Associations of genotypes at the apolipoprotein AI-CIII-AIV, apolipoprotein B and lipoprotein lipase gene loci with coronary atherosclerosis and high density lipoprotein subclasses.
Association studies were carried out in a sample of 86 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) AI-CIII-AIV gene cluster on among-individual differences in plasma lipid and lipoprotein traits, the five high density lipoprotein (HDL) subclasses (2b to 3c), lipoprotein lipase (LPL) activity and presence and progression of atherosclerosis. Individuals were genotyped for four polymorphisms; 5'apoAI (G/A-75), 3'apoAI (PstI; P +/-), apoCIII (C/T1100) and apoCIII (PvuII; V +/-), using PCR-based techniques. Allele frequencies were similar in healthy individuals and patients (frequencies of alleles in combined population: 5'apoAI-A-75 = 0.14, 3'apoAI-P- = 0.05, apoCIII-T1100 = 0.27 and apoCIII-V- = 0.18). In the healthy individuals, levels of low density lipoprotein (LDL) triglycerides were significantly associated with genotypes of the apoCIII-PvuII polymorphism (p = 0.02), but no other associations were found between lipids or HDL subclasses and single polymorphisms in the apoAI-CIII-AIV gene cluster. Levels of triglycerides and very low density lipoprotein (VLDL) triglycerides were significantly higher in the presence of the haplotype defined by the presence of apoCIII-T1100 and common alleles of the other three polymorphisms, explaining 5.8% and 7.8% (p = 0.03 and 0.01), respectively, of sample variance. In the patients, no associations were found between lipids or HDL subclasses and variation at the apoAI-CIII-AIV gene cluster. Associations were also examined between levels of HDL subclasses and variation at the apoE (common isoforms), apoB (signal peptide and XbaI polymorphisms) and lipoprotein lipase (PvuII, HindIII and Serine447/Stop polymorphisms) gene loci. In the patient group only, levels of protein in HDL2b, HDL2a and HDL3b subclasses were significantly associated with genotypes of the LPL-HindIII polymorphism (22.1, 19.3 and 11.4%, respectively, of sample variance; p < 0.05). Finally, associations were examined between genotypes at the apoAI-CIII-AIV gene cluster and the extent of coronary atherosclerosis. Global severity of atherosclerosis at the first angiography was weakly associated with genotypes of the apoCIII-C/T1100 polymorphism, presence of the T1100 allele being associated with 53% lower median score (1.6 vs 0.75; p = 0.09).(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Medicine, Rayne Institute, London, UK.
R E
RE
Peacock
A
A
Hamsten
J
J
Johansson
P
P
Nilsson-Ehle
S E
SE
Humphries
D000328:Adult; D000483:Alleles; D000704:Analysis of Variance; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D053305:Apolipoprotein C-III; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D001056:Apolipoproteins C / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D005810:Multigene Family; D009203:Myocardial Infarction / Q000503:physiopathology; D011110:Polymorphism, Genetic; D011817:Rabbits; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D017741:Survivors
D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D017931:DNA Primers; D008075:Lipoproteins, HDL; C022205:apolipoprotein A-IV; D008071:Lipoprotein Lipase