Common variants of the vitamin D binding protein gene and adverse health outcomes

Figures & data

Figure 1. Genetic variants of the vitamin D-binding protein gene (GC). Shown in this schematic are the 13 exons (coding regions as green bars and untranslated sequences as pink boxes), separated by variable length introns (horizontal grey line, interrupted). Also shown are the DNase I hypersensitive sites (vertical red arrows). Extensively involved in control of gene expression, Site IV (HSIV), located in Intron I, is depicted in greater detail. Binding elements specific for Ccaat-enhancer-binding proteins (C/EBP, blue), GATA transcription factors (GATA, pink), hepatocyte nuclear factor 3-alpha (FoxA, lime) and nuclear factor-1 (NF-1, purple) are indicated. Besides the common missense SNPs – c.1296T > G specifying p.D432E, and c.1307C > A specifying p.T436K – there are a number of other well documented (black) and novel (orange) single-nucleotide variants scattered throughout the gene of relevance to future genetic association studies.

Figure 2. Common electrophoretic variants of the Gc protein (DBP). Shown at the top is the relative electrophoretic separation of the various Gc species, based on their isoelectric points (pI). The corresponding molecular structures are given below that. Only five residues of primary amino acid sequence (residues 432–436 = Asp–Ala–Thr–Pro–Thr = D–A–T–P–T) are depicted, along with their O-linked saccharides. Note that the D432E mutation results in a very small separation (ΔpI = 0.01), since the carboxyl side chains of the wild-type aspartate residue (in the Gc1F species) and the mutant glutamate residue (in Gc1S) have such similar dissociation constants. There is larger separation of the two Gc1 species if the negatively charged sialic acid residue (generating the anodal form, Gc1a) is removed, generating Gc1c, the cathodal form. Gc-MAF, shown at the bottom, arises as a result of sequential deglycosylation removing first the sialic acid and then the galactose residues. At the T436 position, the genetic variant Gc2 shows a more marked cathodal shift in electrophoretic migration due to replacement of the O-glycosylation site by a positively charged lysine residue (436 K).

Table 1.  Association between common genetic variants of the vitamin D binding protein gene (GC) and various diseases.

