The British 1958 cohort (National Child Development Study)

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 blood samples cell line transformations DNA forms a national reference series for case-control studies, including WTCCC and T1DGC (4000 GW typed) and WTCCC2

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

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

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

Incidence of asthma or wheeze to age 42 by atopy

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

The complexity of prognosis

Risk factors for incidence & relapse Prevalence of asthma or wheeze in last year at 42 among subjects with no asthma/WB aged and no asthma or wheezing in last year at 33, by history of asthma or wheezy bronchitis aged Birth Asthma or wheezy bronchitis ? ? None No history of asthma or wheezy bronchitis by 23 No

Prevalence of asthma or wheeze in last year at 42 among subjects with no asthma/WB aged and no asthma or wheezing in last year at 33, by history of asthma or wheezy bronchitis aged Incidence and recurrence of asthma or wheezing by smoking and atopy

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?

Same genotype, changing phenotype

Lifetime asthma by diplotype at chr17q21 locus

Francis Crick and James Watson photographed on 21 May 1953, just before publication of their paper …… and forty years later Same genotype, changing phenotype

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.

Chr17q21 locus Asthma or wheezing ever by age 42 Selected SNPs in positional candidate genes

Chr17q21 locus Asthma or wheezy bronchitis by age 16 Selected SNPs in positional candidate genes

Chr17q21 locus Asthma or wheezing with onset after age 16 Selected SNPs in positional candidate genes

Chr17q21 locus Asthma ever reported at age 42 Selected SNPs in positional candidate genes

Chr17q21 locus Wheeze ever but no asthma by age 42 Selected SNPs in positional candidate genes

Chr17q21 locus Atopy (allergen-specific IgE) at age Selected SNPs in positional candidate genes

Chr17q21 locus Asthma or wheezing ever by age 42 Positional candidate genes and chr17 locus

Chr17q21 locus Asthma or wheezy bronchitis by age 16 Positional candidate genes and chr17 locus

Chr17q21 locus Asthma or wheezing with onset after age 16 Positional candidate genes and chr17 locus

Chr17q21 locus Asthma ever reported at age 42 Positional candidate genes and chr17 locus

Chr17q21 locus Wheeze ever but no asthma by age 42 Positional candidate genes and chr17 locus

Chr17q21 locus Atopy (allergen-specific IgE) at age Positional candidate genes and chr17 locus