Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia

Department of Medicine, Division of General Internal Medicine, 463, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 01/2007; 1772(1):81-8. DOI: 10.1016/j.bbadis.2006.10.012
Source: PubMed

ABSTRACT Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined.
The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (-1131T>C and S19W) were genotyped.
Haplotype analysis of APOA5 showed an association with FCH (p=0.029), total cholesterol (p=0.031), triglycerides (p<0.001), apolipoprotein B (p=0.011), HDL-cholesterol (p=0.013), small dense LDL (p=0.010) and remnant-like particle cholesterol (p=0.001). Compared to S19 homozygotes, 19W carriers had an increased risk of FCH (OR=1.6 [1.0-2.6]; p=0.026) and a more atherogenic lipid profile, reflected by higher triglyceride (+22%) and apolipoprotein B levels (+5%), decreased HDL-cholesterol levels (-7%) and an increased prevalence of small dense LDL (16% vs. 26%). In carriers of the -1131C allele, small dense LDL was more prevalent than in -1131T homozygotes (29% vs. 16%). No association of the APOA5 gene with IMT and CVD was evident.
In Dutch FCH families, variants in the APOA5 gene are associated with FCH and an atherogenic lipid profile.

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Available from: Geesje Dallinga-Thie, Dec 17, 2013
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    • "Liu et al. / Atherosclerosis 208 (2010) 427–432 431 control subjects with the −1131T allele and some other SNPs in APOA5 and APOC3 tended to have increased WHR may represent a similar relationship, which would require confirmation in a larger study population with assessments of dietary fat intake. A number of studies in Caucasians have shown associations with FCH and APOA5 variants such as the MseI enzymatic restriction site [24] or the 56C > G and −1131T > C variants [12] [25] [26]. The 56C > G variant, which is in LD with other SNPs in the APOA1/C3/A4/A5 cluster such as APOA1 −3031C > T but not with −1131T > C or the other common APOA5 variants, defines the APOA5*3 haplotype [12] [25] [27] and is the predominant SNP associated with FCH in most Caucasian studies, probably because of its higher frequency . "
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    ABSTRACT: Familial combined hyperlipidaemia (FCH) is the most common genetic dyslipidaemia associated with coronary artery disease. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A4/A5 gene cluster are associated with FCH in Caucasians and with elevated triglycerides (TG) in various ethnic groups. We examined these associations with FCH in Hong Kong Chinese. Fifty-six Chinese FCH patients and 176 unrelated controls were studied. Thirteen SNPs in the APOA1/C3/A4/A5 cluster were genotyped. Four alleles in APOA5 were associated with FCH (P<0.001). The -1131T>C (rs662799) and -3A>G (rs651821) SNPs in APOA5 were in almost complete linkage disequilibrium (LD, r(2)=0.99), and their minor alleles were more frequent (P<0.001) in FCH than controls (0.60 vs. 0.24). The odds ratio (OR) for FCH was 6.2 (95% CI, 2.6-14.8) and 6.1 (2.6-14.6) per copy of -1131C and -3G, respectively, and 24.6 (8.4-72.0) and 24.4 (8.4-70.9) in -1131C and -3G homozygotes, respectively, as compared to wild-type homozygotes. The 1891T>C (rs2266788) SNP was in LD (r(2)=0.68) with -1131T>C and -3A>G, and the minor allele was more frequent in FCH than controls (0.42 vs. 0.19, P<0.001). The 553G>T (rs2075291) nonsynonymous variant was also associated with FCH (0.15 vs. 0.04, P=0.001) and, along with -3A>G (or -1131T>C) and 1891T>C, contributed to haplotypes predicting FCH. The two tightly linked SNPs, -1131T>C and -3A>G polymorphism were significantly associated with lipid traits in all subjects combined, with variant homozygous subjects having higher TG and LDL-C and lower HDL-C levels. Some common polymorphisms and haplotypes in APOA5 are closely associated with FCH in Hong Kong Chinese, and these differ from those found in Caucasians.
    Atherosclerosis 09/2009; 208(2):427-32. DOI:10.1016/j.atherosclerosis.2009.08.013 · 3.99 Impact Factor
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    • "Talmud et al. [12] reported that APOA5 c.56G and − 1131C had 52% and 40%, respectively, higher triglyceride concentrations compared with the common allele homozygotes (c.56CC and −1131TT), and the two SNPs' effects were independent and additive. Pennacchio and colleagues showed that in Caucasian the predictive genotypes for the disease are APOA5 c.− 3ANG and c.56CNG [13], and that the minor allele of the c.56CNG associated with familial combined hyperlipidemia was also reported in Dutch family [28]. However, neither APOA5 c.− 3ANG nor c.56CNG polymorphism was found in this ethnicity study. "
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    ABSTRACT: Apolipoprotein A5 gene (APOA5) has been shown to modulate plasma triglyceride concentrations. We investigated 2 distinct APOA1/C3/A5 haplotypes roles for hypertriglyceridemia. We recruited 308 cases of hypertriglyceridemia and 281 normal controls from a hospital. Twelve single nucleotide polymorphisms (SNPs) across the APOA1/C3/A5 gene region were genotyped. One haplotype containing the minor alleles of the APOA5 (-1131T>C, c.553G>T) and APOA1 (-3013C>T,-75G>A) was more prevalent in cases than in controls (11.3% vs. 1.1%, respectively) and was statistically significantly associated with high triglycerides (adjusted odds ratio: 12.83, 95% confidence interval [CI]: 5.1-32.4, P<0.001). Another haplotype that was associated with hypertriglyceridemia (adjusted odds ratio 2.13, 95% CI, 1.37-3.29, P=0.001). Participants carrying both minor alleles of APOA5-1131CC and c.553TT had a 116% higher triglyceride concentration compared with those carrying common allele. The APOA1/C3/A5 haplotype represents an important locus for predicting risk of hypertriglyceridemia among Taiwanese.
    Clinica Chimica Acta 05/2008; 390(1-2):56-62. DOI:10.1016/j.cca.2007.12.014 · 2.82 Impact Factor
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    ABSTRACT: Le gène de l'apolipoprotéine (apo) AV, est un nouveau gène candidat pour étudier les mécanismes des hyperchylomicronémies, largement méconnus. Nous avons identifié, dans une cohorte de 286 patients ayant présenté une hyperchylomicronémie, indemnes de mutation sur la lipoprotéine lipase (LPL) ou l'apoCII, 3 mutations de l'APOA5 : Q139X et Q97X, et L242P. Nous présentons, à travers 2 études, la description phénotypique et génotypique des cas index et de leurs familles ainsi que la caractérisation fonctionnelle des mutations. Les mutations Q97X et Q139X ont été clairement impliquées dans l'hyperchylomicronémie à l'état homo ou hétéroygote, et associée à un défaut de lipolyse intravasculaire. L'expression phénotypique des mutations chez les hétérozygotes était très variable, influencée par des co-facteurs génétiques, en particulier les haplotypes variants de l'APOA5, et plus faiblement par l'environnement métabolique. Par ailleurs, nous avons montré, dans une 3ème étude, l'association des haplotypes variants de l'APOA5 et la survenue d'une hypertriglycéridémie modérée ou sévère dans une cohorte de patients diabétiques de type 2. Nos travaux ont permis de confirmer pour la première fois chez l'homme le lien fonctionnel entre l'apoAV et la lipoprotéine lipase (LPL). Nous proposons un nouveau modèle d'interaction entre ces deux protéines : l'apoAV régulerait la lipolyse intravasculaire par la LPL en agissant sur son expression à la surface de l'endothélium vasculaire.
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