Introduction and Rationale: Household Air Pollution (HAP) refers to the pollution of air in the indoor environment, from the combustion of solid fuels such as biomass and coal. The World Health Organization (WHO) estimates that 2.6 billion people today are exposed to HAP daily. Women and children tend to be at a higher risk of exposure due to their increased time spent indoors. This can result in a range of adverse cardio-respiratory outcomes such as asthma, Acute Lower Respiratory Infection (ALRI) and Chronic Obstructive Pulmonary Disease (COPD). This thesis document investigates the association between HAP and the adverse respiratory outcomes, namely lung function, ALRI and asthma in children. Methodology: Systematic Reviews were conducted to synthesize the effect of HAP on lung function, ALRI, and asthma. The lung function outcome was synthesized in a narrative manner, while the pooled estimates for the ALRI and asthma outcomes were synthesized by meta-analysis. Results: Exposure to HAP is associated with decreased lung function growth, and an increased risk of the incidence of ALRI in children. No association was noted between HAP exposure and the incidence of asthma in children. Conclusion: The effect of HAP on childhood growth of lung function and the incidence of ALRI provides evidence justifying the universal transition to cleaner fuels and technologies, such as electricity and natural gas. / Thesis / Master of Science (MSc) / Household Air Pollution (HAP) refers to the pollution of indoor air caused by the combustion of solid fuels, such as biomass, for the purposes of heating and cooking. According to the World Health Organization (WHO), 2.6 billion people are exposed to HAP daily. Women and children are especially at high risk of exposure, due to the time spent indoors. This places them at a higher risk of adverse respiratory outcomes, such as Acute Lower Respiratory Tract Infection (ALRI), asthma, Chronic Obstructive Pulmonary Disease (COPD) and reduced lung function. This thesis document investigates the association between HAP and the adverse respiratory outcomes, namely lung function, ALRI and asthma in children. It was found that HAP is associated with a decrease in childhood lung function growth, and an increased risk of the incidence of ALRI. However, there was no clear association between the incidence of asthma and HAP. The results of the systematic reviews justify a transition from the use of solid fuels to clean fuels and technologies.

Abstract Bronchiolitis is an infection of the small airways of the lung and is a common reason for infant hospitalizations. The most common causative pathogen is the respiratory syncytial virus (RSV). Genetic factors are thought to influence the risk of bronchiolitis, and better knowledge of bronchiolitis genetics will likely help to elucidate the disease process. Severe bronchiolitis in childhood may predispose to asthma. Therefore, an effective treatment of bronchiolitis may affect the present-day as well as lifelong respiratory health. In this project, we aimed to identify genetic loci of bronchiolitis susceptibility by a genome-wide association study (GWAS) and suitable follow-up studies, and to study a previously asthma-associated CDHR3 variant for association across five bronchiolitis populations by meta-analysis. We performed the GWAS on a Finnish-Swedish case-control population and identified several loci below the suggestive genome-wide significance level. Of these, three variants showed nominal associations in a replication population from the Netherlands. One of the loci affected KCND3 expression, and two others were intergenic variants with putative regulatory potential. In a follow-up study conducted on a GWAS sub population, we identified the NKG2D locus as a candidate of susceptibility to bronchiolitis. The genomic region encompassing NKG2D variants was reportedly associated with NKG2D mRNA and protein abundance. We validated the association between NKG2D genotypes and protein expression with flow cytometry. The association between NKG2D and bronchiolitis was supported by a Finnish replication study. The meta-analysis was performed on populations from Denmark, Finland, Sweden, Germany, and the Netherlands. A potential virus-specific role for the CDHR3 variant was detected in a population that comprised mostly RSV-negative cases. In conclusion, we identified new candidates of bronchiolitis susceptibility in GWAS and subsequent studies. We found the CDHR3 variant was a potential susceptibility factor in severe non-RSV bronchiolitis and asthma. Our preliminary results provide interesting starting points for further studies. In the future, better understanding of the disease mechanisms and the relationship of bronchiolitis and asthma could provide means to design new therapeutic options. / Tiivistelmä Bronkioliitti on viruksen aiheuttama alahengitystieinfektio, joka usein johtaa pienten lasten sairaalahoitoon. Yleisin bronkioliitin aiheuttaja lapsilla on respiratory syncytial -virus (RSV). Perintötekijöiden arvellaan altistavan bronkioliitille, joten uusi tieto altistavista geeneistä voi auttaa ymmärtämään taudin taustalla olevia biologisia mekanismeja. Lapsuusiän bronkioliitin ajatellaan voivan altistaa astmalle, joten bronkioliitin tehokas hoito voi vaikuttaa merkittävästi hengitysterveyteen myös pitkällä aikavälillä. Työssä pyrittiin selvittämään lapsuusajan bronkioliitille altistavia geneettisiä tekijöitä genominlaajuisella assosiaatiokartoituksella, joka toteutettiin suomalais-ruotsalaisessa tapaus-verrokkiväestössä. Löydökset pyrittiin varmentamaan soveltuvilla jatkotutkimuksilla. Lisäksi tarkastelimme astmalle altistavaa CDHR3-geenin polymorfismia viidessä eurooppalaisessa bronkioliittikohortissa käyttäen meta-analyysia. Assosiaatiokartoituksessa havaittiin useita mahdollisia bronkioliittialttiuteen vaikuttavia geenikohtia. Näistä kolme sai tukea hollantilaisessa väestössä tehdyssä assosiaatioanalyysissä, jossa testattiin assosiaatiokartoituksen lupaavimmat löydökset. Yksi altistavista polymorfismeista vaikutti KCND3-geenin ilmentymiseen, ja kaksi muuta olivat geenien välisiä, mahdollisesti geeninsäätelyyn osallistuvia variantteja. Assosiaatiokartoituksen osa-analyysissä NKG2D tunnistettiin mahdolliseksi bronkioliitille altistavaksi geeniksi. NKG2D-immuunireseptorin alentunut ilmentyminen voi tulostemme perusteella altistaa vakavalle bronkioliitille. Meta-analyysissä, jonka tutkimuskohortit olivat peräisin Tanskasta, Suomesta, Ruotsista, Saksasta ja Hollannista, todettiin mahdollinen yhteys CDHR3-geenin polymorfismin ja muun viruksen kuin RSV:n aiheuttaman bronkioliitin välillä. Toteutimme tässä työssä ensimmäisen genominlaajuisen bronkioliittialttiutta koskevan assosiaatiokartoituksen. Assosiaatiokartoituksessa, sitä seuranneissa jatkotutkimuksissa ja meta-analyysissä tunnistimme useita lupaavia alttiusgeenejä, mutta tuloksemme vaativat varmentamista suuremmissa tutkimusväestöissä.