We recently reported that genetic polymorphisms of SAH, an acyl-CoA synthetase for fatty acids, might contribute to multiple risk factors, especially hypertriglyceridemia. There are at least 4 members in this SAH gene family, SAH, MACS1, MACS2, and MACS3, and these 4 members are clustered in human Ch16p12. It is possible either that the previously observed associations were due to linkage disequilibrium with truly important polymorphisms in other members of the SAH gene family or that other polymorphisms in this gene family may also influence multiple risk factors. Thus, we performed association studies between genetic polymorphisms in this SAH region and multiple risk factors, using a large cohort representing the general population in Japan. The L513S polymorphism in MACS2 was shown to significantly influence the triglyceride level and the waist-to-hip ratio. The previously observed associations between an SAH polymorphism and the waist-to-hip ratio appear to be due to linkage disequilibrium with the L513S polymorphism. Haplotype analysis indicated that a haplotype defined by the I/D polymorphism of SAH and the L513S polymorphism in MACS2 was highly significantly associated with the triglyceride level. This study confirmed the importance of this chromosomal region in the pathogenesis of hypertriglyceridemia and visceral obesity.