Haplotype associations define target regions for susceptibility loci in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse and variable clinical manifestations. The etiology of SLE is still unknown, but both environmental and genetic factors are involved. Recent genome-wide scans and candidate genes studies in different ethnic groups have already suggested susceptibility loci for SLE, but most of the genetic component remains unexplained. We have previously conducted a genome-wide scan in 35 Finnish families multiply affected with SLE. With 417 microsatellite markers, we detected suggestive linkage in regions on chromosomes 6q and 14q as well as HLA on 6p. The 14q locus has also been implicated in three previous genome scans on SLE, whereas a partially overlapping region on 6q was implicated in one previous study. In an effort to obtain additional evidence for susceptibility loci on 6q and 14q and in order to refine their positions, we performed fine mapping at 1 cM density across the suggestive regions of linkage. Our results show evidence for excess sharing of a haplotype on 14q and excess transmission of a haplotype on 6q. Our results are compatible with the idea of a founder effect for susceptibility genes in SLE in central eastern Finland and suggest a path to the isolation of the putative susceptibility genes.

Data Mining for Gene Mapping

“…There were 32 markers spread over a 25 cM region. The results ( Figure 6B) show suggestive association at 45-50 cM, coinciding with earlier linkage results [13]. Some of the patterns strongly associated with SLE are listed in Table 2.…”

“…Data mining and machine learning can contribute to the field with their concepts and algorithms, as we have illustrated with associations and classification, similarity, and clustering. The association-based gene mapping methodology, HPM, has been applied successfully to real gene mapping studies and has been competitive with previous state of the art methods [21,10,16,17,13]. The similarity and clustering research is more recent and has yet to demonstrate its value in practical gene mapping.…”

“…Genes are not yet very well known, though some candidates have been found by genome scans. We concentrate on a linkage peak area in chromosome 14 [13,11]. Both the linkage peak, as well as an association peak were shown to reside at the same position, in close vicinity of marker D14S1055 at 50.30 cM, which for the present knowledge is, or is very near to, the actual position of the susceptibility gene.…”

“…A data set for SLE (systemic lupus erythematosus), where a founder mutation haplotype has been found very recently [13]. SLE is a rare autoimmune disorder.…”

“…HPM has been found to be a valuable tool for narrowing down the region resulting from an initial linkage analysis. It has been utilized in several disease projects, for instance, asthma and high IgE [10,19], SLE [12,13] glioma [17], and dyslexia (unpublished).…”