Table 1.
Genetic variants with replicating evidence for an association with 25-hydroxyvitamin D concentrations.
| Gene (SNP) | CHR | |
|---|---|---|
| PEX10 (rs6671730) | 1 | PEX10 encodes a protein involved in import of peroxisomal matrix proteins. Mutations in PEX10 gene have led to Zellweger syndrome [40] and osteopenia [41], for which vitamin D supplementation has been the treatment. |
| PADI1 (rs35408430) | 1 | PADI1 encodes an enzyme, which catalyses the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions [42]. Deimination by PADIs occurs during epidermal differentiation [43], with possible influence on skin properties [20]. |
| FOXO6 (rs7522116) | 1 | FOXO6 encodes a protein that has been predicted to enable DNA-binding transcription factor activity, and RNA polymerase related DNA binding activity [44]. FoxO6 expression is downregulated in the brain of dietary obese mice [45]. |
| CELSR2 (rs7528419) | 1 | CELSR2 encodes the cadherin EGF LAG seven-pass G-type receptor 2 that is involved in contact-mediated communication, with cadherin domains acting as homophilic binding regions and the EGF-like domains involved in cell adhesion and receptor-ligand interactions [46]. |
| FLG-AS1 (rs1933064) | 1 | FLG antisense RNA 1 (FLG-AS1) is an RNA Gene that is affiliated with the long non-coding RNA class. Skin pigmentation-related diseases such as Ichthyosis Vulgaris [47] and Peeling Skin Syndrome 6 [48] have been shown to be associated with FLG-AS1. |
| DCST2 (rs76798800) | 1 | DCST2 gene encodes the DC-STAMP domain containing 2 protein that has been shown to be an important regulator of osteoclast cell-fusion in bone homeostasis [49]. DCST2 gene is associated with early length and adult height [50]. |
| GALNT2 (rs6672758) | 1 | GALNT2 gene encodes the polypeptide N-acetylgalactosaminyltransferase 2 which is a member of the glycosyltransferase 2 protein family and which has been linked to post-translational modification of vitamin D-binding protein [51]. |
| LINC01122 (rs727857) | 2 | LINC01122 gene is an RNA gene that is affiliated with the lncRNA class [52]. LINC01122 was one of the 989 differentially expressed genes which was significantly enriched in vitamin D3 biosynthesis [53]. |
| CPS1 (rs1047891) | 2 | CPS1 gene encodes the carbamoyl-phosphate synthase 1 which is a mitochondrial enzyme that catalyses synthesis of carbamoyl phosphate from ammonia and bicarbonate [54]. |
| UGT1A5 * (rs2012736) | 2 | UGT1A5 gene encodes the UDP glucuronosyltransferase family 1 member A5 which has been shown to transform small lipophilic molecules, into water-soluble, excretable metabolites [55]. Related isoenzymes have been identified as catalysts for 25(OH)D3 glucuronidation in the human liver [56]. |
| CADM2 (rs6782190) | 3 | CADM2 gene encodes the cell adhesion molecule 2 which is a member of the synaptic cell adhesion molecule 1 family [57]. In animal studies, CADM2 is associated with metabolic traits [58], suggesting possible influence on vitamin D concentrations through its effect on obesity and storage capacity of 25(OH)D. |
| GC (rs705117, rs1352846) | 4 | GC gene encodes the vitamin D binding protein which binds to vitamin D and its plasma metabolites and transports them to target tissues [59]. |
| CARMIL1/LRRC16A (rs78151190) | 6 | CARMIL1 gene encodes the capping protein regulator and myosin 1 linker 1 with a role in actin filament network formation [60]. Approximately 10% of muscle tissue consists of actin, providing a possible link with 25(OH)D through storage capacity. |
| VGF (rs75741381) | 7 | VGF gene encodes a protein that is expressed in neuroendocrine cells and is upregulated by nerve growth factor [61]. VGF has been linked with appetite control [62], and diet-induced obesity [63], with a possible link through storage capacity. |
