Cohort Profile: The Isle Of Wight Whole Population Birth Cohort (IOWBC)

Why was the cohort set up?

By the late 1980s, it was clear that allergic diseases, including asthma, eczema, allergic rhinitis and food allergy, had been increasing in recent decades, but the extent of this increase and true prevalence in an unselected population had not been estimated. It was also known that allergic diseases may remit and relapse. So one disease may improve as the child grows, but another may take its place; this pattern was termed ‘atopic or allergic march’. However, the extent and the true nature of this transition were not clear. Additionally, little was known why allergic diseases are increasing, and even less about why allergic disease often remits as the child grows but sometimes relapses in adolescent or adult life. We therefore established the Isle of Wight Birth Cohort (IOWBC) 28 years ago, in January 1989.

The Isle of Wight is an island off the south coast of England, with a resident population of approximately 130 000. The environment is semirural with no heavy industry, and the local economy largely relies on tourism.

The focus of the IOWBC is to:

• assess prevalence of allergic sensitization and clinical allergic manifestations in an unselected population during childhood and early adult life;

• explore the natural history of allergic sensitization and clinical allergic manifestations from infancy to early adult life;

• define the heterogeneity of asthma and allergic diseases across the life course;

• identify predictive markers for asthma and allergy development that might guide future disease prevention or treatment measures;

• develop novel therapeutic interventions;

• identify environmental risk factors relevant to asthma and allergic diseases;

• investigate genes, gene-environmental interactions and epigenetic mechanisms in the development of asthma and other allergic diseases.

The IOWBC was originally established with support from the local (Isle of Wight) Health Authority, which helped establish the cohort and the assessments at ages 1, 2 and 4 years. A grant from the charity ‘Asthma UK’ allowed assessment at age 10 years. Further funding from the National Institutes of Health (US) and the Medical Research Council (UK) has supported the cohort up to the most recent assessment at 26 years.

Who is in the cohort?

Recruitment

The IOWBC is a single-centre study designed to represent the community population. All children born on the Isle of Wight in a defined period were eligible for inclusion. Ethics approval was obtained from the local/national ethics committees at recruitment of the birth cohort between January 1989 and February 1990, and subsequently at each assessment. The cohort was recruited through the 1509 women who gave birth to 1536 children on the IOW during the recruitment period. All 1509 mothers were recruited and consented to complete questionnaires and provide samples soon after birth. Parental consent was obtained from 1456 of the 1536 children for inclusion into a longitudinal study of asthma and allergic disease (Figure 1).

Figure 1.

Flow diagram of study progress.

How often have they been followed up?

The children in the IOWBC have been seen on six occasions over the course of 26 years, at 1, 2, 4, 10, 18 and 26 years (Table 1). Extremely high retention rates have been obtained at all time points. Cohort particpants who attended or did not attend at various assessments were compared for information collected at birth, when parents of all 1536 infants responded and provided basic information on family history of allergy, birthweight, social status and exposures to pets and smoking (Table 2).

Table 1.

Information and samples collected from the Isle of Wight birth cohort

Variable	Birth	Year 1	Year 2	Year 4	Year 10	Year 18	Year 26
Family history of asthma, eczema and rhinitis	x	x	x	x	x	x	x
Pregnancy complications and birth characteristics	x	–	–	–	–	–	–
Mode of feeding	–	x	x	–	–	–	–
Household pets	x	x	x	x	x	x	x
Socioeconomic status	x	x	x	x	x	x	x
Exposure to smoking	x	x	x	x	x	x	x
Height, weight, BMI	x	x	x	x	x	x	x
Housing characteristics	–	–	x	x	x	x	x
Wheeze and asthma	–	x	x	x	x	x	x
Nasal symptoms	–	x	x	x	x	x	x
Respiratory infections	–	x	x	x	x	x	x
Allergic symptoms	–	x	x	x	x	x	x
Eczema		x	x	x	x	x	x
Food allergy		x	x	x	x	x	x
Treatment and medications	–	x	x	x	x	x	x
Skin prick test	–	x	x	x	x	x	x
Total and specific IgEa	x	–	–	–	x	x	x
Spirometry and bronchodilator reversibility (FEV1, FVC, FEF25-75)	–	–	–	–	x	x	x
Bronchial provocation test (PC20 and methacholine and dose-response)	–	–	–	–	x	x	x
Exhaled nitric oxide	–	–	–	–	–	x	x
Urinary cotinine	–	–	–	–	x	x	x
Genome-wide genotyping	–	–	–	–	x	–	–
Genome-wide DNA-methylationb	x	–	–	–	x	x	–