		Sample size (N)
Disease	Reference	Cases	Controls	Country	Ethnicity	GC polymorphisms studied	Findings
Cancer
Breast Cancer	Abbas et al.160	1402	2608	Germany	Caucasian^a	Gc1F, Gc1S, Gc2	Genotype Gc2-2 was associated with decreased risk of postmenopausal breast cancer, [OR = 0.72 (CI = 0.54–0.96, p = 0.04)], when compared to the most frequently observed genotype, Gc1S-1S. Gc2 carriers had an OR of 0.88 (CI = 0.77–1.01, p = 0.02) compared to non-carriers.
	Anderson et al.161	1560	1633	Canada	Caucasian	rs7041, rs4588	TT genotype of rs7041 was associated with breast cancer, OR = 1.23 (CI = 1.01–1.51, p < 0.05). Resulting genotype Gc2-2 had OR = 1.22 (CI = 0.93–1.59), when compared to genotype Gc1-1.
	McCullough et al.159	500	500	United States	99% Caucasian^b	rs7041, rs4588	NS
Gastrointestinal Cancer (includes Colorectral Cancer)	Hibler et al.169	1439	N/A	United Status	Caucasian	rs7041 and six other SNPs in GC gene	NS
	Poynter et al.168	1806	2879 (siblings)	United States, Canada, Australia	87% non-Hispanic White; remainder Black, Asian and Other	rs7041, rs4588 and other SNPs in the Gc gene	NS
	Zhou et al.170	964	1187	China	Han Chinese	D432E, T436K	Homozygous KK genotype of T436K had elevated risk for colorectal cancer in comparison to 436 T/T genotype, OR = 3.41 (CI = 1.85–6.57, p < 0.001). When all gastrointestinal cancer types were combined, KK genotype had 1.15 fold increased risk over T/T (CI = 1.02–1.30, p = 0.020) after adjustment for age, sex and smoking status. Carriers of D432- 436 K haplotype (associated with Gc2 allele) also had an increased risk for developing gastrointestinal cancer, OR = 1.22 (CI = 104–1.39, p = 0.015)
Prostate Cancer	Ahn et al.166	749	781	United States	Non-Hispanic White	rs7041, rs4588 and other SNPs in the Gc gene	NS
	Corder et al.167	181	181	United States	182 White, 180 Black	Gc1F, Gc1S, Gc2	NS
	Dimopoulos et al.165	115	155	Greece	Caucasian^a	Gc1F, Gc1S, Gc2	Increased disease risk for carriers of Gc2 allele; RR = 1.81 (p < 0.01)
Skin Cancer, Basal Cell Carcinoma (BCC)	Flohil et al.171	7983	N/A	Netherlands	Caucasian	rs7041, rs4588	Heterozygous Gc1F carriers were significantly more likely to develop a first BCC compared to non-carriers, HR = 1.40 (CI = 1.11–1.78). Homozygote Gc1S carriers aged less than 65 years old has significantly lower risk of BCC compared to non-carriers, HR = 0.53 (CI = 0.31–0.91).
Chronic Diseases
Asthma	Wjst et al.117	947 (201 families)	191	Germany and Sweden	Caucasian^a	rs7041, rs4588 and other SNPs in the GC gene	NS. Weak association with D432E (rs7041) and total serum IgE (p = 0.0249)
	Li et al.116	467	288	China	Chinese Han	rs7041, rs4588	Gc2 allele was associated with asthma susceptibility, OR = 1.35 (CI = 1.01–1.78, p = 0.006); Gc2-2 genotype was strongly associated with risk of asthma compared to Gc1-1, OR = 13.13 (CI = 2.42–7.13, p = 0.001)
Chronic Obstructive Pulmonary Disease (COPD)	Horne et al.90	104	413	Canada	Caucasian	Gc1F, Gc1S, Gc2	Gc2 allele may confer disease protection; Highest disease risk in Gc1F-1F genotype (RR = 4.8), and lowest risk in Gc2-1F genotype (RR = 0.5)
	Ito et al.93	103	88	Japan	Japanese	T436K, D432E	Increased risk of COPD for Gc1F-1F genotype; significantly larger proportion of Gc1F homozygotes in patients (32%) compared to healthy smokers (17%) p = 0.014; OR for Gc2-2 is 2.3 (CI = 1.2–4.6).
	Janssens et al.97	262	152	Belgium	Caucasian ^a	rs7041, rs4588	Individuals with homozygous TT at rs7041 have increased risk for COPD; OR = 2.11 (CI = 1.2–3.71, p = 0.009) for COPD. No association with heterozygous T carriers.
	Kasuga et al.98	532 (low lung function)	537 (high lung function)	Canada	Caucasian	Gc1F, Gc1S, Gc2	NS
	Kueppers et al.91	114	114	United Sates	Caucasian^a	Gc1F, Gc1S, Gc2	Gc2-2 may offer a protective advantage; Gc2-2 genotype was underrepresented in the COPD group (1%) versus the control group (5%), p = 0.049.
