Genetic determinants of quantitative traits associated with cardiovascular disease risk.

Established risk factors for cardiovascular diseases (CVD) may be moderated by genetic variants. In 2403 unrelated individuals from general practice (mean age 40.5 years), we evaluated the influence of 15 variants in 12 candidate genes on quantitative traits (QT) associated with CVD (body mass index, abdominal obesity, glucose, serum lipids, and blood pressure). Prior to multiple testing correction, univariate analysis associated APOE rs429358, rs7412 and ATG16L1 rs2241880 variants with serum lipid levels, while LEPR rs1137100 and ATG16L1 rs2241880 variants were linked to obesity related QTs. After taking into account confounding factors and correcting for multiple comparisons only APOE rs429358 and rs7412 variants remained significantly associated with risk of dyslipidemia. APOE rs429358 variant almost tripled the risk in homozygous subjects (OR = 2.97; 95% CI 1.09-8.10, p < 0.03) and had a lesser but still highly significant association also in heterozygous individuals (OR = 1.67; 95% CI 1.24-2.10; p < 0.001). Associations with hypertension, diabetes mellitus, and metabolic syndrome were not significant after Bonferroni correction. The influence of genetic variation is more evident in dyslipidemia than in other analyzed QTs. These results may contribute to strategic research aimed at including genetic variation in the set of data required to identify subjects at high risk of CVD.

Familial defective apolipoprotein B-100 in Slovakia: are differences in prevalence of familial defective apolipoprotein B-100 explained by ethnicity?

The objective of this study was to examine frequency of familial defective apo-B-100 (FDB, R3500Q mutation) in probands with the phenotype of familial hypercholesterolemia (FH) and in the general population of 40-year-old subjects in Slovakia and to characterize their lipid and clinical criteria and to compare the frequency of FDB with other populations. We identified 35 patients with FDB among 362 probands with clinical diagnosis of FH and two cases of FDB in the 40-year-old cohort of 2323 subjects from general Slovak population. Probands with FDB differed from those with FH only in plasma triglyceride concentrations (1.84+/-1.4 mmol/l versus 1.45+/-0.98 mmol/l, respectively, p<0.01). Evaluation of personal history of premature atherosclerosis did not show any differences (11.4% in FDB versus 20% in FH, p<0.16). The FDB patients had similar manifestation of xanthomatosis as the FH patients (17.1% versus 8.25%, p<0.25). The frequency of FDB of 9.7% found in the FH patients is among the highest of those reported to date. The frequency of R3500Q mutation of 0.09% found in Slovak 40-year-old subjects did not differ significantly from published population molecular data. Our comparison of estimated FDB frequencies with those which were found by DNA analysis demonstrated that estimated frequencies were not only wider in range, but also significantly higher than those which were assessed by the analysis. The definitive answer to the prevalence of FDB and its biochemical and clinical characteristics requires screening of unbiased samples of the general population from different ethnic groups based on molecular genetic methods.

Apolipoprotein E polymorphism in relation to plasma lipid levels and other risk factors of atherosclerosis in two ethnic groups from Slovakia.

The influence of apolipoprotein E (ApoE) genotypes on plasma lipid levels and interaction with other environmental factors was determined in two Slovakian population samples; 146 Romany and 351 Slovak individuals. The two samples differ significantly in the distribution of E3/3 genotypes (p<0.014) and E3/2 (p<0.035). Analysis of variance did not reveal any significant effect of the ApoE genotypes on any of the plasma lipid levels in the Romany individuals. In the Slovak sample the variation in plasma low-density lipoprotein cholesterol (LDL-C) levels was significantly associated with the ApoE genotypes (p=0.012). We detected decreased LDL-C concentrations in males with E2 genotype when compared with E3 and E4 carriers (p=0.008). Further, the E2 genotype was found to be associated with high triglycerides levels (p=0.009). The ethnic samples differ significantly in the prevalence of metabolic syndrome and in the case of males of diabetes. Both the Romany and the Slovak males can be considered as having a more atherogenic profile compared with the females.

Lipid levels and their genetic regulation in patients with familial hypercholesterolemia and familial defective apolipoprotein B-100: the MEDPED Slovakia Project.

We examined, from a cohort of 165 families, 529 individuals for familial hypercholesterolemia (FH). Utilising clinical criteria for diagnosis, we identified 122 patients (n=41 families) as having FH. With PCR testing, 31 individuals (n=12 families) were found to have familial defective Apo B-100 (FDB). From the cohort, 102 normolipidemic (NL) individuals served as a control group. Patients with FH had the highest levels of total cholesterol (TC), LDL-cholesterol (LDL-C) and apolipoprotein B (Apo B), followed by FDB patients and the normolipidemic relatives had the lowest levels (P<0.0001 for all parameters). We did not find any effect of Apo E genotypes on lipid levels in the NL or FH group. Therefore, other genetic and/or environmental factors may be responsible for the diversity in the clinical expression in these populations.