FVC, forced vital capacity; FEF, forced expiratory flow.

^aUsing maternal and cord blood.

^bUsing Guthrie cards collected at day 7.

Table 2.

Comparison of participants who attended or did not attend at various assessments with regard to cohort characteristics and other information collected at birth

	1 year		2 years		4 years		10 years		18 years		26 years
	Attended (n = 1369)a	Not attend (n = 167)	Attended (n = 1231)	Not attend (n = 305)	Attended (n = 1218)	Not attend (n = 318)	Attended (n = 1373)	Not attend (n = 163)	Attended (n = 1313)	Not attend (n = 213)	Attended (n = 1033)	Not attend (n = 503)
Male gender	697/1369 (50.9%)	90/167 (53.9%)	622/1231 (50.5%)	165/305 (54.1%)	621/1218 (51.0%)	166/318 (52.2%)	698/1373 (50.8%)	89/163 (54.6%)	654/1313 (49.8%)*	133/223 (59.6%)	473/1033 (45.8%)*	314/503 (62.4%)
Low birthweight (< 2.5 kg)	52/1347 (3.9%)*	14/165 (8.5%)	42/1210 (3.5%)	24/302 (7.9%)	45/1198 (3.8%)*	21/314 (6.7%)	53/1351 (3.9%)*	13/161 (8.1%)	48/1294 (3.7%)*	18/218 (8.3%)	40/1019 (3.9%)	26/493 (5.3%)
Maternal asthma	150/1362 (11.2%)	15/155 (9.7%)	129/1228 (10.5%)	36/289 (12.5%)	126/1211 (10.4%)	39/306 (12.7%)	143/1364 (10.5%)	22/153 (14.4%)	138/1304 (10.6%)	27/213 (12.7%)	112/1025 (10.9%)	53/492 (10.8%)
Paternal asthma	134/1354 (9.9%)	15/150 (10.0%)	115/1222 (9.4%)	34/282 (12.1%)	117/1208 (9.7%)	32/296 (10.8%)	131/1356 (9.7%)	18/148 (12.2%)	128/1296 (9.9%)	21/208 (10.1%)	98/1019 (9.6%)	51/485 (10.5%)
Sibling asthma	93/805 (11.6%)	13/79 (16.5%)	78/722 (10.8%)*	28/162 (17.3%)	73/712 (10.3%)*	33/172 (19.2%)	88/800 (11.0%)*	18/84 (21.4%)	88/756 (11.6%)	18/128 (14.1%)	70/602 (11.6%)	36/282 (12.8%)
Maternal eczema	166/1359 (12.2%)	17/155 (11.0%)	150/1225 (12.2%)	33/289 (11.4%)	145/1208 (12.0%)	38/306 (12.4%)	162/1361 (11.9%)	21/153 (13.7%)	161/1301 (12.4%)	22/213 (10.3%)	125/1023 (12.2%)	58/491 (11.8%)
Paternal eczema	86/1352 (6.4%)	11/152 (7.2%)	80/1220 (6.6%)	17/284 (6.0%)	78/1206 (6.5%)	19/298 (6.4%)	89/1355 (6.6%)	8/149 (5.4%)	90/1294 (7.0%)*	7/210 (3.3%)	74/1017 (7.3%)	23/487 (4.7%)
Sibling eczema	192/801 (24.0%)	14/79 (17.7%)	168/718 (23.4%)	38/162 (23.5%)	167/708 (23.6)	39/172 (22.7%)	195/796 (24.5%)	11/84 (13.1%)	181/752 (24.1%)	25/128 (19.5%)	136/599 (22.7%)	70/281 (24.9%)
