Povezanost endotoksina i polimorfizma gena za CD14 i TLR4 u djece s astmom [The association of endotoxin and polymorphisms in CD14 and TLR4 among children with asthma]

Kljaić Bukvić, Blaženka (2013) Povezanost endotoksina i polimorfizma gena za CD14 i TLR4 u djece s astmom [The association of endotoxin and polymorphisms in CD14 and TLR4 among children with asthma]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Background: According to the hygiene hypothesis prenatal and early postnatal exposure to environmental endotoxin may be protective against atopy and asthma development (by inducing Th1 type immune response). However, various studies have reported contradictory results. The pathway of endotoxin response involves a complex of innate immunity receptors (CD14, MD2 i TLR4). Genetic variants in CD14, TLR4 and MD2 genes may modify the relationship between endotoxin exposure and asthma Aim: We investigated risk factors for asthma and impact of environmental exposures (endotoxin and house dust mite) on asthma. We evaluated associations between genetic variants in CD14, MD2 and TLR4. In addition, we assesed the effect of endotoxin exposure in the contex of genetic variants. Methods: The study included 837 children 5-18 years old (423 children with asthma and 414 non-asthmatic controls). Data were collected using standardised questionairre. Sensitization was determined by skin prick testing. Dust samples were collected from the child’s mattress, where we measured the endotoxin load (using the Limulus amebocyte lysate test) and Der p1 concentration (using ELISA). We genotyped five variants in CD14 gene, nine in MD2 gene and sixteen in TLR4 by use of mass spectrometry. Results: An increased asthma risk was associated with family history of allergic disease, home dampness, atopy and specific sensitization. Endotoxin exposure was found to have a protective effect against asthma, whereas no such effect was recorded for house dust mite. We found no associations between genetic variants in CD14 and asthma. There were no significant interactions with endotoxin either. Association with asthma was found for variants in MD2 (rs1178659, rs1991262, rs7822407 i rs7838017) and TLR4 (rs1927907 i rs11536889). We observed significant interactions between 4 SNPs in MD2 (rs7822054, rs7822407, rs7838017 i rs11786591), 1 SNP in TLR4 (rs11536889) and endotoxin exposure in relation to asthma. Conclusion: Environmental endotoxin exposure has an important role in pathogenesis of childhood asthma. Genetic variants in the MD2 and TLR4 modify the relationship between endotoxin exposure and asthma.

Abstract in Croatian

Uvod: Prema higijenskoj hipotezi prenatalno i rano postneonatalno izlaganje endotoksinu može usmjeriti imunološke reakcije u Th1-smjeru i prevenirati razvoj i astme. Međutim, rezultati istraživanja su proturječni. Endotoksin svoj učinak atopije ostvaruje vezanjem za receptore prirođene imunosti (CD14, MD2 i TLR4), a varijabilnost njihovih gena u međudjelovanju s okolišnim endotoksinom, mijenja klinički fenotip. Cilj: Istražili smo rizične činitelje i utjecaj endotoksina i alergena Der p1 na astmu. Proučena je povezanost varijabilnosti gena za CD14, MD2 i TLR4 kao i međudjelovanje s endotoksinom na astmu. Metode: Istraživanje je obuhvatilo 837 djece dobi od 5-18 godina (423 djece s astmom, 414 zdravih kontrola). Svim ispitanicima prikupljeni su podaci prema standardiziranom upitniku i učinjen im je kožni ubodni test. Iz madraca dječjih spavaonica uzeti su uzorci prašine u kojima je izmjerena koncentracija endotoksina (primjenom Limulus amebocyte lysate testa) i koncentracija Der p1 (primjenom ELISA). Genotipizirali smo pet polimorfizama gena CD14, devet gena MD2 i šestnaest gena TLR4 primjenom spektrometrije masa. Rezultati: Rizik za astmu su povećavale alergijske bolesti u obitelji, vlažnost doma, atopija i specifična senzibilizacija. Izloženost endotoksinu djelovala je zaštitno na astmu, dok koncentracija alergena grinje u okolini nije pokazala utjecaj. Za polimorfizme gena CD14, kao i za međudjelovanje s endotoksinom nije uočena povezanost s astmom. Polimorfizmi gena MD2 (rs1178659, rs1991262, rs7822407 i rs7838017) i gena TLR4 (rs1927907 i rs11536889) su bili povezani s astmom. Statistički značajno međudjelovanje s endotoksinom uočeno je za polimorfizme MD2 (rs7822054, rs7822407, rs7838017 i rs11786591) i TLR4 (rs11536889). Zaključak: Okolišni endotoksin ima značajnu ulogu u patogenezi astme dječje dobi. Međutim, varijabilnost gena MD2 i TLR4 modificira učinak izloženosti endotoksinu.

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