Period3 VNTR polymorphism influences the time-of-day pain onset of acute myocardial infarction with ST elevation.

It is well established that the incidence and infarct size in acute myocardial infarction (AMI) is subject to circadian variations. At the molecular level, circadian clocks in distinct cells, including cardiomyocytes, generate 24-h cycles of biochemical processes. Possible imbalance or impairment in the cell clock mechanism may alter the cardiac metabolism and function and increase the susceptibility of cardiovascular diseases. One of the key components of the human clock system PERIOD3 (PER3) has been recently demonstrated to affect circadian expression of various genes in different tissues, including the heart. The variable number tandem repeat (VNTR) polymorphism (rs57875989) in gene Period3 (Per3) is related to multiple phenotypic parameters, including diurnal preference, sleep homeostasis, infection and cancer. The aim of our study was to investigate the effect of this polymorphism in AMI with ST elevation (STEMI). The study subjects (314 patients of Caucasian origin with STEMI, and 332 healthy controls) were genotyped for Per3 VNTR polymorphism using an allele-specific polymerase chain reaction. A gender difference in circadian rhythmicity of pain onset was observed with significant circadian pattern in men. Furthermore, the Per3(5/5) variant carriers were associated with higher levels of interleukin-6, B-type natriuretic peptide and lower vitamin A levels. By using cosinor analysis we observed different circadian distribution patterns of AMI onset at the level of genotype and allelic frequencies. Genotypes with at least one 4-repeat allele (Per3(4/5) and Per3(4/4)) (N = 264) showed remarkable circadian activity in comparison with Per3(5/5) (N = 50), especially in men. No significant differences in genotype and/or allele frequencies of Per3 VNTR polymorphism were observed when comparing STEMI cases and controls. Our results indicate that the Per3 VNTR may contribute to modulation of cardiac functions and interindividual differences in development and progression of myocardial infarction.

Per3 VNTR polymorphism and chronic heart failure.

AIMS: The aim of this study was to investigate the relationship between gene Period3 (Per3) variable number tandem repeat (VNTR) polymorphism and chronic heart failure (CHF). METHODS: The study subjects (372 patients of Caucasian origin with CHF and 332 healthy controls) were genotyped for Per3 VNTR polymorphism using an allele-specific PCR. RESULTS: No significant differences in genotype or Per3 VNTR allele frequencies were found between CHF cases and controls (Pg=0.30, Pa=0.52). No significant differences were uncovered either between CHF cases according to etiology (DCMP vs. IHD; Pg=0.87, Pa=0.91). In the multivariate regression modeling, no predictive function of VNTR Per3 polymorphism on ejection fraction or NYHA class, hyperlipidaemia or type II diabetes risk was found. CONCLUSION: Per3 VNTR polymorphism is not a major risk factor for chronic heart failure or a factor modulating the severity of the CHF in this population.

Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population.

Patients with chronic heart failure (CHF) express enhanced catabolic metabolism finally resulting in overall weight loss, whereas adipokines might play a crucial role in signaling among tissues. The aim of this study was to investigate the possible associations of defined variability in leptin (dbSNP ID rs7799039), proopiomelanocortin (dbSNP ID rs3754860 and dbSNP ID rs1009388), and leptin receptor gene (dbSNP rs1137101) with CHF and evaluate their potential as the CHF susceptibility genes. The case-control study comprised a total of 372 patients of Caucasian origin with chronic heart failure (New York Heart Association [NYHA] functional classes II-IV, ejection fraction (EF) <40%) and 407 healthy controls. They were genotyped for the leptin (LEP) -2548 G/A, leptin receptor (LEPR) Gln223Arg, and proopiomelanocortin (POMC) RsaI (5'-untranslated region) and C1032G variants (intron 1) using PCR-based methodology. No case-control differences in genotype as well as allele frequencies were observed between CHF patients and controls. We constructed POMC RsaI/C1032G haplotypes, having found no significant association with body mass index (BMI), left ventricle ejection fraction (LVEF), left ventricle hypertrophy (LVH) and diabetes mellitus (DM). Multivariate regression analyses revealed an approximately 2-fold risk for NYHA class IV associated with the LEPR Gln223Arg (P = 0.0000001, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.56-2.84); it also displayed an independent prediction role for LVEF in heart failure cases of all etiologies (P = 0.002, OR = 4.05, 95% CI = 1.36-10.06). In subanalyses according to CHF etiology the LEPR Gln223Arg showed an independent prediction role for NYHA IV in IHD patients (P = 0.0001, OR = 2.50, 95% CI = 1.69-3.82) and both for NYHA IV(P = 0.007, OR = 2.04, 95% CI = 1.20-3.84) and LVEF (P = 0.004, OR = 11.87, 95% CI = 2.08-55.6) in DCMP patients. The role of the polymorphic variants in the genes encoding for adipokines as potential CHF susceptibility genes is unclear. Based on our findings, the LEPR Gln223Arg polymorphism could be considered a disease susceptibility modulating factor both in ischemic heart disease or dilated cardiomyopathy patients.

Are common leptin promoter polymorphisms associated with restenosis after coronary stenting?

The hypertrophy of vascular smooth muscle cells as well as neointimal proliferation is critical in vascular remodeling, whereas leptin has proved to play an important role recently. The aim of the study was to investigate possible associations of two common leptin gene polymorphisms with restenosis after percutaneous coronary intervention (PCI). To study the association of two promoter polymorphisms, LEP -2548 G/A and LEP -188 C/A (dbSNP ID rs7799039 and rs791620) with neointimal proliferation in humans, 98 consecutive patients undergoing stenting into small coronary arteries (<3 mm) were genotyped. After a 6-month follow-up, the restenosis rate was estimated. Restenosis >50% occurred in 33.3% of patients carrying both A alleles, 33.3% of carriers of A and C alleles, and 31.4% of carriers of two CC alleles of LEP -188 C/A polymorphism; and in 25.0% of patients with AA, 32.7% with AG, and 30.4% with GG genotype of LEP -2548 G/A polymorphism. Interestingly, the heterozygote AG genotype of LEP -2548 polymorphism represented a highly significant risk for multiple-vessel disease when compared to both homozygote genotypes AA/GG (odds ratio = 4.038, 95% confidence interval: 1.732-9.465, P(corr) = 0.001). Based on our findings, the AG genotype of LEP -2548 G/A polymorphism might be considered a genetic marker for multiple-vessel disease but not for restenosis after PCI. The role of the leptin gene polymorphisms as genetic markers of restenosis will require further investigation to elucidate the underlying pathophysiological consequences.