Maternal rhinitis	278/1362 (20.4%)	27/155 (17.4%)	246/1228 (20.0%)	59/289 (20.4%)	257/1211 (21.2%)*	48/306 (15.7%)	270/1364 (19.8%)	35/153 (22.9%)	262/1304 (20.1%)	43/213 (20.2%)	210/1025 (20.5%)	95/492 (19.3%)
Paternal rhinitis	202/1353 (14.9%)	18/152 (11.8%)	179/1222 (14.6%)	41/283 (14.5%)	177/1207 (14.7%)	43/298 (14.4%)	201/1356 (14.8%)	19/149 (12.8%)	189/1296 (14.6%)	31/209 (14.8%)	151/1018 (14.8%)	69/487 (14.2%)
Sibling rhinitis	58/801 (7.2%)	3/79 (3.8%)	50/719 (7.0%)	11/161 (6.8%)	50/708 (7.1%)	11/172 (6.4%)	55/796 (6.9%)	6/84 (7.1%)	55/752 (7.3%)	6/128 (4.7%)	38/599 (6.3%)	23/281 (8.2%)
Maternal smoking	345/1354 (25.5%)	48/155 (31.0%)	295/1221 (24.2%)*	98/288 (34.0%)	257/1206 (21.3%)*	136/303 (44.9%)	325/1357 (23.9%)*	68/152 (44.7%)	311/1298 (24.0%)*	82/211 (38.9%)	233/1020 (22.8%)*	160/489 (32.7%)
Paternal smoking	539/1353 (39.8%)	69/150 (46.0%)	476/1221 (39.0%)*	132/282 (46.8%)	437/1207 (36.2%)*	171/296 (57.8%)	523/1355 (38.6%)*	85/148 (57.4%)	503/1296 (38.8%)*	105/207 (50.7%)	384/1018 (37.7%)*	224/485 (46.2%)
Cat ownership	452/1361 (33.2%)	42/153 (27.5%)	411/1227 (33.5%)	83/287 (28.9%)	403/1211 (33.3%)	91/303 (30.0%)	454/1364 (33.3%)	40/150 (26.7%)	434/1303 (33.3%)	60/211 (28.4%)	340/1023 (33.2%)	154/491 (31.4%)
Dog ownership	403/1361 (29.6%)	38/153 (24.8%)	363/1227 (29.6%)	78/287 (27.2%)	356/1211 (29.4%)	85/303 (28.1%)	396/1364 (29.0%)	45/150 (30.0%)	376/1303 (28.9%)	65/211 (30.8%)	293/1023 (28.6%)	148/491 (30.1%)
Social class I–III	441/799 (55.2%)	45/91 (49.5%)	319/715 (44.6%)	85/175 (48.6%)	347/721 (48.1%)	57/169 (33.7%)	376/811 (46.4%)	28/79 (35.4%)	357/779 (45.8%)	47/111 (42.3%)	292/601 (48.6%)*	112/289 (38.8%)
Cord IgE > 0.5	129/1000 (12.9%)	10/64 (15.6%)	118/928 (12.7%)	21/136 (15.4%)	139/1064 (13.1%)	0/152 (0%)*	130/1016 (12.8%)	9/48 (18.8%)	122/973 (12.5%)	17/91 (18.7%)	96/756 (12.7%)	43/308 (14.0%)

^aAttended n = denotes maximum number of children who provided any information at a given assessment. There was some missing information depending on the specific question, with the details provided for each in the rows below.

