Allele-Specific, Age-Dependent and BMI-Associated DNA Methylation of Human MCHR1 英文参考文献.docVIP

Allele-Specific, Age-Dependent and BMI-Associated DNA Methylation of Human MCHR1 英文参考文献.doc

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Allele-Specific, Age-Dependent and BMI-Associated DNA Methylation of Human MCHR1 英文参考文献

Allele-Specific,Age-DependentandBMI-AssociatedDNA MethylationofHumanMCHR1 StefanieStepanow1*,KathrinReichwald1,KlausHuse1,UlrikeGausmann1,AlmutNebel2 ,Philip Rosenstiel2,MartinWabitsch3,PamelaFischer-Posovszky3,MatthiasPlatzer1 1GenomeAnalysis,LeibnizInstituteforAgeResearch–FritzLipmannInstitute,Jena,Germany,2InstituteofClinicalMolecularBiology,Christian-Albrechts-University,Kiel, Germany,3DepartmentofPediatricsandAdolescentMedicine,UniversityofUlm,Ulm,Germany Abstract Background:Melanin-concentratinghormonereceptor1(MCHR1)playsasignificantroleinregulationofenergybalance, food intake, physical activity and body weight in humans and rodents. Several association studies for human obesity showedcontraryresultsconcerningtheSNPsrs133072(G/A)andrs133073(T/C),whichlocalizetothefirstexonofMCHR1. The variations constitute two main haplotypes (GT, AC). Both SNPs affect CpG dinucleotides, whereby each haplotype containsapotentialmethylationsiteatoneofthetwoSNPpositions.Inaddition,15CpGsinclosevicinityoftheseSNPs constitute a weak CpG island. Here, we studied whether DNA methylation in this sequence context may contribute to population-andage-specificeffectsofMCHR1allelesinobesity. PrincipalFindings:WeanalyzedDNAmethylationofa315bpregionofMCHR1encompassingrs133072andrs133073and theCpGislandinbloodsamplesof49individualsbybisulfitesequencing.TheAChaplotypeshowsasignificantlyhigher methylation level than the GT haplotype. This allele-specific methylation is age-dependent. In young individuals (20–30 years)thedifferenceinDNAmethylationbetweenhaplotypesissignificant;whereasinindividualsolderthan60yearsitis not detectable. Interestingly, the GT allele shows a decrease in methylation status with increasing BMI, whereas the methylationoftheACalleleisnotassociatedwiththisphenotype.Heterozygouslymphoblastoidcelllinesshowthesame patternofallele-specificDNAmethylation.Thecellline,whichexhibitsthehighestdifferenceinmethylationlevelsbetween both haplotypes, also shows allele-specific trans

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