matched systemically healthy adults, n = 29; 18 micromol ml(-1) h(-1)vs 13 micromol ml(-1) h(-1), respectively, P = 0.002). PLTP activity inversely correlated with average periodontal pocket depth (PPD) per tooth (r(s) = -0.372; P = 0.002). Three months after FME, median PLTP activity did not change significantly. CONCLUSIONS: Full-mouth tooth extraction significantly reduces SAA, a marker of inflammation, while it does not affect plasma PLTP activity. However, the inverse correlation between PLTP activity and average PPD suggests that increased PLTP activity may limit periodontal tissue damage.

A fast and cost-effective method for apolipoprotein E isotyping as an alternative to APOE genotyping for patient screening and stratification.

Apolipoprotein E (apoE) is a 34 kDa glycoprotein involved in lipid metabolism. The human APOE gene encodes for three different apoE protein isoforms: E2, E3 and E4. The interest in apoE isoforms is high for epidemiological research, patient stratification and identification of those at increased risk for clinical trials and prevention. The isoform apoE4 is associated with increased risk for coronary heart and Alzheimer's diseases. This paper describes a method for specifically detecting the apoE4 isoform from biological fluids by taking advantage of the capacity of apoE to bind "specifically" to polystyrene surfaces as capture and a specific anti-apoE4 monoclonal antibody as reporter. Our results indicate that the apoE-polystyrene binding interaction is highly stable, resistant to detergents and acid and basic washes. The methodology here described is accurate, easily implementable, fast and cost-effective. Although at present, our technique is unable to discriminate homozygous APOE ε4/ε4 from APOE ε3/ε4 and ε2/ε4 heterozygous, it opens new avenues for the development of inexpensive, yet effective, tests for the detection of apoE4 for patients' stratification. Preliminary results indicated that this methodology is also adaptable into turbidimetric platforms, which make it a good candidate for clinical implementation through its translation to the clinical analysis routine.

The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions.

Genetic factors are believed to influence the development of arterial thromboses. Because integrin alpha(IIb)beta(3) plays a crucial role in thrombus formation, we analyzed receptor adhesive properties using Chinese hamster ovary and human kidney embryonal 293 cells overexpressing the Pl(A1) or Pl(A2) polymorphic forms of alpha(IIb)beta(3). Soluble fibrinogen binding was no different between Pl(A1) and Pl(A2) cells, either in a resting state or when alpha(IIb)beta(3) was activated with anti-LIBS6. Pl(A1) and Pl(A2) cells bound equivalently to immobilized fibronectin. In contrast, significantly more Pl(A2) cells bound to immobilized fibrinogen in an alpha(IIb)beta(3)-dependent manner than did Pl(A1) cells. Disruption of the actin cytoskeleton by cytochalasin D abolished the increased binding of Pl(A2) cells. Compared with Pl(A1) cells, Pl(A2) cells exhibited a greater extent of polymerized actin and cell spreading, enhanced tyrosine phosphorylation of pp125(FAK), and greater fibrin clot retraction. These adhesion differences appear to depend on a signaling mechanism sensitive to receptor occupancy. Thus, the Pl(A2) polymorphism altered integrin-mediated functions of adhesion, spreading, actin cytoskeleton rearrangement, and clot retraction.

Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men.

Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis and is also involved in lipid metabolism. Two biallelic polymorphisms within TNF gene locus-TNFA at the position -308 in the promoter region of the TNF gene and TNFB in the first intron of the lymphotoxin-alpha (LT-alpha) have been reported to be associated with TNF production and with susceptibility to inflammatory diseases. We studied the association of these polymorphisms within the major histocompatibility complex (MHC) III region with coronary atherosclerosis and its manifestations. The autopsy series comprised 700 Caucasian Finnish men, aged 33-70 years (The Helsinki Sudden Death Study). Coronary stenosis and surface area of atherosclerotic changes (fatty streaks, fibrous plaques, complicated lesions and calcification) were measured and the presence of myocardial infarction and coronary thrombosis recorded. TNFA and TNFB genotypes were determined by the PCR-RFLP technique. The allele frequencies were TNFA1/TNFA2=0.88/0.12 and TNFB1/TNFB2=0.30/0.70. There was a strong linkage disequilibrium between the two polymorphisms. There were no differences in coronary stenosis and in the frequency of old or recent myocardial infarction or coronary thrombosis between men with different genotype status in either locus. Men with TNFA22 or TNFB11 genotype tended to have more fibrous lesions and calcification in their coronary arteries. TNFA and TNFB polymorphisms are unlikely to contribute to progression of atherosclerosis in a way clinically important.

