Table 2.

Vitamin D binding protein (VDBP) and human diseases.

Disease	VDBP Influence	Mechanism	Reference
Cancers
Breast cancer	Gc2-2 genotype associated with decreased risk of postmenopausal breast cancer (n = 1402, control: 2608) SNPs: rs17467825, rs2298850 and rs3755967 are associated to the breast cancer risk (n = 818, controls = 935); another study does not support an important role of either calculated circulating free 25(OH)D or circulating VDBP levels in breast cancer risk among predominantly premenopausal women; (controls = 584)	The carcinogenic mechanism is based on the potential to convert Gc to GcMAF, which is a macrophage activator. GcMAF may enhance proapoptotic enzymes activity and induce cell apoptosis via JNK1/2 and p387 pathway—that may inhibit cancer development	[51,54,114,115,116]
Prostate cancer	Decreased risk in of prostate cancer associated with higher serum VDBP levels in men with lower than median 25(OH)D status, where elevated risk in men with higher than median 25(OH)D concentration (n = 950, control = 964); SNP: Rs2282679 in Gc has no significant correlation with non-aggressive and aggressive prostate cancer (n = 10,572, controls = 4975)	Extracellular concentrations of VDBP and 25(OH)D result in an upregulation of megalin-mediated internalization of SHBG-bound testosterone	[65,117]
Pancreatic cancer	Higher serum 25(OH)D and serum VDBP are associated with higher pancreatic cancer risk (n = 234, control = 234) among Finnish men population; VDBP or 25(OH)D were not associated with pancreatic cancer (n = 295, two controls n = 590); rs2282679, rs7041 and rs4588 found no significant correlation with pancreas cancer	Reducing free 25(OH)D by VDBP decreases bioavailability; high concentration of VDBP and 25(OH)D could potentially displace 1,25(OH)D with its antitumorigenic properties	[64,70,71]
Lung cancer	VDBP low serum concentration might be a predictor of subsequent death from non-small cell lung cancer (n = 148 lung cancer patients, 68 patients with other intrathoracic tumors and 33 noncancer controls); GC2-1f combination (TT-CA) has significant and protective association with lung cancer (n = 113, control = 113); Rs7041 in GC gene reduces the risk of Non-Small Cell Lung Cancer risk (n = 446, controls = 425)	Conversion of VDBP to GcMAF may be reduced in malignancy due to the action of α-N-acetylogalactosaminidasa and as a result it might lower macrophage activation	[72,75,90]
Colorectal cancer	Rs7041 (TG/GG) significant association with colorectal cancers among age 60 years old and older (n = 282, control = 113); Rs4588 (CA/AA) significant association with cancer in males aged 60 years old or less (n = 282, control = 113); Both: Gc/Rs7041 and CYP2R1/rs10741657 polymorphisms decreases the risk of colorectal cancer about 9–12% (n = 920, controls = 1743)		[74,76]
Basal cell carcinoma	SNP may affect skin carcinogenesis. Among patients with rs7041 and rs4588 233 of them developed BCC and 52.4% among those patients developed multiple BCCs (n = 7983). GC1s homozygotes had lower BCC risk. Rs7041 was associated with BCC development among the youngest group.	SNPs may be associated with BCC development among younger patients	[77]
Cutaneous Melanoma	Association between VDBP rs12512631 and risk of cutaneous melanoma among Spanish population (n = 530, controls = 314); No association between VDBP rs1155563 and rs7041 and melanoma risk or prognosis (n = 305, controls = 370)	VDBP variants may influence on vitamin synthesis and distribution	[78,79,80]
Other important diseases
Thyroid autoimmunity disorders	Intron 8 (TAAA)n-Alu repeat polymorphism correlates with Graves’ disease (n = 561) but no association with Hashimoto’s thyroiditis; VDBP polymorphisms may contribute to development of autoimmune diseases (n = 332, control = 185).	Ability of VDBP to binding; linkage with nearby gene, affecting on immune system by VDBP’s macrophage activating role	[86,87]
Obesity	Possible role of VDBP in the relation between body fat mass and vitamin D metabolism rs17467825 and its corresponding haplotype GAA—strongest association in females; VDBP has an influence on PFM (percentage of fat mass), more significant associations are more female-specific	A lipid-bound VDBP fraction	[47,88,89,118,119,120,121,122]
Diabetes mellitus	People with Gc1S-2 and 1S-1S had higher fasting plasma insulin concentration than 1F-1F; rs7041 (Glu/Glu-416) and rs4588 (Lys/Lys-420) variants of VDBP were higher in type 2 diabetic comparing to control group (n = 104, controls = 107)	Polymorphisms of VDBP might be associated with insulin resistance in Japanese population with normal glucose tolerance. It might contribute to type 2 diabetes development. VDBP affects glucose metabolism by modulating the action of metabolites of vitamin D; Vitamin D stimulates synthesis of insulin, effects on β-cells and protects them against destruction by inflammatory cytokines	[81,82,83,84,123,124,125,126]
Bone metabolism	An inverse correlation between serum VDBP levels and BMD; A highly significant difference in premenopausal bone fracture risk among women with different VDBP phenotypes (VDBP1-1>VDBP2-1>VDBP2-2); SNPs in the VDBP gene might be associated with BMD; VDBP rs4701 is associated with lower BMD-L4 and higher risk of osteoporosis; multiple of the VDBP SNPs might increase the risk of osteoporosis in postmenopausal women	Phenotype of VDBP is mediated by VDBP-MAF and activation osteoclasts	[90,93,127,128,129,130,131,132,133]
Rheumatoid arthritis	correlation between RA and rs2282679 SNP	1,25(OH)2D3 may have inhibitory effect on osteoclasts formation that is induced by IL-22	[95,97]
Ankylosing spondylitis	Patients with G alleles at rs222016 and rs222020 and an allele at rs3733359 show decreased risk of peripheral arthritis; rs4752 polymorphisms are associated with development of uveitis. Haplotype analysis showed that AGGA haplotype protects against peripheral arthritis development in ankylosing spondylitis patients (n = 223, control = 239).		[48]
Asthma	Upregulation of DBP expression in patients with diphenyl-methane disocyanate occupational asthma DBP SNPs rs4588 and rs7041 are associated with the risk of asthma and the DBP1 allele might confer a protective effect; patients with GC2 (compared to GC1) haplotype are more susceptible for the development of asthma; Gc1, Gc2 was significantly associated with the risk of asthma (n = 467, control = 288); Rs7041 and rs4588 associated with increased risk of bronchial asthma (n = 143, controls = 143); Rs4588 CA and AA genotypes had protective effect, while rs7041 GG genotype had significantly higher frequency among patients diagnosed with asthma (n = 96, controls = 96)	VDBP and enhancing the chemotactic activity of monocytes and neutrophils; VDBP modules Th2-mediated inflammation and influences the susceptibility to asthma	[101,102,103,104,105]
Chronic obstructive pulmonary disease	GC1f and GC2 alleles may be linked to sputum hypersecretion in COPD patients; Gc2 protects against COPD (n = 140, control = 480) 1F-1S genotype was protective factor against deficiency of vitamin D among Korean patients (n = 175); High frequencies of the haplotypes in rs7041 and rs4588—GC1S/1S among COPD patients (n = 233)	VDBP has the potential to influence the respiratory function by determining vitamin D bioavailability and via direct effects on innate cell function	[101,106,108,109]
Tuberculosis	VDBP2-2 phenotype strongly associated to susceptibility to TB among Gujarati Asians (n = 534, control = 400); Among Taiwan patients the GC1F carriers were associated with tuberculosis (n = 198, controls = 170)	Reduced ability of VDBP2 to conversion VDBP to VDBP-MAF	[107,134]
Coronary artery diseases	A strong interaction between A allele VDR rs1544410 and G allele of VDBP rs7041 genes in a protective role; strong association between vitamin D deficiency, lipid profile and the VDR rs1544410G>A and rs7T41>G VDBP genes polymorphisms (n = 157, control = 182) No correlation between rs7041, rs4588 and CAD (n = 1080).		[113,135]