| LINC00536 (rs12056768) | 8 | LINC00536 gene interacts with Wnt3a/β-Catenin signalling [64]. Wnt/β -Catenin signalling is an important signalling pathway in regulating adipose tissue lipogenesis with a possible link with 25(O)D through storage capacity. |
| GRID1 (rs77532868) | 10 | GRID1 gene encodes the glutamate ionotropic receptor delta type subunit 1 which is a subunit of glutamate receptor channels that mediate the fast excitatory synaptic transmission in the central nervous system [65]. |
| CYP2R1 (rs12794714) | 11 | CYP2R1 gene encodes the cytochrome P450 family 2 subfamily R member 1 which acts as 25-hydroxylase of vitamin D [66]. |
| TMEM151A (rs61891388) | 11 | TMEM151A has been predicted to be an integral component of membrane and CD248 enables extracellular matrix binding activity and regulates endothelial cell apoptotic process. |
| AP002387.1/ACTE1P (rs1660839, rs12803256) | 11 | ACTE1P gene is an RNA gene. ACTE1P [67] and vitamin D [68] are both involved in adolescent idiopathic scoliosis (abnormal curvature of the spine), suggesting a possible role of ACTE1P in bone health. |
| S100A11P3 (rs12798050) | 11 | S100A11P3 gene encodes the S100 calcium binding protein A11 pseudogene 3. It has multiple roles in buffering calcium ion concentration, participating in energy metabolism, regulating cell proliferation and differentiation [69]. |
| DGAT2 (rs72997623) | 11 | DGAT2 encodes the diacylglycerol O-acyltransferase 2, catalysing the synthesis of triglycerides [70]. Affects adipose tissue formation [71] with possible link to 25(OH)D storage. |
| GUCY2EP/TSKU (rs1149605) | 11 | GUCY2EP gene encodes guanylate cyclase 2E that is involved in chemosensation and TSKU gene encodes tsukushi, small leucine rich proteoglycan that has been predicted to act upstream/within several processes, including negative regulation of Wnt signaling pathway. |
| HAL (rs10859995) | 12 | HAL gene is upregulated during the differentiation of keratinocytes [72]. HAL deaminates L-histidine to trans-uronic acid [73], which in the stratum corneum absorbs UVB [74] and reduce the production 25(OH)D [75]. |
| SEC23A (rs8018720) | 14 | SEC23A gene encodes the Sec23 homolog A, coat complex II component which plays a role in the ER-Golgi protein trafficking. |
| ALDH1A2 (rs261291) | 15 | ALDH1A2 gene encodes aldehyde dehydrogenase 1 family member A2 which catalyses the synthesis of retinoic acid (RA) from retinaldehyde [76]. |
| PDILT (rs77924615) | 16 | PDILT/PDIA7 gene encodes the protein disulphide isomerase like, testis expressed which catalyses protein folding and thiol-disulphide interchange reactions [77]. |
| SULT2A1 (rs212100) | 19 | SULT2A1 gene encodes a liver- and intestine-expressed sulpho-conjugating enzyme that is responsible for the inactivation by sulphonation of 25(OH)D [78,79]. |
| KLK10 (rs10426) | 19 | KLK10 gene encodes the kallikrein related peptidase 10 that has been shown to play a role in dermal integrity [80]. |
| CYP24A1 † | 20 | CYP24A1 gene encodes cytochrome P450 family 24 subfamily A member 1 which is an important candidate for vitamin D metabolic pathway given that it initiates the degradation of 1,25-dihydroxyvitamin D3 by hydroxylation of the side chain [81]. In addition, this enzyme also plays a role in calcium homeostasis and vitamin D endocrine system [82]. |
| PLA2G3 (rs2074735) | 22 | PLA2G3 gene encodes the phospholipase A2 group III which functions in lipid metabolism and catalyses the calcium-dependent hydrolysis of the sn-2 acyl bond of phospholipids to release arachidonic acid and lysophospholipids [83]. |
* UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10. † rs6123359, rs17216707, rs2585442, rs2762943.