Genetic predisposition to nonsyndromic orofacial clefts
Date
2011-07-21
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Abstract
Mittesündroomsete suulõhede geneetilise tausta uuringus teostati assotsiatsioonanalüüsid 590 SNPga, mis valiti 40 kraniofatsiaalses morfogeneesis ja palatogeneesis osalevast kandidaatgeenist. Uuringurühma moodustasid 404 huulelõhe ning huule- ja suulaelõhega (CL/P) või suulaelõhega (CP) patsienti ning 606 populatsioonipõhist kontrollindiviidi Eesti, Läti ja Leedu populatsioonist. Mainitud kolme populatsiooni geneetiline lähedus on leidnud veenvat kinnitust PCA meetodiga. Käesolevas töös näitasime, et FGF1, FOXE1, TIMP2 ja WNT9B geenide järjestuse variandid on seotud mittesündroomse CL/P ning COL2A1, COL11A2, IRF6 ja WNT3 geenide järjestuse variandid on seotud mittesündroomse CP geneetilise eelsoodumusega Eesti, Läti ja Leedu ühendpopulatsioonis. Lisaks replitseerisime GWAS uuringutes kirjeldatud genoomselt tähendusrikkad assotsiatsioonid 8q24.21 ja 10q25.3 kromosoomilookuste ning CL/P vahel Eesti populatsioonis ning näitasime, et MSX1 ja MTHFR geenide järjestuse variandid on seotud mittesündroomse CL/P geneetilise eelsoodumusega Eesti populatsioonis.
Saadud tulemused annavad tõendust FGF ja Wnt signaalradades osalevate geenide olulisusele nii CL/P kui ka CP etioloogias ning näitavad geen-geen interaktsioonide tähtsust suulõhede patogeneesis. Suurem osa mittesündroomsete suulõhede geneetilisest taustast on siiani avastamata ning uueks väljakutseks on läbi viia eelpoolkirjeldatud regioonide detailne geneetiline kaardistamine tegelike riskiseoseliste variantide funktsionaalsete efektide kindlakstegemiseks ning kraniofatsiaalses patoloogias osalevate erinevate signaalradade molekulaarsete mehhanismide täpsemaks selgitamiseks. Sellised suuremahulised resekveneerimisuuringud annavad parimaid tulemusi uurimiskeskuste ja biopankade rahvusvahelises koostöös, kus on kaasatud täpselt määratletud fenotüübiga patsientide kohordid ning suured kontrollindiviidide rühmad erineva etnilise taustaga populatsioonides.
In order to describe the genetic determinants of nonsyndromic orofacial clefting we analyzed 590 haplotype-tagging SNPs in 40 candidate genes in a previously uncharacterized clefting sample from North-Eastern Europe which included Estonians, Latvians and Lithuanians. The genetic relatedness of these three populations has been confirmed using the principal component analysis. The study sample was comprised of 404 patients and 606 population-based controls. We demonstrated that variation in FGF1, FOXE1, TIMP2, and WNT9B genes contributes susceptibility to nonsyndromic cleft lip with or without cleft palate (CL/P) and variation in COL2A1, COL11A2, IRF6, and WNT3 genes contributes susceptibility to nonsyndromic cleft palate in Estonians, Latvians and Lithuanians. In a follow-up study of the reported genome-wide significant associations from recent GWA studies we replicated associations between 8q24.21 and 10q25.3 locus and CL/P in an Estonian case-control sample. Our results also show that genetic variants in MSX1 and MTHFR genes contribute risk to nonsyndromic CL/P in Estonians. In addition, our results underline the importance of the FGF and Wnt signaling pathway genes in the etiology of both CL/P and CP, and pinpoint the importance of gene-gene interactions in the development of clefts. The majority of genetic variants predisposing to nonsyndromic oral clefts are yet to be discovered and larger samples from different ethnicities and precisely phenotyped cohorts of patients are required for comprehensive sequencing-based studies of the above-mentioned regions which are targeting in addition to common SNPs also rare single nucleotide variants to account for more of the ‘missing’ heritability. The most benefitial approach in these studies will be collaboration between clefting research centers and population-based biobanks.
In order to describe the genetic determinants of nonsyndromic orofacial clefting we analyzed 590 haplotype-tagging SNPs in 40 candidate genes in a previously uncharacterized clefting sample from North-Eastern Europe which included Estonians, Latvians and Lithuanians. The genetic relatedness of these three populations has been confirmed using the principal component analysis. The study sample was comprised of 404 patients and 606 population-based controls. We demonstrated that variation in FGF1, FOXE1, TIMP2, and WNT9B genes contributes susceptibility to nonsyndromic cleft lip with or without cleft palate (CL/P) and variation in COL2A1, COL11A2, IRF6, and WNT3 genes contributes susceptibility to nonsyndromic cleft palate in Estonians, Latvians and Lithuanians. In a follow-up study of the reported genome-wide significant associations from recent GWA studies we replicated associations between 8q24.21 and 10q25.3 locus and CL/P in an Estonian case-control sample. Our results also show that genetic variants in MSX1 and MTHFR genes contribute risk to nonsyndromic CL/P in Estonians. In addition, our results underline the importance of the FGF and Wnt signaling pathway genes in the etiology of both CL/P and CP, and pinpoint the importance of gene-gene interactions in the development of clefts. The majority of genetic variants predisposing to nonsyndromic oral clefts are yet to be discovered and larger samples from different ethnicities and precisely phenotyped cohorts of patients are required for comprehensive sequencing-based studies of the above-mentioned regions which are targeting in addition to common SNPs also rare single nucleotide variants to account for more of the ‘missing’ heritability. The most benefitial approach in these studies will be collaboration between clefting research centers and population-based biobanks.
Description
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Keywords
suulaelõhe, pärilikud haigused, populatsioonigeneetika, Baltimaad, cleft palate, hereditary diseases, population genetics, Baltic states