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The complexity of recognizing the potential contribution of a number of possible predictors of complex disorders is increasingly challenging with the application of large-scale single nucleotide polymorphism (SNP) typing. In the search for putative genetic factors predisposing to coronary artery restenosis following balloon angioplasty, we determined genotypes for 94 SNPs representing 62 candidate genes, in a prospectively assembled cohort of 342 cases and 437 controls. Using a customized coupled-logistic regression procedure accounting for both additive and interactive effects, we identified seven SNPs in seven genes that, together, showed a statistically significant association with restenosis incidence (P <0.0001), accounting for 11.6% of overall variance observed. Among them are candidate genes for cardiovascular pathophysiology (apolipoprotein-species and NOS), inflammatory response (TNF receptor and CD14), and cell-cycle control (p53 and p53-associated protein). Our results emphasize the need to account for complex multi-gene influences and interactions when assessing the molecular pathology of multifactorial medical entities.

The rate at which allelic diversity at the HLA loci evolves has been the subject of considerable controversy. The patchwork pattern of sequence polymorphism within the second exon of the HLA class II loci, particularly in the DPB1 locus, may have been generated by segmental exchange (gene conversion). We have analysed the frequency of variant DPB1 sequences that have been created by interallelic gene conversion in the germline by screening pools of sperm using PCR amplification and oligonucleotide probe typing. Our results indicate that about 1/10,000 sperm represents a new DPB1 sequence generated by short tracts of segmental exchange (gene conversion) within the second exon, suggesting that interallelic gene conversion may have an important role in generating the extensive allelic diversity at the HLA loci.