Coronary heart disease, chronic inflammation, and pathogenic social hierarchy: a biological limit to possible reductions in morbidity and mortality.

We suggest that a particular form of social hierarchy, which we characterize as "pathogenic", can, from the earliest stages of life, exert a formal analog to evolutionary selection pressure, literally writing a permanent developmental image of itself upon immune function as chronic vascular inflammation and its consequences. The staged nature of resulting disease emerges "naturally" as a rough analog to punctuated equilibrium in evolutionary theory, although selection pressure is a passive filter rather than an active agent, like structured psychosocial stress. Exposure differs according to the social constructs of race, class, and ethnicity, accounting in large measure for observed population-level differences in rates of coronary heart disease across industrialized societies. American Apartheid, which enmeshes both majority and minority communities in a social construct of pathogenic hierarchy, appears to present a severe biological limit to continuing declines in coronary heart disease for powerful as well as subordinate subgroups: "Culture"--to use the words of the evolutionary anthropologist Robert Boyd--"is as much a part of human biology as the enamel on our teeth".

Screening for traditional risk factors for cardiovascular disease: a review for oral health care providers.

BACKGROUND: Cardiovascular disease, or CVD, is associated with a very high rate of morbidity and mortality among people in the United States. Primary and secondary prevention measures will help reduce cardiovascular events and increase the overall health of the patient population. METHODS: The author conducted MEDLINE and Internet searches and reviewed publications from professional organizations for the most up-to-date information on CVD and associated risk factors. RESULTS: More than 450,000 articles and monographs on CVD were published in English between January 1990 and May 2001. Of these, approximately 45,000 discussed CVD and risk factors. The author selected and reviewed more than 550 publications on the basis of their relevance to epidemiology, etiology, and primary and secondary prevention of CVD. CONCLUSIONS: Recent information regarding the pathogenesis and treatment of CVD suggests that oral health care providers can perform screening for risk factors and aid in monitoring of specific conditions that put people at an increased risk of developing and exacerbating existing CVD. Dentists need to take a proactive role in this endeavor. CLINICAL IMPLICATIONS: As with most medical conditions, oral health care providers play an important function as it relates to the overall health of their patients. This article provides a timely update on CVD and the relationship between CVD and its risk factors, and offers suggestions for oral health care providers as to when they should interact with patients and patients' primary health care providers to possibly reduce the mortality and morbidity of CVD.

Preventive cardiology for coronary artery disease.

Primary and secondary risk factors and prevention strategies for coronary artery disease are reviewed. Cigarette smoking, hypertension, dyslipidemia, heredity, diabetes mellitus, obesity, beta blockades, and coronary artery bypass surgery are some of the topics discussed.

Blood stasis syndrome in Japan and its molecular biological analysis.

Blood stasis syndrome is one of the pathological concepts of Oriental traditional medicine. In Oriental traditional medicine, blood is thought of as not only blood but also as a living component of the body. In fact, blood stasis syndrome is related to not just circulation disorders but dermatological and gynecological and other diseases. In Japan, the concept of blood stasis syndrome is based on the past literature, for instance, Synopsis of Golden Chamber (Jin Kui Yao Lue), etc. There are many signs of this syndrome, such as a dry mouth, fullness of the abdomen and rough skin. However, the levels of importance of these signs had been unclear. Therefore, in order to determine the levels of seriousness, a scoring system of blood stasis syndrome was made based on multivariate analysis by Dr. Terasawa (Terasawa's Blood Stasis Score). Using the scoring system, we have studied blood stasis syndrome mainly related to blood circulation using modern techniques of analysis. From the results, we found that patients with blood stasis syndrome showed hemorheological abnormalities, and an improvement in these abnormalities was shown after administration of removing-blood stasis formulae. Furthermore, we have studied blood stasis syndrome from the point of view of molecular biology. We searched for the specific protein expression in blood stasis syndrome by proteomic analysis, and found no specific protein expression. However, there may be a possibility of developing a diagnostic algorithm for blood stasis by construction of a decision tree. During the past few years, as one of the molecular biological factors affecting blood stasis syndrome, we have been studying hypoxia inducible factor, which is located in the upstream of many genes. Above all, blood stasis syndrome is more than just circulatory deficit but encompasses the pathological concept of constant multilateral change in the living body.