	Schellenberg et al.89	75	64	Canada	Caucasian^a	Gc1F, Gc1S, Gc2	Homozygous Gc2 appears protective against disease. OR for Gc2-1 = 1.01 (CI = 0.49–2.10) OR for Gc2-2 = 0.17 (CI = 0.03–0.83)
	Shen et al.95	100	100	China	Chinese Han	Gc1F, Gc1S, Gc2	Decreased COPD disease risk for Gc2. OR for Gc1F-1F = 3.08(CI = 1.498–6.347, p = 0.003) OR for Gc2-2 = 0.215 (CI = 0.06–0.772, p = 0.0017)
	Wood et al.92	611 (471 with AATD and 140 with COPD	480	United Kingdom	Caucasian	rs7041, rs4588 and other SNPs in Gc gene	Gc2 decreased risk of COPD, OR = 0.79 (CI = 0.65–0.99, p = 0.048). Gc2 had increased risk of bronchiectasis, OR = 1.51 (CI = 1.02–2.22, p = 0.034). rs7041 was associated with bronchiectasis in α1-antitrypsin deficiency (AATD), OR = 0.52 (0.29–0.93, p = 0.027). No association with rs4588.
Diabetes (Type I)	Cooper et al.224	8517	104 381 and 1933 families	United Kingdom^c	Caucasian	rs7041, rs4588	Association between rs4588 and type 1 diabetes was observed in the case/control dataset, OR = 0.95 (CI = 0.91–1.00, p = 0.05). No associations were observed in the family collection data (p = 0.071). No association with D432E.
	Hodge et al.225	103	N/A	United Sates	Caucasian	Gc1F, Gc1S, Gc2	Excess of Gc2-1 and Gc1-1 phenotypes (0.05 > p > 0.02); however, association not significant when corrected for multiple testing.
	Pani et al.66	527 (152 families with at least one affected offspring)	N/A	Germany	Caucasian^a	Gc1F, Gc1S, Gc2; number of repeats for intron 8 [(TAAA)n]	NS
Diabetes (Type II) (including insulin resistance and altered glucose tolerance)	Baier et al.70	578	595	United States	Pima Indians	D432E, T436K	Gc genotypes differed in plasma glucose concentrations in response to oral glucose tolerance test, highest concentrations observed in Gc1F and lowest in Gc2 (p < 0.028, repeated measures ANOVA).
	Hirai et al.72	208	209	Japan	Japanese	Gc1F, Gc1S, Gc2	Reduced risk for individuals with Gc1F allele. Gc1F-1F genotype was less frequent in cases versus controls (11% versus 19%, p < 0.001). Gc1S-2 genotype was more common in cases than controls (48% versus 28%, p < 0.02).
	Hirai et al.68	N/A	82	Japan	Japanese	Gc1F, Gc1S, Gc2	Fasting insulin concentrations differed in Gc alleles (p < 0.05); individuals with Gc1S allele had highest concentrations, followed by Gc2 allele carriers, the lowest fasting insulin was observed in Gc1F carriers. HOMA was highest in Gc1S carriers (p < 0.03).
	Iyengar et al.71	N/A	468	United States	Anglos (N = 289); Hispanic Americans (N = 179)	Gc1F, Gc1S, Gc2	Gc1F allele associated with highest levels of plasma glucose (p = 0.033).
	Klupa et al.74	396 (Type I, N = 181; Type II, N = 215)	163	United States	Caucasian	Gc1F, Gc1S, Gc2	NS
	Malecki et al.76	231	162	Poland	Caucasian	Gc1F, Gc1S, Gc2	NS
	Szathmary 69	144	N/A	Canada	Dogrib Indians	Gc1F, Gc1S, Gc2	Gc1F-1F had the lowest fasting glucose level. After adjustment for BMI, Gc genotype was the only variable that had a significant effect on insulin concentrations (p = 0.040).
	Ye et al.75	237	143	France	Caucasian	Gc1F, Gc1S, Gc2	NS
Endometriosis	Faserl et al.124	57	24	United States	Caucasian^a	Gc1F, Gc1S, Gc2	Gc alleles differed between cases and controls (p = 0.006). 18% of cases expressed Gc2 allele alone, but none of the control cases did.
Thyroid Autoimmune Disease	Kurylowicz et al.196	332	185	Poland	Caucasians	D432Eand T436E; Variable tandem (TAAA)n-Alu repeat in Intron8	Increased risk for carriers of K allele at T436K, OR = 1.5 (CI = 1.13–1.99, p = 0.005). OR = 1.63 for homozygous 436KK genotype (CI = 0.80–3.32, p = 0.01).
	Pani et al.195	187 nuclear families with an offspring affected by Graves (N = 95) or Hashimoto thyroiditis (N = 92)	N/A	Germany and Italy	Caucasian	Gc1F, Gc1S, Gc2, Variable tandem (TAAA)n-Alu repeat in Intron8	Association with intron 8(*8) polymorphisms in Graves Disease patients (p < 0.03). No association with Hashimoto thyroiditis.
Ischemic Stroke	Wang et al.119	3550	6560	United States, Europe, China	Varied by study; primarily Caucasians and Chinese	rs7041, rs4588	NS