^*Where differences were found to be statistically significant between those who attended and did not attend defined as P < 0.05.

What has been assessed and/or measured?

Hospital records were used to gather information on maternal height and weight at week 14 (± 4) of gestation, pregnancy characteristics and complications and birth characteristics. Samples of maternal blood and cord blood at birth, and the child’s blood from a heel prick at 7 days of age, were collected on Guthrie cards.

Questionnaires, both study-specific and standardized questionnaires (International Study of Asthma and Allergic Diseases in Childhood from 10 years onwards when these became available) seeking information on asthma and allergy status and common environmental exposures, were completed by most participants or their parents at various assessments throughout childhood and early adult life (Table 3). Mothers completed a questionnaire soon after the birth of their children (Table 4); and at 1 and 2 years, children were seen by a doctor, nurse or health visitor and a questionnaire completed. If parents reported any allergy-related symptoms in their child, they were asked to attend the clinic for a visit when examination and allergy skin prick tests (SPT) were carried out. Physical examination at all assessments included height, weight and signs of allergic diseases such as wheeze and eczema. At 4, 10, 18 and 26 years, all participants were invited to attend the research centre for an assessment, which included questionnaire, physical examination and skin prick test. At 10, 18 and 26 years, spirometry and bronchial provocation tests were carried out and blood and urine samples were collected. Exhaled nitric oxide was measured at 18 and 26 years. A subgroup of children were invited for sputum induction at 10 and 18 years. At all ages, those who could not attend the centre for a personal visit were asked to complete a telephone or postal questionnaire. At 26 years online questionnaires were first introduced, in addition to telephone and postal questionnaires, to achieve optimal participation. Where possible, participants were asked to give permission for access to their medical records which provided more accurate data regarding physician diagnosis and treatments received.

Table 3.

Procedures conducted in the Isle of Wight cohort (n)

Variable	Birth	Year 1	Year 2	Year 4	Year 10	Year 18	Year 26
Questionnaires	1536	1369	1231	1218	1373	1313	1033
Physical examination	–	323	410	977	1036	864	544
Height/weight	1501	1090	399	1053	1043	964	681
Skin prick tests	–	323	410	977	1036	851	556
Spirometry	–	–	–	–	980	839	544
Bronchial provocation tests	–	–	–	–	784	586	Ongoing
Sputum induction	–	–	–	–	25	100	–
Exhaled nitric oxide	–	–	–	–	–	822	542
Blood samples	Maternal = 1150 Cord = 1275 Guthrie card at 7 days = 1150	–	–	–	950	550	503
Urine	–	–	–	–	970	650	528
Saliva	–	–	–	–	850	500	22

Table 4.

Demographic characteristics of the parents of the Isle of Wight Birth Cohort particiants (recorded at recruitment)

	Mothers	Fathers
Mean age (years)	27.25	–
Smoking (n)	393	608
Cat ownership (n)	494	–
Dog ownership (n)	442	–
Asthma (n)	165	149
Hay fever (n)	305	220
Eczema (n)	183	97
Food allergy (n)	71	38
Any allergic disease (n)	528	388

Serum total immunoglobulin E (IgE) was measured at birth (in the cord serum), and again at 10 and 18 years. Specific IgE screens for aero and food allergens were carried out at 10 and 18 years. Serum leptin and urinary cotinine were measured at 10 and 18 years. In a subgroup, a panel of cytokines was measured at 10 and 18 years. Genome-wide genotyping is being carried out currently and data will be available shortly. Genome-wide epigenotyping with DNA methylation was carried out in a subgroup of participants in whole-blood-derived DNA collected at 18 years and is now being extended to all participants with blood samples available at birth (using Guthrie cards) and at 10 and 18 years.

What has it found?

