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Polycystic ovarian syndrome (PCOS) is a genetically complex disorder that involves the interplay of multiple genes and environmental factors. It is characterized by anovulation and irregular menses and is associated with type 2 diabetes. Neuroendocrine pathways and ovarian and adrenal dysfunctions are possibly implicated in the disorder pathogenesis. The melatonin system plays a role in PCOS. Melatonin receptors are expressed on the surface of ovarian granulosa cells, and variations in the melatonin receptor genes have been associated with increased risk of PCOS in both familial and sporadic cases. We have recently reported the association of variants in MTNR1A and MTNR1B genes with familial type 2 diabetes. In this study, we aimed to investigate whether MTNR1A and MTNR1B contribute to PCOS risk in peninsular families. In 212 Italian families phenotyped for PCOS, we amplified by microarray 14 variants in the MTNR1A gene and 6 variants in the MTNR1B gene and tested them for linkage and linkage disequilibrium with PCOS. We detected 4 variants in the MTNR1A gene and 2 variants in the MTNR1B gene significantly linked and/or in linkage disequilibrium with the risk of PCOS (P < 0.05). All variants are novel and have not been reported before with PCOS or any of its related phenotypes, except for 3 variants previously reported by us to confer risk for type 2 diabetes and 1 variant for type 2 diabetes-depression comorbidity. These findings implicate novel melatonin receptor genes' variants in the risk of PCOS with potential functional roles. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate whether single‐nucleotide polymorphisms (SNPs) in the genes encoding 5‐HTR2A (5‐Hydroxytryptamine (serotonin) receptor 2A) and MTNR1A (melatonin receptor 1A) may contribute to postoperative pain perception after root canal treatment. We hypothesised that SNPs in HTR2A and MTNR1A genes were associated with postoperative pain after root canal treatment. Methodology: This genetic cohort study enrolled patients with single‐rooted teeth diagnosed with pulp necrosis and asymptomatic apical periodontitis before root canal treatment. Root canal treatment was performed in one session using a standardized protocol. Postoperative pain and tenderness were assessed using a visual analogue scale (recorded every day for 7 days and on the 14th and 30th days after root canal treatment). Genomic DNA was extracted from saliva and used to genotype the SNPs in HTR2A (rs4941573 and rs6313) and MTNR1A (rs6553010, rs6847693 and rs13140012) using real‐time polymerase chain reaction. Genotypes were compared using univariate and multivariate Poisson regression with generalized estimating equations (p <.05). Results: In total, 108 patients were enrolled in this study. The SNPs rs6553010 (MTNR1A), rs4941573 and rs6313 (HTR2A) were associated with an increased risk of developing pain after root canal treatment (p <.05). Conclusions: This study suggests that SNPs in HTR2A and MTNR1A influence pain response after root canal treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this research was to study the effect of MTNR1A gene polymorphisms on the reproductive performance of two Mediterranean sheep breeds. A total of 26 SNPs were found, and three SNPs caused amino acid changes. Two SNPs were totally linked and correlated with reproductive activity resumption. This study consists of a piece of new useful knowledge for the control of sheep reproductive seasonality and farm management that could improve genetic selection, especially in countries where agriculture relies mainly on sheep farming. Sheep farming plays an important economic role, and it contributes to the livelihoods of many rural poor in several regions worldwide and particularly in Tunisia. Therefore, the steady improvement of ewes' reproductive performance is a pressing need. The MTNR1A gene has been identified as an important candidate gene that plays a key role in sheep reproduction and its sexual inactivity. It is involved in the control of photoperiod-induced seasonality mediated by melatonin secretion. The aim of this study was to identify SNPs in the MTNR1A gene in two Tunisian breeds, Barbarine (B) and Queue Fine de l'Ouest (QFO). DNA extracted from the blood of 77 adult ewes was sequenced. Selected ewes were exposed to adult fertile rams. A total of 26 SNPs were detected; 15 SNPs in the promoter region and 11 SNPs in the exon II were observed in both (B) and (QFO) breeds. The SNP rs602330706 in exon II is a novel SNP detected for the first time only in the (B) breed. The SNPs rs430181568 and rs40738822721 (SNP18 and SNP20 in our study, respectively) were totally linked in this study and can be considered a single marker. DTL was associated with SNP18 and SNP20 in (B) ewes (p < 0.05); however, no significant difference was detected between the three genotypes (G/G, G/A, and A/A) at these two SNPs. Fertility rate and litter size parameters were not affected by SNP18 and SNP20. There was an association between these two polymorphisms and (B) lambs' birth weights (p < 0.05). Furthermore, the ewes with the A/A genotype gave birth to lambs with a higher weight compared to the other two genotypes for this breed (p < 0.05). There was not an association between SNP 18 and SNP20 and (QFO) ewes' reproductive parameters. These results might be considered in future sheep selection programs for reproductive genetic improvement. [ABSTRACT FROM AUTHOR]

