title: Genome-wide exploration identifies sex-specific genetic effects of alleles upstream NPY to increase the risk of severe periodontitis in men.
abstract: OBJECTIVE
  Periodontitis (PD) is influenced by genetic as well as lifestyle and socio-economic factors. Epidemiological studies show that men are at greater risk of severe forms of PD, suggesting interplay between sex and genetic factors. We aimed to systematically analyse patients with aggressive periodontitis (AgP) for gene-sex interactions.
  
  
  METHODS
  Three hundred and twenty-nine German AgP cases and 983 controls were genotyped with Affymetrix 500K Arrays and were analysed by logistic regression analysis. The most significant gene-sex interaction was replicated in an independent sample of 382 German/Austrian AgP cases and 489 controls.
  
  
  RESULTS
  Ten single-nucleotide polymorphisms (SNPs) in strong linkage disequilibrium (r(2)  > 0.85) upstream the gene neuropeptide Y (NPY) suggested gene-sex interaction (p < 5 × 10(-5) ). SNP rs198712 showed the strongest association in interaction with sex (p = 5.4 × 10(-6) ) with odds ratios in males and females of 1.63 and 0.69 respectively. In the replication, interaction of sex with rs198712 was verified with p = 0.022 (pooled p = 4.03 × 10(-6) ) and similar genetic effects. Analysis of chromatin elements from ENCODE data revealed tissue-specific transcription at the associated non-coding region.
  
  
  CONCLUSIONS
  This study is the first to observe a sexually dimorphic role of alleles at NPY in humans and support previous genome-wide findings of a role of NPY in severe PD.
authors.affiliation: Institute of Medical Informatics and Statistics, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Freitag-Wolf
authors.forename: Henrik
authors.initials: H
authors.lastname: Dommisch
authors.forename: Christian
authors.initials: C
authors.lastname: Graetz
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Jockel-Schneider
authors.forename: Inga
authors.initials: I
authors.lastname: Harks
authors.forename: Ingmar
authors.initials: I
authors.lastname: Staufenbiel
authors.forename: Joerg
authors.initials: J
authors.lastname: Meyle
authors.forename: Peter
authors.initials: P
authors.lastname: Eickholz
authors.forename: Barbara
authors.initials: B
authors.lastname: Noack
authors.forename: Corinna
authors.initials: C
authors.lastname: Bruckmann
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Søren
authors.initials: S
authors.lastname: Jepsen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Inke R
authors.initials: IR
authors.lastname: König
authors.forename: Arne S
authors.initials: AS
authors.lastname: Schaefer
mesh_terms: D000328:Adult; D010520:Aggressive Periodontitis / Q000235:genetics*; D000483:Alleles; D002843:Chromatin / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D012307:Risk Factors; D012727:Sex Characteristics; D012737:Sex Factors; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D009478:Neuropeptide Y; D022661:RNA, Untranslated
keywords: NPY; Periodontitis; genetic association; interaction; sex