The authors genotyped 874 subjects from the Finnish Kainuu subpopulation by interspersing successive rounds of genotyping that increased the density of markers (SNPs and microsatellites) with analysis using the haplotype pattern mining (HPM) algorithm, which searches large sets of unrelated haplotypes for allele patterns that are shared between several haplotypes. Having identified a strong association of a conserved 47-kb haplotype pattern in this way, Kere and colleagues sequenced 133 kb that encompassed the 47-kb region from a homozygous asthmatic patient. Comparison with the public sequence identified 80 new polymorphisms.
Asthmatics from North-eastern Quebec and individuals with high serum immunoglobin E levels from North Karelia, Finland, also had a 133-kb haplotype pattern with the same limits, for which most SNPs were conserved. For the 3 populations combined, 7 alternative haplotypes were formed by 13 SNPs across the most-conserved region of 77 kb. Sequencing of the 133-kb region from 6 individuals who were homozygous for the remaining 6 haplotypes confirmed that they had different SNP compositions. Phylogenetic analysis showed these risk haplotypes to be related and distinct from non-risk haplotypes. By SNP-tagging the risk haplotypes, the authors confirmed that they confer risk in all three populations, which is consistent with the common-disease/common-variant hypothesis.
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