Analysis of MTNR1B gene polymorphisms in relationship with IRS2 gene variants, epicardial fat thickness, glucose homeostasis and cognitive performance in the elderly

ABSTARCT

Genome-wide association studies pinpointed common variants in or near the MTNR1B gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. IRS2 gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between MTNR1B and IRS2 gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of IRS2 gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that MTNR1B and IRS2 gene variants impacted EF thickness, lipid profile and glucose homeostasis. IRS2 but not MTNR1B variants impacted MMSE scores. In conclusion, MTNR1B SNPs interact with IRS2 gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk.

KEYWORDS:

• Melatonin
• MTNR1B
• IRS2
• epicardial fat
• cognition
• aging
• metabolism

Acknowledgments

The authors are grateful to the patients that each volunteered to participate in this study and to Francesco Sera for statistical analysis assistance.

Declaration of interest

There is no conflict of interest to declare in relationship to this article.

Funding

This work was supported by the “5x1000” voluntary contribution, and by a grant (GM) from the Italian Ministry of Health through Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit (RC1203ME46, RC1302ME31, RC1403ME50, RC1504ME53, RC1603ME43 and RC1703ME43), IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.

Additional information

Funding

This work was supported by the “5x1000” voluntary contribution, and by a grant (GM) from the Italian Ministry of Health through Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit (RC1203ME46, RC1302ME31, RC1403ME50, RC1504ME53, RC1603ME43 and RC1703ME43), IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.

Notes on contributors

Gianluigi Mazzoccoli

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Mariangela Pia Dagostino

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Giulia Paroni

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Davide Seripa

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Filomena Ciccone

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Filomena Addante

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Giovanni Favuzzi

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Elvira Grandone

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Roberto Avola

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Tommaso Mazza

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Caterina Fusilli

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Antonio Greco

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.

Salvatore De Cosmo

G.M., A.G., S.D.C. and M.P.D. conception and design of research; M.P.D. performed echocardiography; F.A. and F.C. administered MMSE; D.S., G.F. E.G. and G.P. performed genetic analysis; T.M., C.F., R.A. and G.M. analyzed data; T.M., C.F., G.M., R.A. A.G., and S.D.C. interpreted results of experiments; G.M., D.S. and A.G. drafted the manuscript; G.M., T.M., C.F. and G.P. prepared figures; G.P., D.S., F.A. and F.C. edited and revised the manuscript. All authors approved the final version of the manuscript.