Association among oral health, apical periodontitis, CD14 polymorphisms, and coronary heart disease in middle-aged adults.

INTRODUCTION: There is evidence to suggest that an association exists between oral infections and coronary heart disease (CHD). Subjects presenting lesions of endodontic origin (LEOs) or pulpal inflammation had an increased risk of developing CHD. However, findings concerning systemic manifestations of apical periodontitis (AP) remain controversial. An association between CD14 gene polymorphisms and atherosclerosis-associated diseases has been shown, but there are no data regarding an association between CD14 polymorphism and AP. This study evaluated associations between clinical oral health status, CD14 polymorphisms, and CHD. METHODS: A case-controlled clinical trial was designed to compare middle-aged adults with acute myocardial infarction or unstable angina (n = 51) within 12 months of the acute event defined as first manifestation with healthy controls (n = 49). Participants were matched for age, sex, and socioeconomic status. Indicators of oral disease and compliance were evaluated. CD14 polymorphisms were analyzed by restriction fragment length polymorphism-polymerase chain reaction. RESULTS: CHD subjects had a higher prevalence of oral diseases and lower compliance to oral preventive strategies than healthy controls. Multivariate analysis showed a positive association between missing teeth (odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.02-1.85), the number of LEOs (OR = 4.37; 95% CI, 1.69-11.28), chronic periodontitis (OR = 5.87; 95% CI, 1.17-29.4), and CHD. No statistically significant association emerged between the CD14 C(-260)T and the CD14 C(-159)T polymorphism, endodontic or periodontal disease, and CHD. CONCLUSIONS: Chronic oral diseases may increase the risk of CHD and may be an unconventional risk factor for CHD.

[Correlation between levels of fibrinogen, beta455 g/A fibrinogen gene polymorphism and chronic periodontitis].

OBJECTIVE: To investigate the relationship between plasma levels of fibrinogen, the-beta455 G/A fibrinogen gene polymorphism and the severity of periodontal inflammation and to explore the possible role of fibrinogen in the association of periodontitis with coronary heart disease (CHD). METHODS: A total of 121 patients with moderate to severe periodontitis and periodontally healthy and gingivitis controls were enrolled in the study. Peripheral blood samples were collected and the plasma fibrinogen levels were determined by the clotting method of Clauss. Polymerase chain reaction and restriction fragment length polymorphism analysis with Hae III were used to examine the -beta455 G/A fibrinogen gene polymorphism. RESULTS: Fibrinogen levels were significantly higher in moderately or severely chronic periodontitis patients [(3.45 +/- 0.68) g/L] than periodontally healthy and gingivitis controls [(2.47 +/- 0.42) g/L, P < 0.001]. The carrier status of the A allele at position -455 in the beta fibrinogen gene was associated with elevated fibrinogen levels and the frequency of the-A455 allele in the beta fibrinogen gene in the patient group was significantly higher than in the control group (P = 0.032). Carriers of the -A455 allele were about 3-fold more likely to have moderate or severe periodontitis as compare to individuals without the -A455 allele( OR = 3. =135, P= 0.008). CONCLUSIONS: Fg-beta455 G/A polymorphism may contribute to the elevated plasma fibrinogen levels and put individuals at higher risk of having severe periodontitis. As the independent risk factor of CHD, fibrinogen levels and Fg-beta455 G/A polymorphism may play a role in the pathogenesis of periodontitis.

Sudden death and sport.

Of 21 sudden deaths in sportsmen, 18 were thought to be caused by heart attacks either during or after sport. There was firm evidence of ischaemic heart-disease in 9, strongly suggestive evidence in 7, but in 2 there was only suggestive clinical evidence. As a group, these subjects were characterised by (1) a mean age above thirty (above twenty-five for rugby players); (2) a family history of early heart-attacks; and (3) antecedent symptoms of chest pain or pressure in 9, fatigue or blackout in 4, and minor complaints in 2. Most were known to their medical practitioners. Psychological factors were thought to be important in 8. Doctors, players and referees should be aware that severe sporting exertion as in rugby football involves a risk which for most players is relatively minor, but in the minority predisposed to heart-attacks by family history, smoking, or age (as in referees) the risk is more serious. To reduce hazard of sudden death in exercise, players and referees should be warned against smoking and informed of the serious implications of the development of chest pain, pressure, or undue tiredness before, during, or after sport.