Nowy marker molekularny genu dla receptora endotelinowego typu A - brak zależności między polimorfizmem G1354C a chorobą miażdżycową tętnic u mężczyzn

Background. There is some evidence pointing toward endothelin system involvement in pathogenesis of atherosclerosis, manifested as coronary heart disease (CHD) and peripheral arterial occlusive disease (PAOD). Material and methods. In the study, 133 male patients - 46 with CHD (age 47.1 ± 4.12 years), 87 with PAOD (51.7 ± 5.31) and 87 healthy controls (46.35 ± 3.81) were genotyped by a polymerase chain reaction and restrictive fragments length polymorphism (PCR-RFLP) for a endothelin-A receptor (ENDRA) polymorphism. The allelic and genotype frequencies were compared between the groups using the χ2 test. Results. The novel single nucleotide polymorphism of the ENDRA gene (G1354C) was studied as a marker in CHD or PAOD. Genotype distribution in each of the groups did not deviate from the Hardy-Weinberg equilibrium. The allelic and genotype frequencies of the ENDRA gene did not differ between the groups. The allele G frequencies were 0.522 in CHD group, 0.506 in PAOD patients and 0.483 in controls. Conclusions. No genetic association between allelic variants of ENDRA and CHD or PAOD was found. It is unlikely that genetic variation at this ENDRA gene locus could contribute to the pathogenesis of arterial disease.Wstęp. Istnieją przesłanki wskazujące na udział układu endotelin w patogenezie miażdżycy objawiającej się klinicznie jako choroba wieńcowa (CHD) i choroba obwodowych naczyń tętniczych (PAOD). Materiał i metody. Badaniem objęto 133 chorych mężczyzn - 46 osób z CHD w wieku 47,1 ± 4,12 roku, 87 pacjentów z PAOD w wieku 51,7 ± 5,31 roku oraz grupę kontrolną 87 zdrowych mężczyzn w wieku 46,35 ± 3,81roku. Genotypowanie polimorfizmu genu dla receptora endotelinowego typu A (ENDRA) wykonano z zastosowaniem reakcji łańcuchowej polimerazy i polimorfizmu długości fragmentów restrykcyjnych (RFLP-PCR). Porównano częstości występowania alleli i genotypów pomiędzy grupami, posługując się testem χ2. Wyniki. Poszukiwano asocjacji genetycznej nowego polimorfizmu pojedynczego nukleotydu genu ENDRA (G1354) z występowaniem CHD i PAOD. We każdej z grup częstości występowania genotypów były zgodne z prawem Hardy’ego-Weinberga. Częstości alleliczne i genotypowe genu ENDRA nie różniły się istotnie w badanych grupach. Częstość występowania allelu G wynosiła 0,522 u osób z CHD; 0,506 u pacjentów z PAOD i 0,483 w grupie kontrolnej. Wnioski. Nie stwierdzono asocjacji genetycznej między wariantami allelicznymi ENDRA a CHD i PAOD. Zbadany wariant genetyczny genu dla receptora endoteliny nie wiąże się z ryzykiem miażdżycy tętnic

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Association of Factor V Leiden with Subsequent Atherothrombotic Events:A GENIUS-CHD Study of Individual Participant Data

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

Genetic Variability of the High-affinity IgE Receptor α Subunit (Fc ε RI α) is Related to Total Serum IgE levels in Allergic Subjects

Known susceptibility genes to atopy and asthma have been identified by linkage or associations with clinical phenotypes, including total serum IgE levels. IgE-mediated sensitivity reactions require a high-affinity IgE receptor (FcεRI), which immobilizes the immunoglobulin on the surface of the effector cells, mostly mast cells and basophils. In this mini-review, recent findings are presented on genetic variation of this receptor, as related to atopy. Transcription of FCER1A gene encoding the receptor α subunit can be initiated from two separate promoters, the proximal one and the distal one, which results in a transcript containing two novel untranslated exons (1A, 2A). Our knowledge on the role of this mechanism in allergic diseases is still at an infancy stage. Within regulatory elements of FCER1A some common single nucleotide polymorphisms have functional associations, which were recently reported and replicated in different ethnical groups. Interestingly, these associations do not confer susceptibility to allergic diseases, but rather modulate serum concentrations of IgE. Similarly to the previously investigated β subunit of the receptor, FCER1A is a good candidate for a quantitative trait locus (QTL) in allergic diseases, and appears to participate in the systemic regulation of IgE levels