An Apolipoprotein CIII Haplotype Protective Against Hypertriglyceridemia is Specified by Promoter and 3' Untranslated Region Polymorphisms

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 10; pp. 4562 - 4566
• Main Authors: Dammerman, Marilyn, Sandkuijl, Lodewijk A., Halaas, Jeffrey L., Chung, Wendy, Breslow, Jan L.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.05.1993; National Acad Sciences; National Academy of Sciences
• Subjects: Alleles; Apolipoprotein C-III; Apolipoproteins C - genetics; Base Sequence; Biological and medical sciences; Cholesterols; Deoxyribonucleic acid; DNA; Errors of metabolism; Gene Frequency; Genes; Genetics; Genotypes; Haplotypes; Humans; Hypertriglyceridemia; Hypertriglyceridemia - genetics; Lipids; Lipids (lysosomal enzyme disorders, storage diseases); Lipoproteins; man; Maximum likelihood estimation; Medical sciences; Metabolic diseases; Molecular Sequence Data; Oligodeoxyribonucleotides - chemistry; Oligonucleotide Probes; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic; promoters; Proteins; restriction fragment length polymorphism; Untranslated regions; Human; Lipoprotein VLDL; Transcription promoter; 3' terminal-Sequence; Inheritance; Lipids; Metabolic diseases; Hyperlipoproteinemia; Triglyceride; Enzymopathy; Gene; Hypertriglyceridemia; Risk factor; Apolipoprotein CIII; Haplotype; Polymorphism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.10.4562

Five DNA polymorphisms were detected in the promoter of the apolipoprotein CIII gene of a type III hyperlipidemic subject with severe hypertriglyceridemia (HTG). The polymorphic sites were C-641→ A, G-630→ A, T-625→ deletion, C-482→ T, and T-455→ C, with the previously reported base at each site designated allele 1 and the variant base designated allele 2. The sites were in strong linkage disequilibrium with each other and with a polymorphic Sst I site in the apolipoprotein CIII 3' untranslated region whose presence (S2 allele) has previously been shown to be associated with HTG. The distribution of haplotypes of the form -625 -482 Sst I among 78 normolipidemic adults and 79 adults with severe HTG was estimated by maximum likelihood analysis. The 211 haplotype was estimated to be 3.8-fold more common in normal subjects than in HTG subjects (estimated proportions, 0.186 and 0.049, respectively). This haplotype was associated with reduced HTG risk (relative risk, 0.28; P = 0.005) when compared with other haplotypes lacking the Sst I site (S1 allele). The 222 haplotype was estimated to be present on 48 of the 54 S2-containing chromosomes observed and was associated with increased risk for HTG (relative risk, 3.14; P < 0.0025). These results support the existence of apolipoprotein CIII promoter/Sst I haplotypes conferring either protection against or susceptibility to severe HTG.