ASTHMA

Significant linkage to chromosome 12q24.32–q24.33 and identification of SFRS8 as a possible asthma susceptibility gene

C Brasch-Andersen¹, Q Tan¹, A D Børglum², A Haagerup³, T R Larsen¹, J Vestbo⁴, T A Kruse¹

¹ Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, University of Southern Denmark, Odense, Denmark
² Institute of Human Genetics, University of Aarhus, Aarhus, Denmark
³ Department of Paediatrics, County Hospital, Sygehus Viborg, Denmark
⁴ Danish Epidemiology Science Centre, Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen & Department of Cardiology and Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark

Correspondence to:
Dr C Brasch-Andersen
Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, DK-5000 Odense C, Denmark; charlotte.b.andersen{at}ouh.fyns-amt.dk

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 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 (p0.0020–0.050) 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.

Abbreviations: IBD, identity by descent; MLS, maximum likelihood score; SFRS8, splicing factor, arginine/serine-rich 8; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test

Keywords: asthma; genetics; linkage; splicing factor arginine/serine-rich 8 (SFRS8); atopy

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