title: Vitamin D receptor gene polymorphisms are associated with obesity and inflammosome activity.
abstract: To explore the mechanisms underlying the suggested role of the vitamin D/vitamin D receptor (VDR) complex in the pathogenesis of obesity we performed genetic and immunologic analyses in obese and non-obese Saudi individuals without other concomitant chronic diseases. Genomic DNA was genotyped for gene single nucleotide polymorphisms (SNPs) of VDR by allelic discrimination in 402 obese (body mass index -BMI≥30 kg/m2) and 489 non-obese (BMI<30 kg/m2) Saudis. Q-PCR analyses were performed using an ABI Prism 7000 Sequence Detection System. The inflammosome pathway was analysed by PCR, cytokines and plasma lipopolysaccaride (LPS) concentrations with ELISA assays. Results showed that the VDR SNPs rs731236 (G) (TaqI) and rs1544410 (T) (Bsm-I) minor allele polymorphisms are significantly more frequent in obese individuals (p = 0.009, β = 0.086 and p = 0.028, β = 0.072, respectively). VDR haplotypes identified are positively (GTA) (p = 0.008, β = 1.560); or negatively (ACC) (p = 0.044, β = 0.766) associated with obesity and higher BMI scores. The GTA "risk" haplotype was characterized by an up-regulation of inflammosome components, a higher production of proinflammatory cytokines (p<0.05) and a lower VDR expression. Plasma LPS concentration was also increased in GTA obese individuals (p<0.05), suggesting an alteration of gut permeability leading to microbial translocation. Data herein indicate that polymorphisms affecting the vitamin D/VDR axis play a role in obesity that is associated with an ongoing degree of inflammation, possibly resulting from alterations of gut permeability and microbial translocation. These results could help the definition of VDR fingerprints that predict an increased risk of developing obesity and might contribute to the identification of novel therapeutic strategies for this metabolic condition.
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA); Prince Mutaib Chair for Biomarkers of Osteoporosis, College of Science, King Saud University, Riyadh, KSA; Center of Excellence in Biotechnology Research, King Saud University, Riyadh, KSA.
authors.forename: Nasser M
authors.initials: NM
authors.lastname: Al-Daghri
authors.affiliation: Don Gnocchi Foundation, ONLUS, Milano and Università degli Studi di Milano, Milano, Italy.
authors.forename: Franca R
authors.initials: FR
authors.lastname: Guerini
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA); Prince Mutaib Chair for Biomarkers of Osteoporosis, College of Science, King Saud University, Riyadh, KSA; Center of Excellence in Biotechnology Research, King Saud University, Riyadh, KSA.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Al-Attas
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA); Prince Mutaib Chair for Biomarkers of Osteoporosis, College of Science, King Saud University, Riyadh, KSA; Center of Excellence in Biotechnology Research, King Saud University, Riyadh, KSA.
authors.forename: Majed S
authors.initials: MS
authors.lastname: Alokail
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA); Prince Mutaib Chair for Biomarkers of Osteoporosis, College of Science, King Saud University, Riyadh, KSA; Clinical Pharmacy Department, College of Pharmacy, King Saud University, Riyadh, KSA.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA); INRS-Institute Armand Frappier, University of Quebec, Laval, Quebec, Canada.
authors.forename: Hossam M
authors.initials: HM
authors.lastname: Draz
authors.affiliation: Don Gnocchi Foundation, ONLUS, Milano and Università degli Studi di Milano, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Agliardi
authors.affiliation: Don Gnocchi Foundation, ONLUS, Milano and Università degli Studi di Milano, Milano, Italy.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Costa
authors.affiliation: Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Saulle
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA).
authors.forename: Abdul Khader
authors.initials: AK
authors.lastname: Mohammed
authors.affiliation: Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia (KSA); Don Gnocchi Foundation, ONLUS, Milano and Università degli Studi di Milano, Milano, Italy; Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D018912:Arabs / Q000235:genetics*; D001483:Base Sequence; D015992:Body Mass Index; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D008070:Lipopolysaccharides / Q000097:blood; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol