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Slide 1
The British 1958 cohort (National Child Development Study)
Slide 2
The British 1958 cohort and its DNA collection All births in
one week in 1958 Pregnancy records Parental interview at 7, 11, 16
School medicals at 7, 11, 16 Interview at ages 23, 33, 41 Nurse
visit at age 44-45: - common disease outcomes - risk factor
measurements - 8000+ blood samples - 7500 cell line transformations
DNA forms a national reference series for case-control studies,
including WTCCC and T1DGC (4000 GW typed) and WTCCC2
Slide 3
Asthma and wheeze in the British 1958 cohort 7:Asthma attacks
Bronchitis with wheezing Attacks in past year 11:Asthma Wheezy
bronchitis 16:Asthma and/or WB 23:A/WB since 16 33:Asthma ever
Wheezing ever & past yr 42:Asthma ever Wheezing ever & past
yr Attacks in past year Inhaler therapy
Slide 4
Asthma and wheeze in the British 1958 cohort 7:Asthma attacks
Bronchitis with wheezing Attacks in past year 11:Asthma Wheezy
bronchitis 16:Asthma and/or WB 23:A/WB since 16 33:Asthma ever
Wheezing ever & past yr 42:Asthma ever Wheezing ever & past
yr Attacks in past year Inhaler therapy Incidence Prognosis
Slide 5
Asthma and wheeze in the British 1958 cohort 7:Asthma attacks
Bronchitis with wheezing Attacks in past year 11:Asthma Wheezy
bronchitis 16:Asthma and/or WB 23:A/WB since 16 33:Asthma ever
Wheezing ever & past yr 42:Asthma ever Wheezing ever & past
yr Attacks in past year Inhaler therapy Allergic diseases in the
British 1958 cohort 7:Eczema before/after 1yr Hay fever or sneezing
Eczema at examination 11:Hay fever or AR Eczema reported & exam
16:HF/AR, eczema at exam 23:HF/AR, eczema reported 33:HF/AR ever
& past yr Eczema not included 42:HF/AR ever & past yr
Eczema ever & past yr 45:Total & specific IgE
Slide 6
Incidence of asthma or wheeze to age 42 by atopy
Slide 7
Total IgE at 45y not associated with incidence except at age
34-42, after adjustment for sex, smoking and specific IgE Change to
a broader form of question Incidence of asthma or wheeze to age 42
by atopy
Slide 8
The complexity of prognosis
Slide 9
Risk factors for incidence & relapse Prevalence of asthma
or wheeze in last year at 42 among subjects with no asthma/WB aged
16-23 and no asthma or wheezing in last year at 33, by history of
asthma or wheezy bronchitis aged 0-16. Birth 7 11 16 23 33 42
Asthma or wheezy bronchitis ? ? None No history of asthma or wheezy
bronchitis by 23 No
Slide 10
Prevalence of asthma or wheeze in last year at 42 among
subjects with no asthma/WB aged 16-23 and no asthma or wheezing in
last year at 33, by history of asthma or wheezy bronchitis aged
0-16. Incidence and recurrence of asthma or wheezing by smoking and
atopy
Slide 11
Relapse or re-incidence? Is asthma/wheeze a single disorder
from childhood to adult-onset asthma? Is apparent relapse or
recurrence of childhood wheezing simply incidence of a new form of
wheezing tendency? Do teenagers who have outgrown their childhood
wheezing tendency have a higher risk of adult wheezing?
Slide 12
Same genotype, changing phenotype
Slide 13
Slide 14
http://www.b58cgene.sgul.ac.uk/
Slide 15
Slide 16
Slide 17
Slide 18
Lifetime asthma by diplotype at chr17q21 locus
Slide 19
Francis Crick and James Watson photographed on 21 May 1953,
just before publication of their paper and forty years later Same
genotype, changing phenotype
Slide 20
Asthma genetics: state of the art 2005 Positional candidate
genes Four [now five] potential asthma susceptibility genes have
been identified by positional cloning studies in families and
pedigrees. Biochemical mechanisms linking three of these (ADAM33,
DPP10 and PHF11) to asthma and related traits are poorly
understood. Plausible links exist for GPR154 (glucocorticoid
receptor) [and PTGDR prostaglandin receptor]. Inconsistent
replication of the associations of ADAM33, DPP10, GPR154, PHF11
[and PTGDR] by groups other than the original reporters.
Slide 21
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma or wheezing
ever by age 42 Selected SNPs in positional candidate genes
Slide 22
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma or wheezy
bronchitis by age 16 Selected SNPs in positional candidate
genes
Slide 23
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma or wheezing
with onset after age 16 Selected SNPs in positional candidate
genes
Slide 24
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma ever
reported at age 42 Selected SNPs in positional candidate genes
Slide 25
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Wheeze ever but no
asthma by age 42 Selected SNPs in positional candidate genes
Slide 26
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Atopy
(allergen-specific IgE) at age 44-45 Selected SNPs in positional
candidate genes
Slide 27
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma or wheezing
ever by age 42 Positional candidate genes and chr17 locus
Slide 28
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma or wheezy
bronchitis by age 16 Positional candidate genes and chr17
locus
Slide 29
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma or wheezing
with onset after age 16 Positional candidate genes and chr17
locus
Slide 30
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Asthma ever
reported at age 42 Positional candidate genes and chr17 locus
Slide 31
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Wheeze ever but no
asthma by age 42 Positional candidate genes and chr17 locus
Slide 32
2.0 1.6 1.25 1.0 0.8 0.63 0.5 Chr17q21 locus Atopy
(allergen-specific IgE) at age 44-45 Positional candidate genes and
chr17 locus