Genetic Determinants of Osteoporosis: Common Bases to Cardiovascular Diseases?

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 (𝐸𝑅𝛼 and 𝐸𝑅𝛽)	6q25 and 14q22-24	Control of bone remodelling, reduction of bone resorption	(TA)n repeat (promoter region) and XbaI and PvuII (intron 1) (𝐸𝑅𝛼); (CA)𝑛 repeat (promoter region) and AluI (exon 8) (𝐸𝑅𝛽)
(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)