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Diabet Med. 2011 Nov;28(11):1373-80. doi: 10.1111/j.1464-5491.2011.03374.x.

Association and evolutionary studies of the melatonin receptor 1B gene (MTNR1B) in the self-contained population of Sorbs from Germany.

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1
Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.

Abstract

AIMS:

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.

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