Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families.
We have previously reported suggestive linkage to chromosome 5p13-q13 in type 1 diabetic families. ISL1, a transcription factor involved in pancreas development, maps to this region. Sequencing of the ISL1 gene in patients and control subjects identified seven single nucleotide polymorphisms (SNPs) and one microsatellite in noncoding regions. Four haplotypes formed by six of these SNPs and one microsatellite were associated with type 1 diabetes in Swedish families (P < 0.04). To identify possible interactions with the 5q11-q13 region, we applied pathway-restricted linkage analysis by analyzing for effects from regions encoding other transcription factors that are active during pancreas development and maintenance of insulin production. Linkage analysis allowing for interaction between 5q11-q13 and 7q32 resulted in an increase of logarithm of odds from 2.2 to 5.3. This increase was estimated to correspond to a P value <0.0016 using permutation. The transcription factor PAX4 is located at 7q32 and participates downstream of ISL1 in the transcription factor cascade critical to beta-cell development. Association with type 1 diabetes was also observed using the transmission disequilibrium test for two haplotypes at the PAX4 locus (P < 0.05). We conclude that pathway-restricted linkage analysis assists in the identification of possible gene-gene interactions and that 5q11-q13 and 7q32 together constitute a significant susceptibility factor for type 1 diabetes.
Holm
Pernilla
P
Department of Molecular Medicine, Karolinska Institutet, CMM L8:00, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Rydlander
Berit
B
Luthman
Holger
H
Kockum
Ingrid
I
D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D002897:Chromosomes, Human, Pair 7; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008126:Lod Score; D018895:Microsatellite Repeats; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051761:Paired Box Transcription Factors; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D014157:Transcription Factors
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1