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Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy.

ABSTRACT: BACKGROUND: The risk of coronary heart disease (CHD) is related to environmental factors and genetic variants. Apolipoprotein E (apoE) polymorphisms are heritable determinants of total and low-density lipoprotein cholesterol, with some authors suggesting an association between the ?4 allele and CHD. We investigated the relationship between apoE genotype and age at referral to a specialized lipid clinic by the primary care physician and whether the benefits of treatment with statin differed between genotypes. METHODS: We assessed individual apoE genotypes and lipid blood profile in a total of 463 patients followed at a specialized lipid clinic due to dyslipidemia, with a 3-year median follow-up time. The primary care physician at the time of the referral had no access to the apoE genotyping results. Carriers of apoE ?4/?2 genotype were excluded. RESULTS: The frequencies of ?2, ?3 and ?4 alleles were 7.8, 78.9 and 13.3%, respectively. There were no significant differences between genders. Although with similar lipid profiles and antidyslipidemic drug usage at baseline, ?4-carriers were referred to the clinic at a younger age (44.2 ± 14.7 years) compared with non-?4 carriers (50.6 ± 13.8 years) (p < 0.001), with a substantially younger age of referral for homozygous E4/4 and for all genotypes with at least one copy of the ?4 allele (p < 0.001 for trend). Although both ?4 and non-?4 carriers achieved significant reductions in total cholesterol during follow-up (p < 0.001 vs. baseline), the mean relative decrease in total cholesterol levels was higher in non-?4 carriers (-19.9 ± 2.3%) compared with ?4 carriers (-11.8 ± 2.3%), p = 0.003. CONCLUSION: Our findings support the concept that there is a reduced response to anti-dyslipidemic treatment in ?4 carriers; this can be a contributing factor for the earlier referral of these patients to our specialized lipid clinic and reinforces the usefulness of apoE genotyping in predicting patients response to lipid lowering therapies.

SUBMITTER: Baptista R

PROVIDER: S-EPMC3078893 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy.

Baptista Rui R Rebelo Marta M Decq-Mota Joana J Dias Patrícia P Monteiro Pedro P Providência Luís A LA Silva José M JM

Lipids in health and disease 20110330

<h4>Background</h4>The risk of coronary heart disease (CHD) is related to environmental factors and genetic variants. Apolipoprotein E (apoE) polymorphisms are heritable determinants of total and low-density lipoprotein cholesterol, with some authors suggesting an association between the ε4 allele and CHD. We investigated the relationship between apoE genotype and age at referral to a specialized lipid clinic by the primary care physician and whether the benefits of treatment with statin differe ...[more]

PMID: 21450082

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Project description:BackgroundSchistosomiasis mansoni is a parasitic liver disease, which causes several metabolic disturbances. Here, we evaluate the influence of Apolipoprotein E (APOE) gene polymorphism, a known modulator of lipid metabolism, on plasma lipid levels in patients with hepatosplenic schistosomiasis.Methodology/principal findingsBlood samples were used for APOE genotyping and to measure total cholesterol (TC), LDL-C, HDL-C and triglycerides. Schistosomiasis patients had reduced TC, LDL-C and triglycerides (25%, 38% and 32% lower, respectively; P<0.0001) compared to control individuals, whereas HDL-C was increased (10% higher; P?=?0.0136). Frequency of the common alleles, ?2, ?3 and ?4, was similar (P?=?0.3568) between controls (n?=?108) and patients (n?=?84), implying that APOE genotype did not affect susceptibility to the advanced stage of schistosomiasis. Nevertheless, while patient TC and LDL-C levels were significantly reduced for each allele (except TC in ?2 patients), changes in HDL-C and triglycerides were noted only for the less common ?2 and ?4 alleles. The most striking finding, however, was that accepted regulation of plasma lipid levels by APOE genotype was disrupted by schistosomiasis. Thus, while ?2 controls had higher TC and LDL-C than ?3 carriers, these parameters were lower in ?2 versus ?3 patients. Similarly, the inverse relationship of TG levels in controls (?2>?3>?4) was absent in patients (?2 or ?4>?3), and the increase in HDL-C of ?2 or ?4 patients compared to ?3 patients was not seen in the control groups.Conclusion/significanceWe confirm that human schistosomiasis causes dyslipidemia and report for the first time that certain changes in plasma lipid and lipoprotein levels depend on APOE gene polymorphism. Importantly, we also concluded that S. mansoni disrupts the expected regulation of plasma lipids by the different ApoE isoforms. This finding suggests ways to identify new metabolic pathways affected by schistosomiasis and also potential molecular targets to treat associated morbidities.

Project description:ObjectiveWe previously observed the association of the co-occurrence of the HLA-DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF)-positive European American patients with early-onset RA. The aim of this study was to fine-map the 48-kb RANKL region in the extended cohort of 210 European American RF-positive patients with early RA, to seek replication of RA-associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA-associated SNPs.MethodsSNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme-linked immunosorbent assay and reverse transcription-PCR. Site-directed mutagenesis of rs7984870 within the 2-kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay.ResultsA single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti-cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive patients with RA, significantly elevated RANKL messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5.ConclusionThe RANKL promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients.

Dataset Information

Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy.

Publications

Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy.

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