Inflammatory Bowel Diseases (IBD)	Eloranta et al.125	636 (232 with ulcerative colitis; 404 with crohn disease)	248	Switzerland	Caucasian^a	D432E, T436K	Homozygous 436KK genotype was more common in control group than in IBD patients (p = 0.006). Association was significant in separate comparisons of healthy controls with ulcerative colitis patients (p = 0.022) and Crohn disease patients (p = 0.016). DBP_2 TA haplotype (D432-436 K, Gc2 allele) was found at higher frequencies in healthy controls than in IBD cases [OR = 2.53, (CI = 1.48–4.34, p = 0.0005)], particularly when comparing healthy controls to the ulcerative colitis cases [OR = 4.39, (CI = 1.87–10.31, p = 0.0003)]
Liver Disease	Constans et al.35	17 (15 cirrhosis; 2 hepatitis)	100	France	Caucasian^a	Gc1F, Gc1S, Gc2	Gc1 was overrepresented in the cases versus healthy controls. An unusual electrophoretic form of Gc1 was found in many of the cases (10 out of 17 cases), perhaps differentiated by the presence of two sialic acid residues.
Osteoporosis	Al-oanzi et al.87	56	114	United Kingdom	Caucasian	Variable tandem (TAAA)n-Alu repeat in Intron8	Allele *10 was associated with lower risk of osteoporosis, OR = 0.39 (CI = 0.25–0.64, p < 0.0005). Allele 11 was also associated with reduced risk, OR = 0.09 (CI = 0.01–0.67, p < 0.007). Allele *8 and *9 both showed increased susceptibility.
	Eichner et al.226	258	N/A	United States	Caucasian^a (non-Black)	Gc1F, Gc1S, Gc2	No association between Gc alleles and BMD. Homozygous Gc1F phenotype was associated with higher bone mass density, but only 7 individuals with this phenotype.
	Ezura et al.85	384	N/A	Japan	Japanese	rs7041, rs4588 and 12 other SNPs in the Gc gene	Several SNPs were associated with bone mass density (BMD); D432E (rs7041) in conjunction with IVS1 + 827C > T showed the strongest relationship with BMD (r^2= 0.029, p = 0.005).
	Fang et al.88	6181	N/A	Netherlands	Caucasians	rs7041, rs4588	Gc variants were not associated with fracture risk in entire study. In a subgroup of individuals with calcium intake <1.09 g/day, the hazard ratio for fracture risk for the Gc1S homozygote was 1.47 (CI = 1.06–2.05), compared to non-carriers.
	Lauridsen et al.77	595	N/A	Denmark	Caucasian	Gc1F, Gc1S, Gc2	Lowest fracture risk in Gc2-2 group (14%) compared to Gc1-2 (27%) and Gc1-1 (34%) (p = 0.017). Fracture risk OR for Gc2-2 = 0.32 (CI = 0.13–0.80) Compared to the other genotypes, none of the Gc2-2 individuals had any low energy fractures (p = 0.021).
	Papiha et al.86	26	21	United Kingdom	Caucasian	Gc1F, Gc1S, Gc2; Variable tandem (TAAA)n-Alu repeat in Intron8	Intron 8*Alu repeat had significant association with lumbar spine and femoral neck BMD. BMD was observed to be lower in men with 10/8 genotype than 10/10 genotype (p < 0.05).
Sarcoidosis	Milman et al.192	44	44	Denmark	Caucasian^a	Gc1F, Gc1S, Gc2	NS
Infections Diseases
Human Immunodeficiency Virus (HIV)	Alonso et al.216	318 (at risk or infected)	187	Spain	Caucasian	Gc1F, Gc1S, Gc2	NS
	Cleve et al.217	97	1523	United Kingdom	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Eales et al.219	203 (at risk males)	177 (50 homo-sexual and 122 hetero-sexual males)	United Kingdom	Caucasian^a	Gc1F, Gc1S, Gc2	30% of AIDS patients were homozygous for Gc1F compared to 0.8% of controls (p < 0.0001). Gc2-2 individuals were overrepresented in sero-negative contacts of AIDS patients (p < 0.05).
	Pronk et al.212	447 (96 AIDS patients and 351 homosexual men	86	Netherlands	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Putkonen n et al.218	125 (85 AIDS patients and 40 couples with 1 infected partner)	3394	Sweden	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Rosberger et al.227	121	1011	United States	Caucasians and African Americans	Gc1F, Gc1S, Gc2	NS
Rheumatoid Fever	Bahr et al.208	39	90	Kuwait	Arabic	Gc1F, Gc1S, Gc2	An association was observed between Gc2 allele with rheumatic fever (p = 0.0024); 56% of all rheumatic fever patients were carriers of Gc2 allele.
