Coronary heart disease (CHD) remains a leading cause of death across the world. A region on chromosome 9p21.3 has been recently reported to be associated with CHD. We evaluated 3 SNPs and 3 common haplotypes in the 9p21.3 region in 1494 individuals from 580 Irish families, where at least 1 member had early-onset (males <or=55 yr, females <or=60 yr) CHD. Genotypes were determined by multiplex SNaPshot technology. Using the combined TDT/S-TDT test, the 3 single nucleotide polymorphisms (SNP), rs10757274, rs2383206 and rs1333049, were strongly associated with early-onset CHD (p = 2.7 x 10(-6), 2.7 x 10(-6), 3.8 x 10(-7), respectively). Analysis of haplotypes by the TRANSMIT program also showed that the GGC haplotype was associated with early-onset CHD (p=7.9 x 10(-7)). In conclusion, using a family-based approach in the Irish population, we have confirmed previous reports of association between a region on chromosome 9p21.3 and early-onset CHD.