Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy.
BACKGROUND
Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease.


OBJECTIVE
To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG ) and one of the signal transducers and activators of transcription (STAT6 ), we conducted further linkage studies among 33 multiplex families.


METHODS
We characterized 528 subjects from Barbados for asthma; 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning approximately 79 centimorgan) was performed.


RESULTS
Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P <.05 to.002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P =.002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P =.01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric linkage analysis score at D12S326 (nonparametric linkage score = 3.8, P =.0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P =.036).


CONCLUSIONS
Our findings suggest that (1) one or more loci in the chromosome 12q13. 12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.
Barnes
K C
KC
Division of Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Freidhoff
L R
LR
Nickel
R
R
Chiu
Y F
YF
Juo
S H
SH
Hizawa
N
N
Naidu
R P
RP
Ehrlich
E
E
Duffy
D L
DL
Schou
C
C
Levett
P N
PN
Marsh
D G
DG
Beaty
T H
TH
D000328:Adult; D000483:Alleles; D001249:Asthma / Q000235:genetics*; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics*; D008297:Male; D008875:Middle Aged