Genetics of melatonin receptor type 2 is associated with left ventricular function in hypertensive patients treated according to guidelines.

BACKGROUND: Melatonin exerts multiple biological effects with potential impact on human diseases. This is underscored by genetic studies that demonstrated associations between melatonin receptor type 2 gene (MTNR1B) polymorphisms and characteristics of type 2 diabetes. We set out to test the hypothesis whether genetic variants at MTNR1B are also relevant for other disease phenotypes within the cardiovascular continuum. We thus investigated single nucleotide polymorphisms (SNPs) of MTNR1B in relation to blood pressure (BP) and cardiac parameters in hypertensive patients. METHODS: Patients (n=605, mean age 56.2±9.4years, 82.3% male) with arterial hypertension and cardiac ejection fraction (EF) ≥40% were studied. Cardiac parameters were assessed by echocardiography. RESULTS: The cohort comprised subjects with coronary heart disease (73.1%) and myocardial infarction (48.1%) with a mean EF of 63.7±8.9%. Analysis of SNPs rs10830962, rs4753426, rs12804291, rs10830963, and rs3781638 revealed two haplotypes 1 and 2 with frequencies of 0.402 and 0.277, respectively. Carriers with haplotype 1 (CTCCC) showed compared to non-carriers a higher mean 24-hour systolic BP (difference BP: 2.4mmHg, 95% confidence interval (CI): 0.3 to 4.5mmHg, p=0.023). Haplotype 2 (GCCGA) was significantly related to EF with an absolute increase of 1.8% (CI: 0.45 to 3.14%) in carriers versus non-carriers (p=0.009). CONCLUSION: Genetics of MTNR1B point to impact of the melatonin signalling pathway for BP and left ventricular function. This may support the importance of the melatonin system as a potential therapeutic target.

Genetic variants implicated in telomere length associated with left ventricular function in patients with hypertension and cardiac organ damage.

Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9 ± 9.8 years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8 ± 21.0 g/H2.7 and 61.1 ± 9.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CI = 0.1% to 4.2%, p = 0.044) and an absolute increase in EF of 0.6% (CI = 0.1% to 1.1%, p = 0.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CI = 0.7% to 4.6%; p raw = 0.008, p mt = 0.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele −1.8%; CI = −2.8% to −0.7%; p raw = 0.002, p mt = 0.018; rs1151026, G allele −1.9%, CI = −3.0% to −0.8%; p raw < 0.001, p mt = 0.002) with the extension that a frequent haplotype in BICD1 showed an absolute −1.8% (CI = −3.0% to −0.7%; p raw = 0.002, p mt = 0.008) lower EF compared with those lacking this haplotype. Our results point to a role of genetic variants recently implicated in LTL for left ventricular function in hypertensive patients.

Role of the angiotensin II type 2 receptor gene (+1675G/A) polymorphism on left ventricular hypertrophy and geometry in treated hypertensive patients.

OBJECTIVE: A genetic polymorphism in the angiotensin II type 2 receptor (AGTR2 +1675G/A) has been associated with left ventricular hypertrophy (LVH). We tested whether this polymorphism affects LVH and left ventricular geometry parameters in patients with essential hypertension and cardiovascular disease who are treated according to guidelines. METHODS: We analyzed a cohort of 208 women and 1030 men with essential hypertension, associated cardiovascular disease and left ventricular ejection fractions 40% or more. Previous cardiac diseases included coronary heart disease (81%) and myocardial infarction (MI; 52%). Ten parameters of left ventricular mass, geometry and function were determined by echocardiography. Genotyping was performed by PCR. Due to the X chromosomal location of AGTR2, genotype-phenotype analysis was separated for women and men. Statistical analysis was performed by univariate and multivariate analysis accounting for confounding factors. RESULTS: The mean age was 58.4 +/- 10 years. In the overall cohort, mean left ventricular mass index was 54 +/- 23.6 g/h without significant differences between patients with and without MI. The frequency of LVH (49% overall) was also similar in patients with or without MI. In men, AGTR2 +1675G/A had no influence on echocardiographic parameters. Similar findings were obtained in women, with the exception that the thickness of the interventricular septum was significantly lower in A allele carriers (-11%) in both crude (P = 0.002) and multivariate analysis (P = 0.044). CONCLUSION: In treated patients with arterial hypertension, cardiac disease and preserved left ventricular systolic function AGTR2 (+1675G/A) exhibits only a minor effect on left ventricular geometry in women and none in men.