Nearly 100 original articles have been published, describing prevalence, natural history and genetic and environmental risk factors for asthma and allergic diseases up to 18 years of age, and data collected at the age of 26 years are currently being analysed. A list of publications arising from the IOWBC can be found at [http://www.allergyresearch.org.uk].

Prevalence

We described the population prevalence of allergic disorders at various ages in this unselected birth cohort. The prevalence was generally described as period prevalence, i.e. in the past 12 months, at each assessment. We used study-specific questionnaires in the first three assessments, and later repeated these questionnaires also using standardized International Study of Asthma and Allergy in Childhood (ISAAC) questionnaires¹ which had become available between the 4- and 10-year follow-ups. The overall prevalence of one or more allergic diseases varied from ∼25% in the first 2 years to 40% at 4 and 50% by the age of 18 years.^2–6

Asthma

Reported asthma at 1, 2 and 4 years, defined as recurrent wheezing, increased from 8.7% at 1 year to 14.9% at 4 years.^2,4,7 At ages 10, 18 and 26 years, we characterized cohort children extensively for asthma and allergic diseases using standardized questionnaires, lung function, bronchial provocation tests, and sputum induction.^5,6,8–11 We also described wheezing phenotypes during the first 10 years of life, identifying that more severe disease had an early onset and could be distinguished from more transient disease using risk scoring systems.^8,9,12,13 We investigated early life risk factors for the development of asthma and bronchial hyper-responsiveness (BHR) during later childhood^10,13 and how these factors influence symptom expression in those with BHR¹⁰ and induce earlier onset of disease.¹⁴

Nearly 5% of adolescents reported wheezing in the absence of diagnosed asthma and showed few pathophysiological hallmarks of asthma. This ‘undiagnosed wheeze’ phenotype was associated with smoking and paracetamol use.¹⁵ Applying cluster analysis methods on IOWBC data, we have defined wheeze and rhinitis clusters to explore phenotypes of these conditions using adolescents.^16,17 By 18 years, severe asthma clusters with evidence of impaired lung function, high morbidity and higher smoking prevalence were identifiable.

Allergic rhinitis

Rhinitis was defined as nasal and/or eye symptoms of sneezing, rhinorrhoea, nasal blockage and streaming/itchy eyes when not having a ‘cold’ or respiratory infection. At 1 and 2 years, the prevalence was low (∼3%) but gradually increased so that by 26 years it had reached 42%.^{2–4,7,16,18–20}

Atopic dermatitis

Atopic dermatitis, using modified Hannifin and Rajka definition, was approximately 10% during early childhood.^2–4,7,21

Peanut allergy

We were among the first to describe the prevalence of peanut allergy in 4-year-old children in the IOWBC.²² More recently we described the natural history of peanut allergy over the first 18 years of life.²³ Subsequently, the prevalence rates in the IOWBC were compared with another cohort of children of the same age, born a few years later on the IOW and assessed for peanut allergy. This showed that sensitization increased 3-fold and clinical allergy to peanut doubled during the 1990s.²⁴ In early 2000, we recruited another birth cohort on the IOW (Food Allergy and Intolerance Research cohort) and assessed children for food allergy during early childhood. Therefore, we were able to compare prevalence in these three sequential cohorts of children, all aged 3–4 years but born 5–6 years apart. We found that after the initial rise in 1990s, the peanut prevalence in the UK stabilized during the past decade.²⁵

Allergic sensitization

The relationship of allergic sensitization, asthma and allergic disease was investigated from the ages of 4 to 26 years.^4,12,26–28 Atopy (SPT positive to any allergen) was 29% at 4 years.⁴ A strong relationship was found between allergic diseases such as asthma with house dust mite, allergic rhinitis with grass pollen, and eczema with egg.⁷ Various childhood atopic phenotypes were described and their relationships with wheeze and asthma were defined. The population-attributable risk of atopy for asthma was 44%, for rhinitis it was 46% and for eczema, 32%.² We recently showed that fractional exhaled nitric oxide (FeNO) is associated with atopy and atopic asthma, but not with non-atopic asthma. This has implications for the use of FeNO for the diagnosis and management of asthma.²⁷

