HAPLOTYPE ANALYSIS OF 2 APOA1 MSPI POLYMORPHISMS IN RELATION TO PLASMA-LEVELS OF APO A-I AND HDL-CHOLESTEROL/

A common MspI polymorphism (G/A) in the promoter region of the APOA1 g ene (- 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 Msp I polymorphic site (+/-) in the 5' region of APOA1 (+83 bp) has been i dentified 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 53 4 normoglycemic US Whites from the San Luis Valley, Colorado. Both pol ymorphisms were in strong linkage disequilibrium (P < 0.005); of the e xpected four haplotypes (G+, G-; A+, A-) the A- was not observed in th is sample. Single site RFLP analysis revealed an independent and signi ficant effect associated with each polymorphism on plasma apo A-I vari ation but not on HDL-C variation. Further analyses showed that the gen otype effects of both polymorphisms were confined to non-smokers only. Haplotype analysis, combining both RFLPs, was more informative as thi s explained almost twice the amount of phenotypic variation in plasma apo A-I compared to single RFLP analysis in non-smokers. Compared to t he most common haplotype (G+), the A+ and G- haplotypes were associate d with increased plasma apo A-I levels by 6.7 mg/dl and 22.0 mg/dl, re spectively 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 analys is in this region may be important to elucidate the functional signifi cance of the APOA1 gene in HDL metabolism.