The symptomatology of Attention-Deficit/Hyperactivity Disorder and the genetic control of vitamin D levels.

OBJECTIVES: Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes. METHODS: We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software. RESULTS: Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity. DISCUSSION: Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.

Association of CYP2R1 and VDR Polymorphisms with Metabolic Syndrome Components in Non-Diabetic Brazilian Adolescents.

Associations between vitamin D deficiency and metabolic syndrome (MS) have been reported; however, the underlying biological mechanisms remain controversial. The aim of this study was to investigate the associations of CYP2R1 and VDR variants with MS and MS components in non-diabetic Brazilian adolescents. This cross-sectional study included 174 adolescents who were classified as overweight/obese. Three CYP2R1 variants and four VDR variants were identified by allelic discrimination. The CYP2R1 polymorphisms, rs12794714 (GG genotype) (odds ratio [OR] = 3.54, 95% confidence interval [CI] = 1.24-10.14, p = 0.023) and rs10741657 (recessive model-GG genotype) (OR = 3.90, 95%CI = 1.18-12.92, p = 0.026) were significantly associated with an increased risk of MS and hyperglycemia, respectively. The AG + GG genotype (dominant model) of the rs2060793 CYP2R1 polymorphism was associated with hyperglycemia protection (OR = 0.28, 95%CI = 0.08-0.92, p = 0.037). Furthermore, the CC genotype (recessive model) of the rs7975232 VDR polymorphism was significantly associated with a risk of hypertension (OR = 5.91, 95%CI = 1.91-18.32, p = 0.002). In conclusion, the CYP2R1 rs12794714 polymorphism could be considered a possible new molecular marker for predicting the risk of MS; CYP2R1 rs10741657 polymorphism and VDR rs7975232 polymorphism are associated with an increased risk of diabetes and hypertension in adolescents with overweight/obesity.

Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies.

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

Genetic polymorphisms in vitamin D pathway influence 25(OH)D levels and are associated with atopy and asthma.

BACKGROUND: Vitamin D deficiency or insufficiency, has been associated with atopy and lack of asthma control. Our objective was to investigate associations between variants in genes of vitamin D pathway with serum levels of 25-hydroxyvitamin D (25(OH)D), atopy, asthma and asthma severity in teenagers from Northeast Brazil. METHODS: This is a cross sectional study nested in a cohort population of asthma. 25(OH)D was quantified from 968 of 11-17 years old individuals by ELISA. Asthma diagnosis was obtained by using the ISAAC Phase III questionnaire. Specific IgE was determined by ImmunoCAP; genotyping was performed using the 2.5 HumanOmni Biochip from Illumina. Statistical analyses were performed in PLINK 1.07 and SPSS 22.1. RESULTS: After quality control, 104 Single Nucleotides Variants (SNVs) in vitamin D pathway genes, typed in 792 individuals, were included in the analysis. The allele A of rs10875694 on VDR was positively associated with atopy (OR = 1.35; 95% CI 1.01-1.81). The allele C of rs9279 on VDR, was negatively associated with asthma risk (OR = 0.66; 95% CI 0.45-0.97), vitamin D insufficiency (OR = 0.78; 95% CI 0.70-0.96) and higher VDR expression. Two variants in VDR were associated with asthma severity, the allele A of rs2189480 (OR = 0.34; 95% CI 0.13-0.89) and the allele G of rs4328262 (OR = 3.18; 95% CI 1.09-9.28). The combination of variants in CYP2R1 and CYP24A1 (GAC, to rs10500804, rs12794714 and rs3886163, respectively) was negatively associated with vitamin D production (ß = - 1.24; 95% CI - 2.42 to - 0.06). CONCLUSIONS: Genetic variants in the vitamin D pathway affect vitamin D serum levels and, thus, atopy and asthma.