The apolipoprotein A-V gene (APOA5) plays an important role in determining plasma triglyceride levels. We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease. We found 15 polymorphisms, three of which were novel. Seven haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen and genotyped in similar to 3,000 subjects. The rare alleles of the -1464T > C, -1131T > C, S19W, and 1259T > C SNPs were significantly associated with increased triglyceride levels (19-86 mg/dl; P < 0.05) and had clear gene-dose effects. Haplotype analysis of the nine common APOA5 haplotypes revealed significant effects on triglyceride levels (P < 0.001). Detailed analysis of haplotypes clearly showed that the -1464T > C polymorphism had no effect by itself but was a marker for the -1131T > C. C, S19W, and 1259T >. C polymorphisms. The -1131T > C and 1259T > C polymorphisms were in a strong but incomplete linkage disequilibrium and appeared to have independent effects. Thus, the APOA5-1131T > C, S19W, and 1259T > C rare alleles were associated with significant increases in plasma triglyceride levels. At least one of these alleles was present in similar to 40% of the Turks. Similar associations were observed for -1131T > C and S19W in white Americans living in San Francisco, California.