Tuberculosis (TB)	Bahr et al.208	41	90	Kuwait	Arabic	Gc1F, Gc1S, Gc2	No association with GC alleles and TB, although an association was observed between Gc2 allele with rheumatic fever (p = 0.0024); 56% of all rheumatic fever patients were carriers of Gc2 allele.
	Martineau et al.206	123 (United Kingdom); 130 (Brazil); 281 (South Africa)	140 (United Kingdom); 78 (Brazil); 182 (South Africa)	United Kingdom	Varied based on study location^d	Gc1F, Gc1S, Gc2	Associations between GC polymorphism and TB only observed in Gujarati Asians from United Kingdom. Gc2-2 associated with susceptibility to active TB compared to wild type (Gc1-1): OR = 2.81 for Gc2-2 versus Gc1-1 (CI = 1.19–6.66, p = 0.009) No associations were observed in the populations from Brazil and or South Africa.
Neurodegeneration
Amyotrophic Lateral Sclerosis (ALS)	Palma et al.182	11 (7 ALS, 4 other muscular disorders)	4	Portugal	Caucasian^a	Gc1F, Gc1S, Gc2	Gc2 may represent a disease risk, Gc2 was present in all familial ALS patients and 2 patients with other muscular diseases but in none of the healthy controls.
Multiple Sclerosis (MS)	Hollsberg et al.176	95	227	Denmark	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Lindblom et al.177	88	3394	Sweden	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Niino et al.173	107	109	Japan	Japanese	D432E, T436K	NS
	Orton et al.179	1364	1661 (first degree relatives)	Canada	Caucasian^a	rs7041, rs4588 and 2 other SNPs in the Gc gene	NS
	Simon et al.178	214	428	United States	Various (Nurses Health Study)	rs7041, rs4588	NS
	Steckley et al.174	236 sib pairs (1 affected, 1 not)	N/A	Canada	Caucasian^a	Gc1F, Gc1S, Gc2	NS
Parkinson’s Disease	Suzuki et al.191	137	N/A	Japan	Japanese^a	Gc1F, Gc1S, Gc2	No association with GC and severity of Parkinson disease as evaluated by Hoehn & Yahr (HY) stages and Unified Parkinson’s Disease Rating Stage (UPDRS).
Schizophrenia	Beckman et al.187	47	2361	Sweden	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Fananas et al.189	162	365	Spain	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Lange, 184	222	176	Germany	Caucasian^a	Gc1F, Gc1S, Gc2	Excess of Gc1-1 and a deficit of Gc2-1 and Gc2-2 (p < 0.01) in cases versus controls
	Papiha et al.185	215	402 (203 family &199 unrelated)	United Kingdom	Caucasian^a	Gc1F, Gc1S, Gc2	NS with Gc2 allele. However, lower frequency of Gc1S in female cases than controls (50% versus 63%, p < 0.025)
	Rudduck et al.188	152	3384	Sweden	Caucasian^a	Gc1F, Gc1S, Gc2	NS
	Saha and Tsoi, 186	423 males	595	Singapore	Asian^a	Gc1F, Gc1S, Gc2	Gc1S appears to offer protection against schizophrenia. Excess of Gc2 allele over Gc1 (p < 0.005) and lack of Gc1S in cases (p < 0.001) was observed. RR for Gc1F, Gc1S, and Gc2 estimated as 1.12, 0.76, and 1.15, respectively.

Acronyms used in table: CI = Confidence Interval (95%); OR = Odds Ratio; RR = Relative Risk. Abbreviations used in table: NS = no significant association between polymorphisms studied and disease risk; AATD = α1-antitrypsin deficiency; HOMA (Homeostatis model assessment) is a measure used to quantify insulin resistance and beta cell function. In the cited study, HOMA(R) was calculated as [the fasting plasma glucose concentration (mg/dL)] × [fasting plasma insulin concentration (μU/mL)]/405 68.

^aIn these studies, ethnicity was not clearly provided so they are assumed to be representative of the ethnic majority of the country where the study originates.

^bSample was 99% Caucasian; the remainder of the sample was comprised of African-American, Asian, Hispanic and other ethnicities.

^cFamily collections included samples from Ireland, Romania, Norway and families from the Human Biological Data Interchange.

^dEthnicity included Gujarati Asians (United Kingdom), White, Black, Mixed Ethnicity (Brazil), Xhosa and Cape Colored (South Africa).

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