18 research outputs found
Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study
<p>Abstract</p> <p>Background</p> <p>Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including <it>LPL</it>, <it>APOA5 </it>and <it>APOE</it>. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.</p> <p>Methods</p> <p>A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the <it>LPL</it>-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the <it>APOA5</it>-S19W (rs3135506) and -1131T/C (rs662799) variants, and the <it>APOE </it>polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.</p> <p>Results</p> <p>We found a significant lowering effect of the <it>LPL</it>-HindIII and S447X polymorphisms (<it>p </it>< 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the <it>APOE</it>-ε4 allele were significantly associated with an independent additive TG-raising effect (<it>p </it>< 0.05, <it>p </it>< 0.01, <it>p </it>< 0.001, <it>p </it>< 0.0001 and <it>p </it>< 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (<it>p </it>< 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; <it>p </it>= 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; <it>p </it>< 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; <it>p </it>< 0.001) were associated with HTG.</p> <p>Conclusion</p> <p>Our results showed a significant independent additive effect on TG levels of the <it>LPL </it>polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of <it>APOA5</it>, and the ε4 allele of <it>APOE </it>in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.</p
FH clinical phenotype in Greek patients with LDL-R defective vs. negative mutations
Background Familial hypercholesterolaemia (FH) is caused by mutations in
the low-density lipoprotein receptor gene and the gene encoding
apolipoprotein B-100, affecting one in 500 individuals.
Methods One hundred and eighty-three Greek FH patients were screened for
mutations on the LDLR and ApoB genes.
Results We identified mutations in 67 probands and 11 relatives. Sixteen
mutations located in eight different exons and the promoter of the LDLR
were discovered. Among them 10 were missense mutations (C6W, S265R,
A370T, Q363P, D365E, V408M, A410T, A517T, G528D, G571E), two were
nonsense mutations (Q363X and C660X), three were splice defects (2140 +
5G–>A and 2140 + 9C–>T, 1706 - 10G–>A), and one was a nucleotide
substitution (- 45delT) on the promoter. None of the subjects carried
any apoB mutation. The detection rate of mutations in this study was
43%. From the above mutations, A410T, A519T and the splice site defects
2140 + 9C–>T were detected for the first time in the Greek population.
Among them V408M, G528D, C6W and S265R account for 73% of heterozygous
FH probands. V408M mutation is more common in Central West, while C6W is
more common in Central East. Separating the patients into two groups
(receptor defective and receptor negative) we found that the receptor
negative group had higher levels of total cholesterol, low-density
lipoprotein cholesterol and higher prevalence of tendon xanthomas
compared with the receptor-defective group.
Discussion The homogenous molecular basis of familial
hypercholesterolaemia in Greece facilitates the application of a DNA
diagnostic strategy based on the origin of the patient. The early
mutation analysis would add valuable information on the severity of the
disease
Apolipoprotein E polymorphism is not associated with lipid levels and coronary artery disease in Greek patients with familial hypercholesterolaemia
Familial hypercholesterolaemia is a genetic disorder characterised by
high low-density lipoprotein (LDL) cholesterol concentrations, which
frequently gives rise to premature coronary artery disease (CAD). The
clinical expression of familial hypercholesterolaemia is highly variable
even in patients carrying the same LDL receptor gene mutation. This
variability may be due to environmental and other genetic factors.
Apolipoprotein E (Apo-E) has been extensively studied for its effects on
the phenotype of familial hypercholesterolaemia. In this study we
examined the influence of Apo-E genotype on lipid parameters and the
incidence of CAD in 93 Greek patients with familial
hypercholesterolaemia. Apo-E E2, E3 and E4 allele frequencies were 0.06,
0.86 and 0.09 respectively. The levels of total cholesterol, LDL
cholesterol, HDL cholesterol, triglycerides, apolipoproteins A and B and
lipoprotein alpha did not differ significantly among carriers and
non-carriers of the E4 allele. The prevalence of CAD and hypertension
did not differ either. Our results suggest that the E4 allele is not
associated with lipid levels or with the prevalence of CAD among
familial hypercholesterolaemia patients of the Greek population
LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance
Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C>T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH