Table 2.
Main osteoporosis candidate genes.
| Putative candidate genes | Chromosome location | Biological functions in bone and mineral metabolism | Main polymorphisms analyzed in osteoporosis association studies | |
|---|---|---|---|---|
| Calciothropic and sex hormones and their receptors | ||||
| (i) Vitamin D receptor (VDR) | 12q12-14 | Calcium and phosphatase homeostasis; regulation of osteoclasts and osteoblasts functions. | Cdx2 (promoter region); FokI (exon 2); BsmI, ApaI, EcoRV and TaqI (3′ UTR) | |
| (ii) Parathyroid hormone (PTH) and PTH receptor (PTHR) | 11p15 and 3p22-21 | Calcium homeostasis, endogenous vitamin D synthesis and regulation of bone cells activity | BstBI (intron 2 of PTH gene); (AAAG)n repeat (P3 promoter of PTHR gene) | |
| (iii) Estrogen Receptor Alpha and Beta (E R α and E R β) | 6q25 and 14q22-24 | Control of bone remodelling, reduction of bone resorption | (TA)n repeat (promoter region) and XbaI and PvuII (intron 1) (E R α); (CA)n repeat (promoter region) and AluI (exon 8) (E R β) | |
| (iv) Calcitonin (CT) and its receptor (CTR) | 11p15 and 7q21 | Increasing of osteoblast activity, retaining of calcium in bones and prevention of phosphorus and calcium loss | (CA)n repeat (5′ flanking region of CT gene); AluI (nucleotide 1377 of CTR gene) | |
| (v) Aromatase (CYP19A1) | 15q21 | Catalyzation of androgens conversion to estrogens | (TTTA)n repeat (intron 4) | |
| (vi) Androgen receptor (AR) | Xq11-12 | Regulation of osteoblast function and suppressive action on bone resorption | (CAG)n repeat (exon 1) | |
| (vii) Calcium-sensing receptor (CaSR) | 3q13-21 | Regulation of calcium homeostasis at parathyroid, kidney, bowel and bone level | (CA)n repeat (5′ flanking region at the CaSR locus); T/C Ala986Ser (exon 7) | |
| (viii) Glucocorticoid receptor (GR) | 5q31 | Inhibition of bone formation, suppression of calcium absorption | Asp363Ser (exon 2) | |
|
| ||||
| Cytokine, growth factors and local regulators | ||||
| (i) Interleukin-6 (IL6) | 7p21 | Effect on osteoclastogenesis and bone resorption | (CA)n repeat (5′ flanking region at the IL6 locus); −634 C/G, −572G/C and −174G/C (promoter region). | |
| (ii) Insulin-like growth factor 1 (IGF-I) | 12q22-24 | Stimulation of bone formation, recruitment of pre-osteoblasts, growth factor for osteoblasts | (CA)n repeat (promoter region) | |
| (iii) Transforming growth factor β1 (TGF β -1) | 19q13 | Osteoclast and osteoblast activity | −1348C/T and −509C/T (promoter region), 29T/C Leu10Pro and 74G/C Arg25Pro (exon 1), 869T/C and 788C/T Thr263Ile (exon 5), 713-8delC (intron 4), 861-20T/C (intron 5) | |
| (iv) Bone morphogenetic protein 7 (BMP7, OP1) | 20q13 | Promotes mesenchymal cells into osteoblastic differentiation | — | |
| (v) Bone morphogenetic protein 4 (BMP4) | 14q22-q23 | Involved in bone and cartilage development and in fracture repair | −5826G/A (promoter region); 3564C/T (intron 2); 6007C/T Ala147Val (exon 4) | |
| (vi) Bone morphogenetic protein 2 (BMP2) | 20p12 | Stimulates the differentiation and/or activity of osteoclasts | Ser37Ala (exon 2); A/G Ser87Ser (exon 2); Arg190Ser (exon 3) | |
|
| ||||
| Bone matrix proteins | ||||
| (i) Collagen type I alpha1 (COLIA1) | 17q21-22 | Encode for collagen type I alpha1 chain | Sp1 (binding site of the transcription factor Sp1 in the intron 1) | |
| (ii) Collagen type I alpha2 (COLI-A2) | 7q22 | Encode for collagen type I alpha2 chain | PvuII, RsaI, (ACT)n repeat (intron 12) | |
| (iii) Osteopontin (OPN, SPP1) | 4q21-25 | Anchoring osteoclasts to the mineral matrix of bones | Intragenic (CA)n repeat | |
| (iv) Osteocalcin (OCN, BGLAP) | 1q25-q31 | Role in bone matrix mineralization and calcium homeostasis | C/T and (CA)n repeat (promoter region) | |
| (v) Osteonectin (ON, SPARC) | 5q31.3-q32 | Binds calcium, initiates mineralization and promotes mineral crystal formation | Intragenic (CA)n repeat | |
|
| ||||
| Miscellaneous | ||||
| (i) Low-density lipoprotein receptor-related protein 5 (LRP5) | 11q13 | Regulates osteoblasts proliferation and bone formation | Val667Ala (exon 9); Ala1330Val (exon 18) | |
| (ii) Low-density lipoprotein receptor-related protein 6 (LRP6) | 12p13.3-p11.2 | Regulates osteoblasts proliferation and bone formation | Ile1062Val (exon 14) | |
| (iii) Receptor activator of nuclear factor kappa B (RANK) | 18q22.1 | Receptor of RANKL expressed on osteoclast precursors and osteoclasts. The association of RANK-RANKL regulates osteoclast formation, activation and survival in normal bone modelling | 421C/T, 575C/T | |
| (iv) RANK ligand (RANKL) | 13q14 | Ligand of RANK expressed on osteoblasts and stromal cells. The association of RANK-RANKL regulates osteoclast formation, activation and survival in normal bone modelling | −290C/T, −643C/T, −693G/C and −1594G/A (promoter region) | |
| (v) Osteoprotegerin (OPG) | 8q24 | Soluble “decoy receptor” of RANKL, inhibits osteoclast development by blocking the RANK-RANKL interaction | 163A/G, 209G/A, 245T/G and 1181G/C (exon 1) | |
| (vi) Sclerotin (SOST) | 17q11.2 | Potent osteocyte expressed negative regulator of bone formation in vitro | −9247T/C, −7859C/G, −1605C/T and −1396delGGA (promoter region); 27G/A (exon 1) | |
| (vii) Chloride channel 7 (CLCN7) | 16p13 | Encodes a Chloride channel highly expressed in osteoclasts and essential for acidification of the resorption lacuna | Ala390Ala (exon 14), Val418Met (exon 15) | |
| (viii) Methylentetrahydrofolate reductase (MTHFR) | 1p36.3 | Involved in collagen synthesis | 677C/T (exon 4) | |