An Analysis of Linkage Disequilibrium in the Interleukin-1 Gene Cluster, Using a Novel Grouping Method for Multiallelic Markers

In population- and family-based association studies, it is useful to have some knowledge of the patterns of linkage disequilibrium that exist between markers in candidate regions. When such studies are carried out with multiallelic markers, it is often convenient to group the alleles into a biallelic system, for analysis. In this study, we specifically examined the interleukin-1 (IL-1) gene cluster on chromosome 2, a region containing candidates for many inflammatory and autoimmune disorders. Data were collected on eight markers, four of which were multiallelic. Using these data, we investigated the effect of three allele-grouping strategies, including a novel method, on the detection of linkage disequilibrium. The novel approach, termed the “δ method,” measures the deviation from the expected haplotype frequencies under linkage equilibrium, for each allelic combination. This information is then used to group the alleles, in an attempt to avoid the grouping together of alleles at one locus that are in opposite disequilibrium with the same allele at the second locus. The estimate haplotype frequencies (EH) program was used to estimate haplotype frequencies and the disequilibrium measure. In our data it was found that the δ method compared well with the other two strategies. Using this method, we found that there was a reasonable correlation between disequilibrium and physical distance in the region ( r =−.540, P =.001, one-tailed). We also identified a common, eight-locus haplotype of the IL-1 gene cluster.