Analysis of lipoprotein lipase haplotypes reveals associations not apparent from analysis of the constituent loci

Simulating analysing genotype effects at several closely-linked loci may be preferable to analysing them seperately, but can be difficult, due to mult iple genotype classes, small class sizes, and non-independence induced by a ssociations amoung loci. Analysis of haplotype effects offers an alternativ e approach. We studied effects of haplotypes comprising 3 loci (5' to 3': P vuII, HindIII, and Ser(447)-Stop) in the lipoprotein lipase (LPL) gene on p lasma lipid levels and LPL activity, in 807 Dutch males with coronary ather osclerosis. We analysed haplotype effects in individuals for whom haplotype s could either be determined unequivocally or inferred with high probabilit y, using contrasts suggested by likely evolutionary relationships amoung th e haplotypes. One haplotype was associated with significantly higher total cholesterol, while another was associated with significantly lower triglyee ride levels. Though these two haplotypes had generally opposite effects on lipids, both were associated with significantly higher LPL activity. In gen otype analysis, the HindIII (-) allele was associated with higher LPL activ ity; however, one haplotype bearing it had no significant effect on LPL act ivity. Haplotypes thus provided more information than genotypes alone would have. The two haplotypes with consistently different effects on lipid leve ls despite similar effects on LPL activity, provide further evidence that a spects of LPL biology, apart from its catalytic function in lipolysis, may mediate its effects on plasma lipids at least in corinary artery disease pa tients .