title: Association and evolutionary studies of the melatonin receptor 1B gene (MTNR1B) in the self-contained population of Sorbs from Germany.
abstract: OBJECTIVE
  Several polymorphisms of the melatonin receptor 1B gene (MTNR1B) have been shown to be associated with elevated fasting plasma glucose and impaired early insulin release. The aim of this study was to assess the effects of MTNR1B variants on traits related to the metabolic syndrome in the self-contained population of Sorbs from Germany. As comprehensive studies concerning the conservation of MTNR1B are lacking, we also evaluated natural selection in vertebrates and human populations at this locus.
  
  
  METHODS
  Five single nucleotide polymorphisms representing all blocks of linkage disequilibrium within and surrounding the MTNR1B locus were genotyped in 937 Sorbs for association analyses on metabolic traits related to Type 2 diabetes. The associations were assessed by regression analyses, the conservation between species was investigated with phylogenetic analysis by maximum likelihood (PAML). In addition, various tests of population genetic measures (e.g. fixation index, Tajima's D) were performed.
  
  
  RESULTS
  Previously reported association between MTNR1B variants (rs10830963, rs4753426) and oral glucose tolerance test-derived indices of β-cell function (homeostasis model assessment-B, P = 3.7 × 10⁻⁶ and P = 0.004, respectively), as well as insulin (fasting insulin: P=2×10⁻³ and P=0.02; 30-min insulin: P = 2.1 × 10⁻⁴ and P=0.03, respectively) and fasting glucose (rs10830963, P=1.2×10⁻⁶) parameters could be replicated in the present study. Phylogenetic analysis by maximum likelihood analyses showed that the gene was strongly conserved between species (ω=0.2583). Structures important for the receptor function are also conserved. On the lineage leading to human adaptive selection was present (ω=1.1030). Population genetic measures further indicated natural selection.
  
  
  CONCLUSIONS
  Our data support the physiologic importance of MTNR1B in the context of glucose homeostasis and suggest evidence of selection at this locus.
authors.affiliation: Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Dietrich
authors.forename: S
authors.initials: S
authors.lastname: Birkmeier
authors.forename: D
authors.initials: D
authors.lastname: Schleinitz
authors.forename: J
authors.initials: J
authors.lastname: Breitfeld
authors.forename: B
authors.initials: B
authors.lastname: Enigk
authors.forename: I
authors.initials: I
authors.lastname: Müller
authors.forename: Y
authors.initials: Y
authors.lastname: Böttcher
authors.forename: T
authors.initials: T
authors.lastname: Lindner
authors.forename: M
authors.initials: M
authors.lastname: Stumvoll
authors.forename: A
authors.initials: A
authors.lastname: Tönjes
authors.forename: P
authors.initials: P
authors.lastname: Kovacs
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005858:Germany / Q000453:epidemiology / Q000208:ethnology; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000208:ethnology / Q000235:genetics*; D015810:Linkage Disequilibrium; D024821:Metabolic Syndrome / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D044123:Receptor, Melatonin, MT2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D044123:Receptor, Melatonin, MT2