Natural history

Overall, the prevalence of wheeze and asthma has continued to rise from early childhood to early adult life. However, there was fluidity such that a proportion of children who had wheeze at one follow-up were not wheezing at the next, but other non-wheezing children had acquired wheeze, so that the trend of period prevalence remained upwards. The remission, relapse and new onset (in those who were previously disease free) was also seen in other allergic manifestations including eczema, rhinitis, food allergy and allergic sensitization.^{20,23,29–32} However, the net trend for asthma and rhinitis was generally upwards, whereas for eczema and food allergy there was a relatively high prevalence in early childhood followed by overall stable figures of around 10-15% for eczema and 1–3% for food allergy.

We were among the first to report that children with egg allergy in infancy have a 5–6-fold increased risk of acquiring aeroallergen sensitization and respiratory symptoms by age 4,³³ thus shifting the allergic phenotype from food allergy to aeroallergen sensitization with associated asthma and rhinitis.

Risk factors for allergic diseases

Sex

Boys suffered from asthma, eczema, rhinitis and atopy (allergic sensitization) more than girls throughout childhood and early adult life (up to age 26 years). For asthma, a gender reversal occurs during adolescence; thus at age 18 girls had more asthma than boys.^{2,4,6–8,20,21,31,34}

Parental allergy

As expected, parental asthma and allergy had a consistent effect on childhood asthma and eczema over the entire childhood and adolescent period,^{2,3,6,7,18,21,34–36} with some disease specificity such that parental asthma increased the risk of asthma more than of eczema or rhinitis.⁴ We also showed that the risk is sex specific, such that boys had higher risk of asthma when their fathers were affected by asthma and girls had a higher risk when mothers were diagnosed with asthma.³⁵

Breastfeeding and asthma

The effect of breastfeeding on asthma remains controversial. We showed that breastfeeding for at least 3 months protects against early childhood wheezing, ^3,7 possibly as a result of attenuating the adverse effect of respiratory infections and maternal smoking on asthma.^37–39 We also showed that breastfeeding is associated with better lung function at 10 and 18 years of age.^38,40 However, the effect on allergic diseases in later childhood and adolescence was less clear.⁴¹ Our data suggest that some of the conflicting results on method of feeding and allergy may be due to reverse causation.⁴²

Low birthweight

Low birthweight was shown to be a risk factor for asthma, atopy and lung function.^{34,36,39,43–45}

Exposure to smoking

We demonstrated the adverse effects of maternal smoking exposure on the developing fetus, with increased risk of wheeze and nasal symptoms during infancy,^2,7,18,34,46 and of active smoking on lung health during adolescence.^6,15 Maternal smoking also had an effect on eczema at age 4 years.⁴⁶ The genetic susceptibility and epigenetic mechanisms mediating this susceptibility have been studied (see below). These findings have paved the way to identifying susceptible smokers at risk of future chronic obstructive pulmonary disease (COPD).

Lower socioeconomic group

Children among the lower socioeconomic group had a higher level of infant wheezing, even after adjusting for confounding factors such as maternal smoking and lack of breastfeeding.^2,3,7

Presence of pets

We have not found an effect of exposure to furry pets on asthma or other allergic diseases at any age.^{2,3,18,21,34,47} A similar conclusion was reached in a meta-analysis of data from various European birth cohorts including the Isle of Wight.⁴⁸

Season of birth

We have found effect of season of birth, with a higher level of asthma and rhinitis during the summer.^2,3,7,49 Autumn births were associated with rhinitis, and autumn and winter combined had more eczema.