Primary brain tumors remain among the deadliest of all cancers. Glioma grade IV (glioblastoma), the most common and malignant type of brain cancer, is associated with a 5-year survival rate of < 5%. Melatonin has been widely reported as an anticancer molecule, and we have recently demonstrated that the ability of gliomas to synthesize and accumulate this indolamine in the surrounding microenvironment negatively correlates with tumor malignancy. However, our understanding of the specific effects mediated through the activation of melatonin membrane receptors remains limited. Thus, here we investigated the specific roles of MT1 and MT2 in gliomas and medulloblastomas. Using the MT2 antagonist DH97, we showed that MT1 activation has a negative impact on the proliferation of human glioma and medulloblastoma cell lines, while MT2 activation has an opposite effect. Accordingly, gliomas have a decreased mRNA expression of MT1 (also known as MTNR1A) and an increased mRNA expression of MT2 (also known as MTNR1B) compared to the normal brain cortex. The MT1/MT2 expression ratio negatively correlates with the expression of cell cycle-related genes and is a positive prognostic factor in gliomas. Notably, we showed that functional selective drugs that simultaneously activate MT1 and inhibit MT2 exert robust anti-tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in glioma stem-like cells. Overall, we provided the first evidence regarding the differential roles of MT1 and MT2 in brain tumor progression, highlighting their relevance as druggable targets. Key messages: • MT1 impairs while MT2 promotes the proliferation of glioma and medulloblastoma cell lines. • Gliomas have a decreased expression of MT1 and an increased expression of MT2 compared to normal brain cortex. • Tumors with a high MT1/MT2 expression ratio have significantly better survival rates. • Functional selective drugs that simultaneously activate MT1 and inhibit MT2 downregulate the expression of cell cycle and energy metabolism genes in glioma stem-like cells and exert robust anti-tumor effects in vivo. [ABSTRACT FROM AUTHOR]

Summary: Melatonin is a circadian regulatory hormone with neuroprotective properties. We have previously demonstrated the association of the genetic variant rs12506228 near the melatonin receptor 1A gene (MTNR1A) with intolerance to shift‐work. Furthermore, this variant has been connected to Alzheimer's disease. Because of the previously suggested role of melatonin signalling in foetal neurocognitive and sleep development, we studied here the association of rs12506228 with early development. The study sample comprised 8‐month‐old infants from the Finnish CHILD‐SLEEP birth cohort (n = 1,301). Parental questionnaires assessed socioemotional, communication and motor development, as well as sleep length and night awakenings. The A allele of rs12506228 showed an association with slower socioemotional (p =.025) and communication (p =.0098) development, but no direct association with sleep. However, the association of the Finnish seasons with infant sleep length interacted with rs12506228. Taken together, rs12506228 near MTNR1A, which has been previously linked to adult and elderly traits, is shown here to associate with slower early cognitive development. In addition, these results suggest that the darker seasons associate with longer infant sleep time, but only in the absence of the rs12506228 AA genotype. Because the risk allele has been connected to fewer brain MT1 melatonin receptors, these associations may reflect the influence of decreased melatonin signalling in early development. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a condition in which a woman's levels of the sex hormones (estrogen and progesterone) are out of balance, leading to the growth of ovarian cysts. PCOS can affect the menstrual cycle, fertility, cardiac function and even appearance of women. Therefore, we aimed to explore the genetic polymorphism of the melatonin receptors 1A and 1B in obese patients with PCOS to identify a new theoretical basis for its treatment. Patients presenting with PCOS (n=359) were enrolled and classified into an obese OB-PCOS group [body mass index (BMI) of PCOS patients ≥25 kg/m2] or a nonobese NOB-PCOS group, and 215 oviduct infertile patients who experienced normal ovulation were used as the control group. All baseline characteristics, endocrine hormone levels, lipid and glucose metabolism, and insulin indices were measured. The genotypes of rs2119882 within the MTNR1A gene and of rs10830963 within the MTNR1B gene were determined by PCR-RFLP; the genotype frequency and the difference in the distribution of allele frequency were compared. For rs2119882, C allele carriers who were not diagnosed with PCOS had an increased risk of developing PCOS, and C allele carriers with PCOS had an increased risk of developing OB-PCOS. For rs10830963, G allele carriers who were not diagnosed with PCOS had an increased risk of developing PCOS. The TT genotype in rs2119882 and the CC genotype in rs10830963 were protective factors for OB-PCOS, and increased levels of LH, testosterone, and estradiol and abnormal menstruation were key risk factors for PCOS. Furthermore, the TT genotype at the rs2119882 site was the key protective factor for OB-PCOS patients. Our study found that MTNR1A rs2119882 and MTNR1B rs10830963 could increase the risk for PCOS and cause glycolipid metabolism disorder in PCOS patients. [ABSTRACT FROM AUTHOR]

