TY - JOUR
T1 - β2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort
T2 - a genetic association study
AU - Hall, Ian P.
AU - Blakey, John D.
AU - Al Balushi, Khalid A.
AU - Wheatley, Amanda
AU - Sayers, Ian
AU - Pembrey, Marcus E.
AU - Ring, Susan M.
AU - McArdle, Wendy L.
AU - Strachan, David P.
N1 - Funding Information:
This genetic study was funded in part by Asthma UK (grant 05/055). The 1992–93 field survey was funded by the Wellcome Trust (grant 034523/Z/91) and the 2002–04 biomedical survey and the directly extracted DNA collection used here were funded by the Medical Research Council (grant G0000934). We are grateful to all members of the 1958 birth cohort who participated in the 1992–03 and 2002–04 field studies, particularly to those who gave consent to use of their DNA for genetic epidemiological analyses, and to the research nurses who contributed to the successful completion of both field studies.
PY - 2006/8/26
Y1 - 2006/8/26
N2 - Background: Functionally relevant polymorphisms of the β2-adrenoceptor gene (ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the ADRB2 gene. Methods: The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses. Findings: Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36·3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44·6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16-Gln27 haplotype at these loci, 19·3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11·9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1·5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies. Interpretation: ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population.
AB - Background: Functionally relevant polymorphisms of the β2-adrenoceptor gene (ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the ADRB2 gene. Methods: The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses. Findings: Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36·3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44·6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16-Gln27 haplotype at these loci, 19·3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11·9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1·5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies. Interpretation: ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population.
UR - http://www.scopus.com/inward/record.url?scp=33747760084&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747760084&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(06)69287-8
DO - 10.1016/S0140-6736(06)69287-8
M3 - Article
C2 - 16935688
AN - SCOPUS:33747760084
SN - 0140-6736
VL - 368
SP - 771
EP - 779
JO - The Lancet
JF - The Lancet
IS - 9537
ER -