Çocukluk çağı astım etiyolojisi ile ilişkili genetik özelliklerin hastalık fenotipine etkisinin araştırılması
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Tarih
2020
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Aksaray Üniversitesi Fen Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Astım, çocukluk çağının en sık görülen inflamatuar hastalığıdır. Astımın gelişiminde genetik, çevresel risk faktörleri ve epigenetik mekanizmalar birlikte rol oynamaktadır. Bu çalışmada GWAS (Genom Çapı İlişkilendirme Çalışmaları) ile doğrulanan 7 genetik lokusun (IL18R1 rs3771166, IL33 rs1342326, SMAD3 rs744910, GSDMA rs3894194, IL2RB rs2284033, ORMDL3/GSDMB rs2305480 ve RAD50 rs6871536) çocukluk çağı astımı ile ilişkisi araştırılmıştır. Çalışma kapsamında ISAAC (Çocuklarda Astım ve Alerjiler Uluslararası Çalışması) Faz II anketi ile değerlendirilen bireylere ait DNA örnekleri (n=920) KASP (Kompetatif Allel-Spesifik PCR) yöntemi kullanılarak genotiplenmiştir. Sonuçlar, Türk pediatrik gruba ait 114 farklı klinik ve kişisel karakteristikler kullanılarak değerlendirilmiştir. Tek varyantilişki analizi rs6871536, rs2284033, rs2305480 varyantlarının astımla ilişkili fenotipler için risk faktörü olduğunu göstermiştir. Verilerin PheWAS analizi ile genetik özelliklerden 6'sının (IL33 rs1342326 hariç) 44 farklı astım fenotipi ile ilişkili olduğu belirlenmiştir. Genotip-Doku İfadesi (Genotype-Tissue Expression) analizi ile alellerin astım ve akciğer fonksiyonları ile ilişkili dokular dahil 48 farklı dokuda gen ifadesi üzerine etkisi araştırılmış, bakılan genetik özelliklerin genom çapı öneme sahip 237 eQTL ile ilişkili olduğu ve birçok genin transkripsiyonel regülasyonunu etkilediği belirlenmiştir. Genetik özelliklerin poligenik etkisini belirlemek amacıyla PRS (Poligenik Risk Skoru) hesaplanmış, RAD50 rs6871536 ve IL2RB rs2284033 arasında kombine etki gözlenmiştir. Bu araştırmanın sonuçları astım ve onların komorbiditelerine ilişkin yeni veriler ortaya koymakta, astım ile ilişkili lokusların genetik karakterizasyonuna dair bilgiler sağlamaktadır. Anahtar Kelimeler: Astım fenotipleri, Astım genetiği, PheWAS, GTEx, Genotipfenotip korelasyonu.
Asthma is the most common inflammatory disease of childhood. Genetic- epigenetic mechanisms and environmental risk factors have the main role in disease development. In this study GWAS (Genome-Wide Association Studies) confirmed 7 genetic loci (IL18R1 rs3771166, IL33 rs1342326, SMAD3 rs744910, GSDMA rs3894194, IL2RB rs2284033, ORMDL3/GSDMB rs2305480 and RAD50 rs6871536) were investigated for their relationship with childhood asthma. Distribution of the risk alleles was genotyped by KASP (Competitive Allele-Specific PCR) technology, in individuals (n=920), selected with ISAAC (International Study on Asthma and Allergies in Children) Phase II questionnaire. Results were evaluated using 114 different clinical and personal characteristics of the Turkish pediatric group. According to the results of single variant-association analysis; rs6871536, rs2284033, rs2305480 variants were found to be risk factors for asthma-related phenotypes. PheWAS (Phenome Wide Association Study) analysis revealed 44 different phenotypic associations for 6 of investigated variants (except IL33 rs1342326). GTEx (Genotype-Tissue Expression) data were used to determine the effect of investigated alleles on gene expression in 48 different tissues, relevant for asthma and lung function. It was observed that the investigated loci associated with 237 eQTL and affect the transcriptional regulation of many genes. A PRS (Polygenic Risk Score) was calculated to determine the combined effect of genetic variants and, the interaction was observed between RAD50 rs6871536 and IL2RB rs2284033. This study generated novel data regarding the genetics of asthma and its comorbidities, providing a genetic characterization of loci associated with asthma. Key Words: Asthma phenotypes, Asthma genetics, PheWAS, GTEx, Genotypephenotype correlation.
Asthma is the most common inflammatory disease of childhood. Genetic- epigenetic mechanisms and environmental risk factors have the main role in disease development. In this study GWAS (Genome-Wide Association Studies) confirmed 7 genetic loci (IL18R1 rs3771166, IL33 rs1342326, SMAD3 rs744910, GSDMA rs3894194, IL2RB rs2284033, ORMDL3/GSDMB rs2305480 and RAD50 rs6871536) were investigated for their relationship with childhood asthma. Distribution of the risk alleles was genotyped by KASP (Competitive Allele-Specific PCR) technology, in individuals (n=920), selected with ISAAC (International Study on Asthma and Allergies in Children) Phase II questionnaire. Results were evaluated using 114 different clinical and personal characteristics of the Turkish pediatric group. According to the results of single variant-association analysis; rs6871536, rs2284033, rs2305480 variants were found to be risk factors for asthma-related phenotypes. PheWAS (Phenome Wide Association Study) analysis revealed 44 different phenotypic associations for 6 of investigated variants (except IL33 rs1342326). GTEx (Genotype-Tissue Expression) data were used to determine the effect of investigated alleles on gene expression in 48 different tissues, relevant for asthma and lung function. It was observed that the investigated loci associated with 237 eQTL and affect the transcriptional regulation of many genes. A PRS (Polygenic Risk Score) was calculated to determine the combined effect of genetic variants and, the interaction was observed between RAD50 rs6871536 and IL2RB rs2284033. This study generated novel data regarding the genetics of asthma and its comorbidities, providing a genetic characterization of loci associated with asthma. Key Words: Asthma phenotypes, Asthma genetics, PheWAS, GTEx, Genotypephenotype correlation.
Açıklama
Anahtar Kelimeler
Astım Fenotipleri, Astım Genetiği, PheWAS, GTEx, Genotip-Fenotip Korelasyonu
