Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene.
BACKGROUND
Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21-q24.33 was investigated in 167 Danish families with asthma.


METHODS
A two step procedure was used: (1) a genome-wide scan in one set of families followed by (2) fine scale mapping in an independent set of families in candidate regions with a maximum likelihood score (MLS) of > or =1.5 in the genome-wide scan. Polymorphisms in a candidate gene in the region on 12q24.33 were tested for association with asthma in a family based transmission disequilibrium test.


RESULTS
An MLS of 3.27 was obtained at 12q24.33. The significance of this result was tested by simulation, resulting in a significant empirical genome-wide p value of 0.018. To our Knowledge, this is the first significant evidence for linkage on chromosome 12q, and suggests a candidate region distal to most previously reported regions. Three single nucleotide polymorphisms in splicing factor, arginine/serine-rich 8 (SFRS8) had an association with asthma (p < or = 0.0020-0.050) in a sample of 136 asthmatic sib pairs. SFRS8 regulates the splicing of CD45, a protein which, through alternative splice variants, has an essential role in activating T cells. T cells are involved in the pathogenesis of atopic diseases such as asthma, so SFRS8 is a very interesting candidate gene in the region.


CONCLUSIONS
Linkage and simulation studies show that the very distal part of chromosome 12q contains a gene that increases the susceptibility to asthma. SFRS8 could act as a weak predisposing gene for asthma in our sample.
Brasch-Andersen
C
C
Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, DK-5000 Odense C, Denmark. charlotte.b.andersen@ouh.fyns-amt.dk
Tan
Q
Q
Børglum
A D
AD
Haagerup
A
A
Larsen
T R
TR
Vestbo
J
J
Kruse
T A
TA
D001249:Asthma / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins
D011506:Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C484205:SFSWAP protein, human