The major circadian pacemaker ARNT-like protein-1 (BMAL1) is associated with susceptibility to gestational diabetes mellitus Kalliopi I. Pappa a,b, *, Maria Gazouli b , Eleni Anastasiou c , Zoe Iliodromiti d , Aristides Antsaklis a , Nicholas P. Anagnou b a First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Athens, Greece b Department of Basic Medical Sciences, Laboratory of Biology, University of Athens School of Medicine and Laboratory of Cell and Gene Therapy, Biomedical Research Foundation of the Academy of Athens, Athens, Greece c Department of Internal Medicine, First Endocrine Section and Diabetes Centre, Alexandra Hospital, Athens, Greece d Second Department of Obstetrics and Gynecology, University of Athens School of Medicine, Athens, Greece 1. Introduction Gestational diabetes mellitus (GDM) is defined as glucose intolerance that is first diagnosed during pregnancy [1]. GDM occurs in about 2–5% of all pregnancies, following failure of insulin secretion to overcome the additive effect of insulin resistance, which usually develops during GDM pregnancy [2]. However, the prevalence varies among populations [3]. It is d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 9 9 ( 2 0 1 3 ) 1 5 1 – 1 5 7 a r t i c l e i n f o Article history: Received 16 July 2012 Received in revised form 18 September 2012 Accepted 5 October 2012 Published on line 1 December 2012 Keywords: Gestational diabetes mellitus BMAL1 Clock genes Circadian rhythm Type 2 diabetes a b s t r a c t Aims: Recently a relationship between circadian clock function and the risk for type 2 diabetes (T2D) has been shown. BMAL1 is a key component of the mammalian molecular clock. Two SNPs in the BMAL1 gene have been identified to confer T2D susceptibility. In the present study we investigated for the first time the association between the BMAL1 gene and the risk for GDM, in a Greek population. Methods: We studied 185 women with GDM and 161 non-diabetic controls for BMAL1 polymorphisms. For BMAL1 mRNA expression, peripheral leukocytes were harvested from 20 GDM and 20 control women, harboring different genotypes for the tested polymorphisms, using real-time quantitative PCR. Results: The minor allele (A) of the BMAL1 rs7950226 (G > A) polymorphism was found to be significantly associated with an increased risk of GDM (P = 0.025). Analysis of the second BMAL1 rs11022775 (T > C) polymorphism, showed that the C-allele frequency was strongly increased in women with GDM (P = 4.455eÀ06). The CC genotype was also significantly overrepresented in GDM vs. controls (P = 0.00001). Additionally, the rs7950226G/rs11022775C and rs7950226A/rs11022775C haplotypes were also found to be associated with increased susceptibility to GDM. Furthermore, the expression levels of BMAL1 mRNA were signifi- cantly lower in GDM patients than in controls. Conclusion: These data suggest that the impairment of the BMAL1 clock gene expression is closely associated with GDM susceptibility. # 2012 Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Athens, Greece. Tel.: +30 210 746 2356; fax: +30 210 746 2412. E-mail address: kpappa@med.uoa.gr (K.I. Pappa). Contents available at Sciverse ScienceDirect Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres 0168-8227/$ – see front matter # 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2012.10.015