Impact of chronic kidney disease on carotid plaque vulnerability.

OBJECTIVE: Little is known about the effect of chronic kidney disease (CKD) on plaque morphology in cerebral vessels. We therefore analyzed plaque composition and metabolic and chemical parameters with regard to clinical outcome in patients with advanced carotid artery stenosis (>70%) and normal or impaired renal function. METHODS: Carotid endarterectomy plaques were collected from 114 patients, 51 with CKD and 63 without CKD (mean estimated glomerular filtration rate, 49 ± 9 vs 88 ± 14 mL/min), and analyzed by histology and immunohistochemistry. Serum levels of matrix metalloproteinases (MMP-1, -2, -3, -7, -8, and -9), calcium, phosphate, parathyroid hormone, fetuin-A, osteoprotegerin, and inflammatory factors, including fibrinogen, and high-sensitive C-reactive protein (hsCRP) were measured by appropriate enzyme-linked immunosorbent assay. RESULTS: Compared with patients without CKD, patients with CKD had significantly more early-stage (11.2% vs 2.8%, P = .002) and end-stage (7.4% vs 0.2%, P = .036) calcification, unstable (50.8% vs 20.4%, P = .001) and ruptured (53.1% vs 32.8%, P = .035) lesions, and a significantly lower amount of collagenous fibers (39.2% vs 54.6%, P = .001). Serum samples of CKD patients had significantly enhanced levels of fibrinogen (393 ± 88 vs 331 ± 60 mg/dL, P = .018), hsCRP (1.7 ± 2.9 vs 0.8 ± 0.9 mg/dL; P = .042), parathyroid hormone (47.3 ± 24.1 vs 32.8 ± 12.2 ng/L, P = .010), fetuin-A (0.21 ± 0.05 vs 0.18 ± 0.04 mg/mL, P = .039), and MMP-7 (13.0 ± 5.3 vs 8.3 ± 3.0 ng/mL; P < 0.001). The incidence of cerebrovascular events >6 months before carotid surgery was significantly increased in CKD patients (84.0% vs 26.2% P < .001). CONCLUSIONS: In patients with CKD and advanced carotid artery stenosis, morphologic changes in plaque composition may contribute to plaque vulnerability and consequently to the risk of cerebrovascular events. Furthermore, relevant serum markers of inflammation, vascular calcification, and vessel wall degradation might be an indication of stroke risk in CKD patients.

Are "functionally related polymorphisms" of renin-angiotensin-aldosterone system gene polymorphisms associated with hypertension?

BACKGROUND: Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype. METHODS: Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates. RESULTS: Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations. CONCLUSIONS: We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.

Are RGS2 gene polymorphisms associated with high blood pressure in an ethnicity- and gender-specific manner?

BACKGROUND: Polymorphisms in the Regulator of G-protein Signaling 2 (RGS2) gene have been reported to be associated with hypertension (HT) in Japanese women and black Americans of either gender but not in white Americans or Japanese men. We have tested whether these proposed ethnicity- and gender-specific associations between RGS2 gene polymorphisms and HT can be confirmed in an independent population of male and female blacks, whites, and south Asians. METHODS: A population-based sample of 1379 black, white Dutch, and south Asian subjects from the Amsterdam area was genotyped for eight polymorphisms in the RGS2 gene. All analyses were done separately per ethnic group. The phenotype high blood pressure was defined as a dichotomous variable comparing HT vs. normotension (NT) and as a linear variable using systolic blood pressure (SBP) in a multiple regression analysis with concomitant antihypertensive medication, age and body mass index as coexplanatory variables. RESULTS: Ethnic differences in the frequency of polymorphisms and haplotypes (HAPs) derived thereof were in line with previous studies. Our data do not confirm previously reported ethnicity- or gender-specific associations regardless which phenotype definition was used. While the D allele of 1891-1892TC insertion/deletion polymorphism showed association in several groups, they differed from previously reported ones. Haplotype-phenotype analysis was not more sensitive to detect genotype-phenotype associations than individual alleles. CONCLUSIONS: Previously reported ethnicity- and gender-specific associations of RGS2 genotype and hypertensive phenotype are not robust. Nevertheless, the 1891-1892TC insertion/deletion polymorphism warrants further investigation.

The angiotensin converting enzyme insertion/deletion polymorphism and differences in fasting plasma glucose in Hindustani Surinamese, African Surinamese and ethnic Dutch: the population-based SUNSET-study.

We investigated the association between the angiotensin converting enzyme (ACE) insertion/deletion polymorphism and glycemic state. Diabetes mellitus, impaired fasting glucose and mean fasting glucose were not associated with genotype among Hindustani Surinamese, African Surinamese and Dutch participants. Our results cast (further) doubts on the association between ACE and glycemic state.

Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets.

By virtue of their large number, widespread distribution and important roles in cell physiology and biochemistry, G-protein-coupled receptors (GPCR) play multiple important roles in clinical medicine. Here, we focus on 3 areas that subsume much of the recent work in this aspect of GPCR biology: (1) monogenic diseases of GPCR; (2) genetic variants of GPCR; and (3) clinically useful pharmacological agonists and antagonists of GPCR. Diseases involving mutations of GPCR are rare, occurring in <1/1000 people, but disorders in which antibodies are directed against GPCR are more common. Genetic variants, especially single nucleotide polymorphisms (SNPs), show substantial heterogeneity in frequency among different GPCRs but have not been evaluated for some GPCR. Many therapeutic agonists and antagonists target GPCR and show inter-subject variability in terms of efficacy and toxicity. For most of those agents, it remains an open question whether genetic variation in primary sequence of the GPCR is an important contributor to such inter-subject variability, although this is an active area of investigation.

Expression of cyclin E in resting and activated B-chronic lymphocytic leukaemia cells: cyclin E/cdk2 as a potential therapeutic target.

Disease progression in B-cell chronic lymphocytic leukaemia (B-CLL) is determined by the interplay between proliferation kinetics in the proliferating compartment and cell death in the accumulating compartment. Improving our knowledge of cell cycle regulation in B-CLL cells might therefore be important for identifying therapeutic targets. Cyclin E was detected by Western blotting in purified B-CLL cells from peripheral blood samples of all 12 patient tested but not in normal peripheral blood B cells. While cyclin-dependent kinase 2 (cdk2) expression was similar in different samples, p27 and cyclin E expression was highly variable. We further investigated the regulation of p27, cyclin E and cdk2 in an in vitro model of cycling B-CLL cells. Cyclin E and cdk2 expression was increased in B-CLL cells stimulated with a CpG-oligodeoxynucleotide and interleukin-2, while p27 expression rapidly declined. This was accompanied by the increased formation of cyclin E-cdk2 complexes, which were able to phosphorylate Histone H1 in vitro. Pharmacological inhibition of cdk2 activity with Roscovitine-inhibited thymidine incorporation and Histone H1 phosphorylation. We conclude that further evaluation of cyclin E and p27 in peripheral blood cells might help to identify prognostic subgroups. In addition, inhibition of Cyclin E-cdk2 activity by Roscovitine might be a new therapeutic strategy in B-CLL.