Genetic background and the risk of otitis media

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Abstract

Objective

Otitis media is a multifactorial disease where genetic background may have an important role. For genome-wide association studies, it is important to understand the degree of heritability. The objective of this study was to estimate the heritability of recurrent acute otitis media and chronic otitis media with effusion.

Methods

Children operated because of recurrent or chronic otitis media at the Helsinki University Central Hospital, Finland, as well as their families were recruited during 2008–2009. A cohort of 2436 subjects was enrolled consisting of 1279 children and their parents. The study subjects answered a questionnaire concerning their otitis media history and treatment, as well as tobacco exposure, allergy and asthma history. Heritability estimates were calculated for recurrent acute, chronic and any episodes of otitis media using software especially designed for estimating heritability in family cohorts.

Results

Altogether 901 subjects suffered from recurrent otitis media and 559 from chronic otitis media with effusion. The heritability estimates in our cohort were 38.5% for recurrent (P = 7.3 × 10−9), 22.1% for chronic (P = 4.6 × 10−3) and 47.8% for any otitis media (P = 1.5 × 10−11).

Conclusions

Our results demonstrate a moderately strong and statistically significant genetic component for both recurrent acute otitis media and chronic otitis media with effusion. These results highlight the importance of unraveling the genetic factors for otitis media that are still poorly known.

Introduction

Acute otitis media (AOM) is one of the most common diseases among children [1], [2]. At the age of 3 years, over 80% of the children have experienced an episode of AOM and by the age of 7 years 40% have had six or more AOMs [3], [4]. AOM is characterized by effusion in the middle ear as well as signs of an acute infection, such as fever, otalgia, otorrhea, or pain. The clinical manifestations of childhood otitis media (OM) are variable. Some children may suffer only a few AOMs or may even have no clinically manifest AOM during their entire childhood. In some other children, especially in those who have their first AOM before the age of 1 year, AOM may be followed by recurrent episodes, and the children suffer from recurrent acute otitis media (RAOM). In RAOM the intervals between AOM episodes may be free of middle ear inflammatory effusion. In some children the middle ear effusion (MEE) may persist for months leading to chronic otitis media with effusion (COME). COME can be accompanied by recurring episodes of otalgia and other signs of an acute middle ear infection. Sometimes COME may even present without an apparent history of AOM and is only detected in a child with impaired hearing caused by the indolent MEE [5].

The burden of OM for the health care system and the society in general is significant. AOM is the most frequent reason for children to be treated with antibiotics [6]. COME is a common reason for hearing impairment among children and may hence further influence the learning ability of the child [7], [8], [9]. RAOM and COME are treated with insertion of tympanostomy tubes and sometimes with adenoidectomy [10], [11] that are among the most ordinary causes for children to be anesthetized. The annual cost for OM in Finland has been calculated to be $138 million in 1999 [12].

The most common bacterial pathogens causing AOM are Streptococcus pneumonia, Haemophilus influenzae and Moraxella catarrhalis [13]. AOM is usually preceded by a viral upper respiratory tract infection causing impairment of the mucociliary function of the Eustachian tube, which permits the bacterial infection to proceed into the middle ear. Thereby, an important risk factor for AOM is exposure to respiratory pathogens, which may occur during daycare outside home [14]. Airborne irritants, the most significant being exposure to passive tobacco smoke, also influence the risk of AOM. Furthermore, male children have more often AOM than female children for unknown reasons [15]. Immature immune system and the relatively short and patent Eustachian tube in young children may also contribute to the risk of OM, as the peak incidence of OM is at the age of 12 months decreasing thereafter [16], [17], [18]. An excessive use of pacifiers may to some extent increase the risk of OM, whereas prolonged breastfeeding may have a protective effect on OM [14]. The mechanical function of the epipharynx has presumably a role in OM, as children with cleft palate and craniofacial abnormalities have an increased risk of OM. Insufficient closure of the soft palate in these children is thought to increase the bacterial flora of the nasopharynx [14] and abnormalities in the nasopharyngeal muscles may cause impairments in the function of the Eustachian tubes.

OM is a multifactorial disease. It seems that the susceptibility to AOM is genetically determined, despite the fact that it is an infectious disease that is influenced by various environmental factors. Twin studies have been utilized to investigate the genetic component of OM by estimating the heritability (h2), which is the proportion of phenotypic variation among individuals in a given population that is due to genotype [19]. In a Norwegian longitudinal twin study with a cohort of 2750 twin pairs the h2 for recurrent ear infections was estimated to be 74% [20]. In an American prospective twin and triplet study, 168 same-sex twin pairs and 7 triplets were examined for MEE. It was observed that the estimate of h2 of MEE was 73% [21]. In a prospective study of 1373 English and Welsh twin pairs, the h2 of OM at ages 2, 3 and 4 years was estimated to be 49%, 66% and 71%, respectively [22]. These above studies strongly implicate that the susceptibility of OM is genetically determined.

Our aim was to evaluate the h2 of OM by studying trios consisting of an affected child and his/her parents. In addition, we estimated, if there were any differences in the h2 of diverse clinical presentations of OM by studying the h2 of COME and RAOM separately. To our knowledge this is the first study where h2 of OM is estimated by using pedigrees as opposed to twin studies.

Section snippets

Study subjects

The index cases for the present study were recruited during the years 2008–2009 among patients who were treated for RAOM or COME at the Department of Otorhinolaryngology in the Helsinki University Central Hospital (HUCH), Finland. Parents and siblings of the index case were asked to participate as well. Patients filled in a questionnaire concerning their OM history, operations due to RAOM and COME and other relevant medical conditions (Table 1). RAOM was defined as more than 3 AOMs during 6

Description of the study population

Out of the 590 families, 255 consisted of 2 children and a mother and a father. Sixteen families included a mother and from one to three children, and one family was represented only by a father and a child. The family size ranged from 2 to 15 individuals. The composition of the families is described in detail in Table 2.

A total of 1279 children, 584 mothers and 573 fathers were analyzed for h2 of OM. Of the children, 566 (44.3%) were female. The mean age of the children was 6 years (range 0–33

Discussion

We have collected data and analyzed a large set of Finnish families with an index child, who had a history of OM. To our knowledge this is the first family based study to specifically address the h2 of OM. Our results showed a clear and statistically significant genetic component for OM.

The data of the OM history was obtained by a questionnaire. To evaluate the reliability of the questionnaire data, we compared the data of the questionnaire to the data in the patient records. A high concordance

Role of the funding source

This study was supported by the Academy of Finland and Sigrid Jusélius Foundation as well as Research Funds of Helsinki University Central Hospital. These funds were used to cover the cost of collection and management of the data as well as analysis and interpretation of the data.

Personal support was provided by Helsinki Biomedical Graduate School LERU PhD Program in Biomedicine, Biomedicum Helsinki Foundation and University Helsinki Funds (T.M.J.).

Conflict of interest statement

The authors report no conflicts of interest that could inappropriately bias the work.

Acknowledgment

The authors would like to thank study nurse Tiina Puttonen for her invaluable help with collecting the patient data.

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