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Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks.

Radwan ZH, Wang X, Waqar F, Pirim D, Niemsiri V, Hokanson JE, Hamman RF, Bunker CH, Barmada MM, Demirci FY, Kamboh MI - PLoS ONE (2014)

Bottom Line: We identified a total of 40 sequence variants, of which 10 are novel.A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations.Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Although common APOE genetic variation has a major influence on plasma LDL-cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that APOE also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the APOE gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the APOE gene in 190 subjects with extreme HDL-cholesterol levels selected from two well-defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol. We have also identified multiple associations of uncommon and common APOE variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that APOE genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL-cholesterol.

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LD Plot of the genotyped variants with MAF>1% in NHWs.The values in the cells are the pairwise degree of LD indicated by r2×100. r2 = 0 is shown as white, 0<r2<1 is shown in gray and r2 = 1 is shown in black.
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pone-0114618-g001: LD Plot of the genotyped variants with MAF>1% in NHWs.The values in the cells are the pairwise degree of LD indicated by r2×100. r2 = 0 is shown as white, 0<r2<1 is shown in gray and r2 = 1 is shown in black.

Mentions: The LD plot of the genotyped variants with MAF>1% in NHWs is shown in Fig. 1, the association results for all genotyped variants with the three lipid traits (LDL-C, TG, and HDL-C) and ApoB are presented in Table 1 and the adjusted mean distributions of all the evaluated lipid traits among the genotype groups are given in Table S5 in S1 File. As expected, the two known and well-established SNPs as part of the APOE epsilon polymorphism, E*4 (rs429358) and E*2 (rs7412) were significantly associated with plasma levels of LDL-C (β = 8.10; p = 0.0103, and β = −21.84; p = 1.84E-07, respectively) and ApoB (β = 2.14; p = 0.0005, and β = −5.60; p = 9.65E-13, respectively). Four additional LDL-C associations were observed independent of E*2/E*4: APOE832/rs405509 in 5′ flanking (β = −5.17; p = 0.0345; FDR = 0.139), APOE1163/rs440446 in intron 1 (β = 6.11; p = 0.018; FDR = 0.139), APOE2440/rs769450 in intron2 (β = 5.52; p = 0.0275; FDR = 0.139), and APOE4310/rs199768005 (Val254Glu) in exon4 (β = −35.36; p = 0.043; FDR = 0.139). These same four SNPs were also associated with TG (p = 0.0019 and FDR = 0.01, p = 0.0012 and FDR = 0.01, p = 0.002 and FDR = 0.01, and p = 0.028 and FDR = 0.074, respectively). An additional SNP, APOE4528/rs374329439 in 3′UTR, was also associated with TG (p = 0.022; FDR = 0.071).


Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks.

Radwan ZH, Wang X, Waqar F, Pirim D, Niemsiri V, Hokanson JE, Hamman RF, Bunker CH, Barmada MM, Demirci FY, Kamboh MI - PLoS ONE (2014)

LD Plot of the genotyped variants with MAF>1% in NHWs.The values in the cells are the pairwise degree of LD indicated by r2×100. r2 = 0 is shown as white, 0<r2<1 is shown in gray and r2 = 1 is shown in black.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264772&req=5

pone-0114618-g001: LD Plot of the genotyped variants with MAF>1% in NHWs.The values in the cells are the pairwise degree of LD indicated by r2×100. r2 = 0 is shown as white, 0<r2<1 is shown in gray and r2 = 1 is shown in black.
Mentions: The LD plot of the genotyped variants with MAF>1% in NHWs is shown in Fig. 1, the association results for all genotyped variants with the three lipid traits (LDL-C, TG, and HDL-C) and ApoB are presented in Table 1 and the adjusted mean distributions of all the evaluated lipid traits among the genotype groups are given in Table S5 in S1 File. As expected, the two known and well-established SNPs as part of the APOE epsilon polymorphism, E*4 (rs429358) and E*2 (rs7412) were significantly associated with plasma levels of LDL-C (β = 8.10; p = 0.0103, and β = −21.84; p = 1.84E-07, respectively) and ApoB (β = 2.14; p = 0.0005, and β = −5.60; p = 9.65E-13, respectively). Four additional LDL-C associations were observed independent of E*2/E*4: APOE832/rs405509 in 5′ flanking (β = −5.17; p = 0.0345; FDR = 0.139), APOE1163/rs440446 in intron 1 (β = 6.11; p = 0.018; FDR = 0.139), APOE2440/rs769450 in intron2 (β = 5.52; p = 0.0275; FDR = 0.139), and APOE4310/rs199768005 (Val254Glu) in exon4 (β = −35.36; p = 0.043; FDR = 0.139). These same four SNPs were also associated with TG (p = 0.0019 and FDR = 0.01, p = 0.0012 and FDR = 0.01, p = 0.002 and FDR = 0.01, and p = 0.028 and FDR = 0.074, respectively). An additional SNP, APOE4528/rs374329439 in 3′UTR, was also associated with TG (p = 0.022; FDR = 0.071).

Bottom Line: We identified a total of 40 sequence variants, of which 10 are novel.A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations.Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Although common APOE genetic variation has a major influence on plasma LDL-cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that APOE also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the APOE gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the APOE gene in 190 subjects with extreme HDL-cholesterol levels selected from two well-defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol. We have also identified multiple associations of uncommon and common APOE variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that APOE genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL-cholesterol.

Show MeSH