Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

// Laura Bertoccini 1 , Diego Bailetti 1 , SUMMER Study in Diabetes Group * , Raffaella Buzzetti 1 , Maria Gisella Cavallo 1 , Massimiliano Copetti 2 , Efisio Cossu 3 , Paola D'Angelo 4 , Salvatore De Cosmo 5 , Lazzaro Di Mauro 6 , Frida Leonetti 1 , Susanna Morano 1 , Lelio Morviducci 7 , Nicola Napoli 8 , Sabrina Prudente 9 , Giuseppe Pugliese 10 , Vincenzo Trischitta 1, 9 and Marco Giorgio Baroni 1 1 Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy 2 Unit of Biostatistics, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 3 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy 4 Unit of Diabetology, Sandro Pertini Hospital, Rome, Italy 5 IRCSS Casa Sollievo della Sofferenza, Department of Medicine, San Giovanni Rotondo, Italy 6 Laboratory of Clinical Chemistry, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 7 Unit of Diabetology, S. Spirito Hospital – AslRM1, Rome, Italy 8 Campus Biomedico University, Rome, Italy 9 IRCCS Casa Sollievo della Sofferenza, Research Unit of Metabolic and Cardiovascular Diseases, San Giovanni Rotondo, Italy 10 Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy * The Investigators of the “Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes” Study Group are: Elena Alessi 10 , Francesco Bagella 1 , Ilaria Barchetta 1 , Danila Capoccia 1 , Silvia Carletti 4 , Federica Coccia 1 , Francesco Conti 9 , Luca D'Onofrio 1 , Tiziana Filardi 1 , Giulia Leanza 8 , Gianluca Margiotta 1 , Michela Incani 3 , Chiara Moretti 1 , Serena Pezzilli 9 , Carlotta Pibiri 1 , Pamela Piscitelli 5 , Maria Giovanna Scarale 2 , Federica Sentinelli 1 , Federica Tavaglione 1 Correspondence to: Marco Giorgio Baroni, email: marco.baroni@uniroma1.it Keywords: genetic risk score; DHCR7 (7-dehydrocholesterol reductase); CYP2R1 (Cytochrome P450 Family 2 Subfamily R Member 1); GC (Vitamin D Binding Protein); SUMMER Study in Diabetes Received: July 18, 2018 Accepted: September 17, 2018 Published: October 09, 2018 ABSTRACT Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism ( DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the “Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes”. Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 ( p = 1 x 10 –4 ) and GC rs4588 ( p = 1 x 10 –6 ) but not CYP2R1 rs10741657 ( p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels ( p = 1.1 x 10 –11 ) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16–1.41, p = 1.1 x 10 –7 ). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D.