title: Haplotype analysis of two APOA1/MspI polymorphisms in relation to plasma levels of apo A-I and HDL-cholesterol.
abstract: A common MspI polymorphism (G/A) in the promoter region of the APOA1 gene (-75 bp) has been shown to be associated with plasma apo A-I and HDL-C variation in several, but not all, studies. Recently another MspI polymorphic site (+/-) in the 5'region of APOA1 (+83 bp) has been identified which may also be relevant to HDL metabolism. This study was undertaken to elucidate the individual and combined effects of these two polymorphisms on plasma apo A-I and HDL-C levels in a cohort of 534 normoglycemic US Whites from the San Luis Valley, Colorado. Both polymorphisms were in strong linkage disequilibrium (P < 0.005); of the expected four haplotypes (G+, G-, A+, A-) the A- was not observed in this sample. Single site RFLP analysis revealed an independent and significant effect associated with each polymorphism on plasma apo A-I variation but not on HDL-C variation. Further analyses showed that the genotype effects of both polymorphisms were confined to non-smokers only. Haplotype analysis, combining both RFLPs, was more informative as this explained almost twice the amount of phenotypic variation in plasma apo A-I compared to single RFLP analysis in non-smokers. Compared to the most common haplotype (G+), the A+ and G- haplotypes were associated with increased plasma apo A-I levels by 6.7 mg/dl and 22.0 mg/dl, respectively in non-smoking men, and by 4.6 mg/dl and 15.1 mg/dl in non-smoking women, respectively. These data indicate that haplotype analysis in this region may be important to elucidate the functional significance of the APOA1 gene in HDL metabolism.
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA. Ikamboh@helix.hgen.pitt.edu
authors.forename: M I
authors.initials: MI
authors.lastname: Kamboh
authors.forename: C E
authors.initials: CE
authors.lastname: Aston
authors.forename: C M
authors.initials: CM
authors.lastname: Nestlerode
authors.forename: A E
authors.initials: AE
authors.lastname: McAllister
authors.forename: R F
authors.initials: RF
authors.lastname: Hamman
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics*; D001161:Arteriosclerosis / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D015342:DNA Probes / Q000737:chemistry; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D015342:DNA Probes