Cord and maternal IgE

The presence of cord IgE was associated with maternal IgE³⁶ and increased the risk of allergic sensitization at 4 years.³ We also showed that IgE at birth (cord IgE) decreases with increasing birth order.⁵⁰ This provides an alternative explanation to the hygiene hypothesis for the lower incidence of allergic disease observed in younger siblings, as it seems they are born with lower cord IgE. We subsequently showed that this effect on children may be transmitted from mothers, as their IgE also decreases with the increasing number of children they have delivered.⁵¹ We demonstrated that the birth order effect is dependent on genetic susceptibility. An interaction between an IL13 gene single nucleotide polymorphism (SNP; rs20541) and birth order was found, whereby the effect of this SNP on skin test (ages 4 to 18), total IgE (age 10), and inhalant screen (age 10) was restricted to first-born children.⁵²

Predictors

Using longitudinal and repeated assessments of allergic disease in our birth cohort and available information on risk factors and biomarkers, we attempted to identify predictive markers for asthma and allergy.^13,33,53,54 We initially focused on cord blood IgE, and found that an elevated cord IgE increases the risk of allergic sensitization during childhood.^53,55 Although it did not increase the risk of respiratory symptoms in early childhood, it did increase the risk of asthma at age 10.⁵⁵ However, the sensitivity of cord IgE was too low to be used as a predictive marker for allergic disease.^53,54 Another important issue in paediatric allergy is the outcome of infant wheeze and its relationship with later childhood asthma. We developed predictive scores, based on a set of four risk factors (maternal asthma, allergic sensitization, recurrent chest infections and absence of nasal symptoms). Among children with a risk score of 4, 83% persisted with their wheeze, whereas of those with a risk score of zero, 80% went into remission.¹³ Egg allergy combined with eczema during infancy had a high (> 80%) positive predictive value for allergic sensitization and respiratory symptoms.³³

Genetics

We identified a novel gene (ATPAF1) association with childhood asthma, using a genome-wide approach on pooled DNA.⁵⁶ Cohort data were also used to identify a novel gene regulating neutrophil function, which is responsible for severity in cystic fibrosis.⁵⁷ Using a candidate gene approach, we investigated the association of IL13 with cord IgE and atopic eczema.^58,59 We have also demonstrated that filaggrin loss-of-function mutations contribute to allergic comorbidity including food allergy.^60–63 Gene-gene interaction between GATA3 and STAT6 with IL13 on rhinitis and eczema, respectively, was demonstrated.^64,65

Exposure to tobacco smoke increases the risk of wheeze and lung function deficit. We have shown the interaction of pre- and postnatal smoking exposure with genetic polymorphisms in genes encoding IL-13, IL-1R antagonist and GSTM2-5, on development of asthma and lung function.^66–68 Exposures related to birth order modified the effect of IL13 polymorphism on allergic sensitization, whereas filaggrin loss-of-function mutations modified the effect of breastfeeding on eczema.^52,69

Epigenetics

We have explored epigenetic mechanisms using genome-wide DNA methylation.^49,70–82 Common environmental exposures such as smoking alter epigenetic profile, which in turn is shown to be associated with the risk of allergic diseases (Table 5). Interestingly, tetanus vaccination between 10 and 18 years was related to differential methylation, which in turn reduced the risk of asthma at 18 years.⁷⁹ Using a two-stage model we showed that genetic variants in combination with living conditions, for instance use of oral contraceptives in girls, may change the DNA methylation, which in turn modifies the genetic associations related to asthma.⁸² The interaction of DNA methylation with genetic variants was demonstrated for a number of allergic markers and diseases.^70–73,77

Table 5.