The water buffalo is a fundamental resource, especially in developing countries, however, differently from other species, its genetic potential is still poorly investigated. In this work, we performed a candidate gene association study for milk composition in 491 female buffaloes. Animals were from four farms located in Southern Italy, where the Out-of-Breeding-Season-Mating technique is usually performed. We analysed three genes: (1) the signal transducer and activator of transcription 5A (STAT5A), (2) the tumour necrosis factor alpha (TNFα) and (3) the melatonin receptor 1A (MTNR1A). We confirmed the mutation at theMTNR1Agene and we found five novel single nucleotide polymorphisms (SNPs): one in theTNFαand four in theSTAT5A. No associations were found for the SNPs in theMTNR1AandTNFαgenes, while we identified a marked association with milk protein % for a C > T substitution at theSTAT5Agene. At thislocus, the TT buffaloes showed significantly higher protein percentage in milk. Conversely, this genotype class was the less frequent in the population. Moreover, an A > G substitution at theSTAT5Ashowed an influence on reproductive seasonality, with the advantageous allele most frequent in the population, suggesting a possible effect of selection for this trait. The C > T substitution onSTAT5Adetected in present study could be used in marker assisted selection of Mediterranean Italian buffalo, and should be monitored to understand the reasons behind the low frequency of the favourable genotype at thislocusand to stop this unfavourable trend in the population. [ABSTRACT FROM PUBLISHER]

Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4+ T cells secreting IFN-γ (TH1) or IL-17 (TH17); and FoxP3+ regulatory T cells and IL-10+ type 1 regulatory T cells (Tr1 cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential. [ABSTRACT FROM AUTHOR]

The melatonin receptor 1A (MTNR1A) and inhibin alpha subunit (INHA) genes play a significant role in the reproductive characteristics of animals. Blood samples were collected from 371 goats (Honamli and Hair) reared in Antalya and Burdur. The polymerase chain reaction (PCR) products were digested by RsaI for the MTNR1A gene and HaeII for the INHA gene. Two alleles (A and G) and three genotypes (AA, AG, and GG) were observed for the INHA gene, while two alleles (R and r) and two genotypes (RR and Rr) were observed for the MTNR1A gene. The highest allelic frequency value for G (91.8%) was found in Honamli goat breeds for the INHA gene while the highest value for R (98.1%) was found in Hair goat breeds for the MTNR1A gene. The GG genotype for the INHA gene and the RR genotype for the MTNR1A gene were identified as the most common genotypes of the Honamli and Hair goat breeds. The rr genotype for the MTNR1A gene could not be determined in the breeds. Both Honamli and Hair goat breeds were in Hardy-Weinberg equilibrium for the genes that were studied. In conclusion, this study confirms the existence of genetic polymorphism in the MTNR1A and INHA genes as detected by PCR-RFLP analysis in Honamli and Hair goat breeds. [ABSTRACT FROM AUTHOR]

Melatonin regulates some major physiological processes such as maturation and function of reproductive system, pubertal development, seasonal reproduction and adaptation. The activation of melatonin hormone is mediated by melatonin receptor. Previous studies showed melatonin receptor 1A gene (MTNR1A) is highly polymorphic in seasonally breeding species. The aim of the present study was detection of MTNR1A polymorphism and its association with production (body weights at birth, 1, 3, 6, 9 and 12 month of age) and reproduction (litter size) traits in Zandi sheep using PCR-RFLP methodology. Hundred blood samples were randomly collected and genomic DNA was isolated using modified salting out method. A large fragment of exon 2 of MTNR1A gene was amplified by PCR using specific primer pairs. After amplification, the PCR product was digested with MnlI endonuclease. Restricted digestion allowed the determination of two alleles (M, m) and two genotypes (MM, Mm) with frequencies of 0.91, 0.09 and 0.82, 0.18, respectively. Least square means showed that MM individuals had higher body weight at one month of age (BW1) than Mm individuals (P<0.05). No associations were found between observed genotypes and other studied traits. In the subsequent studies using a large number of samples along with the other important parameters such as sire effect and the lamb health status which may influence lamb body weight is recommended. [ABSTRACT FROM AUTHOR]

