A Major Susceptibility Gene for Asthma Maps to Chromosome 14q24

Abstract

Asthma is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Numerous loci and candidate genes have been reported to show linkage and association to asthma and atopy. Although some studies reporting these observations are compelling, no gene has been mapped that confers a sufficiently high risk of asthma to meet the stringent criteria for genomewide significance. Using 175 extended Icelandic families that included 596 patients with asthma, we performed a genomewide scan with 976 microsatellite markers. The families were identified by cross-matching a list of patients with asthma from the Department of Allergy/Pulmonary Medicine of the National University Hospital of Iceland with a genealogy database of the entire Icelandic nation. We detected linkage of asthma to chromosome 14q24, with an allele-sharing LOD score of 2.66. After we increased the marker density within the locus to an average of one microsatellite every 0.2 cM, the LOD score rose to 4.00. We designate this locus "asthma locus one" (AS1). Taken together, these results provide evidence of a novel susceptibility gene for asthma on chromosome 14q24.

Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients

“…The original patient list contained the names of Ͼ7,000 patients who attended the clinic of allergists practicing at the Allergy͞Pulmonary Divisions of the National Hospital of Iceland from 1977 to 2001 (14). The diagnosis of asthma is based on standard diagnostic criteria outlined by the National Heart, Lung, and Blood Institute and the American Thoracic Society (ATS) (15,16).…”

A sequence variant on 17q21 is associated with age at onset and severity of asthma

“…Informed consent was obtained locally from all participants and all studies were approved by the local ethics committees. The individual sample sets have been described in detail elsewhere [13][14][15][16][17][18][19][20][21][22][23][24] (see also brief cohort descriptions in Supplementary text).…”

The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology

“…In the past few years it became feasible to genotype cheaply large pedigrees with much greater numbers of microsatellites than were previously used for genome scans, and statistical programs that are now available permit efficient computation of linkage even in complex pedigrees 28,29 . These advances allowed a substantial increase in the scale of pedigree-based linkage studies 2,4,[30][31][32][33][34][35][36][37][38] . Inadequate technology and statistical methodology have similarly hindered implementation of alternatives to pedigreebased mapping.…”