Epigenetic associations identified in the Isle of Wight Birth Cohort participants

Main CpG site/s	Genes	Exposure	Outcomes	Reference
cg09791102 cg26937798	IL-4 IL-4	–	On asthma risk and temporal asthma transition	Zhang et al. Clin Epigenet 2014;6:8
cg07548383	FLG	–	Eczema	Ziyab. J Eur Acad Dermatol Venereol 2012;7:e32721
cg09791102	IL-4R	–	Asthma at age 18 years	Soto-Ramirez et al. Clin Epigenet 2013;5:1
cg00666422	LEP	–	Lung function and asthma	Mukherjee. Int J Mol Epidemiol Genet 2016;7:1–17
cg04850479 cg01427769	PROZ NEU1	–	Eczema	Quraishi et al. Clin Epigenet 2015;7:68
cg04983687 cg18219873 cg27469152 cg09332506	ZFPM1 PRG2 EPX COPA	–	Atopy and high serum IgE	Everson. Genome Med 2015;7:89
cg11807188 cg03050981	LEPR/LEPROT	Smoking	Serum pleptin/BMI	Yousefi et al. Int J Mol Epidemiol Genet 2013;4:86–100
cg13566430	IL-13	Smoking	Asthma	Patil et al. Clin Epigenet 2013;5:22
cg00787537 cg24577417 cg07175945	KCNH1 HGC6.3 ZFR	Season of birth	Allergic disease	Lockett. Allergy 2016. Mar 12. doi: 10.1111/all.12882
cg05575921	AHRR	Maternal smoking	–	Joubert. Am J Hum Genet 2016;98:680–96
Cg14472551 cg01669161	KIAA1549L PSMG3, TFAMP1	Tetanus vaccination	Asthma	Janjanam et al. Vaccine 2016;34:6493–501
CpG islands	NHP2L1, WRB and PPIEL	–	–	Docherty et al. J Med Genet 2014;51:229–38

What are the main strengths and weaknesses?

Strengths

The IOWBC is an unselected whole-population cohort that truly represents the community from which the cohort is drawn. There has been a high retention rate of over 70% throughout, with availability of information and samples from the parental generation, comprehensive assessment that covered not only asthma but all chronic allergic conditions, prospective and extensive phenotyping, and genome-wide (epi)genotyping.

Weaknesses

Despite reletively high retention, some self-selection was observed in chidren who attended at various assessments (Table 2). For instance at 18 and 26 years, girls attended more than boys and children who were assessed tended to have a lower proportion of parental smoking and low (< 2.5 kg) birthweight. However, as the follow-up rates were consistently high (80-90%) and imbalances were few, this reletively modest selection bias does not affect the validity or generalizability of the findings. The Isle of Wight is a relatively small island (∼20 miles across) and therefore there is a lack of diversity, both in terms of environment (no industrial exposure) and race (> 90% Caucasian), hence raising potential questions regarding generalizability of findings. The population is, however, not genetically inbred and there is frequent movement of people from mainland England.

Can I get hold of the data? Where can I find out more?

The cohort profile is available on [www.allergyresearch.org.uk]. We encourage collaboration to maximize the use of data and samples. We are in the process of finalizing details of how the data can be accessed and the process of submitting an application to access the data. Please contact Mr Stephen Potter [stephen.potter@iow.nhs.uk].

Profile in a nutshell

• IOWBC is a whole-population prospective, observational study investigating prevalence, natural history and risk and protective factors for the development of asthma and allergic diseases.

• All children (n = 1536) born on the Isle of Wight between 1 January 1989 and 28 February 1990 were enrolled, with 1456 consenting for long-term follow-up.

• Participants have been assessed six times since birth, with a high (> 70%) retention of the cohort participants.

• A wide range of phenotypic and environmental information has been collected using questionnaires and hospital medical records, study procedures and genetic and epigenetic assessments; and over 10 000 biological samples have been collected.

Funding

Recruitment and initial assessment for the first 4 years of age was supported by the Isle of Wight Health Authority. The 10-year follow-up of this study was funded by the National Asthma Campaign, UK (Grant No 364) and the 18-year follow-up by NIH/NHLBI R01 HL082925-01. The 21 year assessment was funded by Medical Research Council, UK (G23369). The 26 years assessment was supported by The David Hide Asthma & Allergy Research Trust.

Conflict of interest: None declared.