Background/Aims: The purpose of this study was to investigate the association between MTNR1A and MTNR1B gene polymorphisms and gestational diabetes mellitus (GDM) in Han Chinese women. Methods: Study participants included 350 patients with GDM and 480 control subjects. Three single-nucleotide polymorphisms (SNPs; rs2119882 in MTNR1A and rs10830963 and rs10830962 in MTNR1B) were genotyped using direct sequencing. Genotype and allele distributions of SNPs in cases of GDM and controls were analyzed. Association of the MTNR1A and MTNR1B gene variants with plasma glucose and insulin levels as well as blood lipid levels was further investigated. Results: The frequencies of genotypes and allele types of rs2119882 in MTNR1A and rs10830963 in MTNR1B were significantly different between women with GDM and controls (p < 0.05). Moreover, in the GDM group, these SNPs were associated with increased fasting plasma glucose concentrations (p < 0.001) and increased homeostasis model assessment of insulin resistance (p < 0.001). The rs10830962 polymorphism in MTNR1B was not associated with an increased risk of developing GDM or any of the clinical or metabolic characteristics in patients with GDM (p > 0.05). Conclusion: The genetic polymorphisms rs2119882 in MTNR1A and rs10830963 in MTNR1B are associated with an increased risk of developing GDM and insulin resistance in Han Chinese women. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives. Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes ( MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study. Methods. Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes ( MRNR1A, MTNR1B) was then performed for each subject. Results. Four hundred and eighteen inpatients (TD==256, non-TD==162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P==0.037), and the association was also found to be significant by global haplotype analyses (permutation P==0.045). Conclusions. Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated. [ABSTRACT FROM AUTHOR]

The variant red phenotype in Holstein cattle is indistinguishable from the traditional e/e recessive red phenotype caused by a mutation in melanocortin 1 receptor, but is inherited as a dominant trait in relation to black. Co-segregation analysis in four half-sib families segregating for variant red was conducted, excluding melanocortin 1 receptor, agouti signalling protein, attractin and melatonin receptor 1A as causative genes. However, variant red co-segregated with markers in a region of BTA27 that includes beta-defensin 103 ( DEFB103). Two newly identified microsatellites and 5 SNPs 5′ of DEFB103 were used for linkage mapping in four segregating families (LOD = 3.26). One haplotype was inherited in VR cattle in a 6-generation pedigree. [ABSTRACT FROM AUTHOR]

A recent study suggested that the cadherin gene FAT exerts an influence on susceptibility to bipolar affective disorder (BPAD). We aimed to replicate this finding in a German sample (425 BPAD I and 419 controls). In addition, we performed a comprehensive linkage disequilibrium mapping of the whole genomic region of FAT and the neighboring circadian gene MTNR1A (48 single nucleotide polymorphisms (SNPs) covering 191 kb). No significant association was observed for SNPs located in the MTNR1A gene. In FAT, however, nine SNPs showed association, eight of them being located in the same haplotype block found to be associated with BPAD by Blair et al. The smallest P-value of 0.00028 (OR 1.71) was seen for non-synonymous SNP rs2637777. A combination of five markers including this marker showed a haplotype distribution with a nominal P-value of 1.8 × 10−5 that withstands correction for multiple testing. While the control allele frequencies between our sample and the samples of the original study are comparable, tendencies of risk allele frequencies are opposite. Possible explanations for this include potential differences in linkage disequilibrium structure between the German, Australian, UK, and Bulgarian populations sampling variation, multilocus effects and/or the occurrence of independent mutational events. We conclude that our results support an involvement of variation at the FAT gene in the etiology of BPAD, but that further work is needed both to clarify possible reasons for the observed risk allele differences and to ultimately identify the functionally relevant variant(s).Molecular Psychiatry (2008) 13, 277–284; doi:10.1038/sj.mp.4002111; published online 16 October 2007 [ABSTRACT FROM AUTHOR]