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Vitamin D deficiency associates with susceptibility to tuberculosis in Pakistan, but polymorphisms in VDR, DBP and CYP2R1 do not.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in the genes encoding the vitamin D receptor (VDR) and the vitamin D binding protein (DBP) have been reported to modify the influence of vitamin D deficiency on susceptibility to active tuberculosis (TB) in the UK, but this phenomenon has not been investigated in settings with a high TB burden. SNPs in CYP2R1, which encodes a vitamin D 25-hydroxylase enzyme, are known to influence vitamin D status, but their potential role in determining susceptibility to TB has not previously been investigated in any setting.We conducted a case-control study in 260 pulmonary TB patients and 112 controls recruited in Lahore, Pakistan. Analyses were conducted to test for main effects of vitamin D status and SNPs in VDR (rs731236, rs2228570 and rs1544410), DBP (rs7041 and rs4588) and CYP2R1 (rs2060793, rs10500804 and rs10766197) on susceptibility to TB, and to investigate whether these SNPs modify the association between vitamin D status and disease susceptibility.Profound vitamin D deficiency (serum 25-hydroxyvitamin D concentration???20 nmol/L) was common among TB patients (118/260, 45 %), and was independently associated with susceptibility to TB (adjusted odds ratio 1.87, 95 % CI 1.15 to 3.04, P?=?0.01). However, none of the SNPs investigated associated with susceptibility to TB, either in main effects analysis, or in interaction with vitamin D status.Profound vitamin D deficiency was common among TB patients in this high-burden setting, and was independently associated with disease susceptibility. However, no statistically significant associations between SNPs in the vitamin D pathway and disease susceptibility was demonstrated.

SUBMITTER: Junaid K

PROVIDER: S-EPMC4862192 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Vitamin D deficiency associates with susceptibility to tuberculosis in Pakistan, but polymorphisms in VDR, DBP and CYP2R1 do not.

Junaid Kashaf K Rehman Abdul A Jolliffe David A DA Saeed Tahir T Wood Kristie K Martineau Adrian R AR

BMC pulmonary medicine 20160510 1

<h4>Background</h4>Single nucleotide polymorphisms (SNPs) in the genes encoding the vitamin D receptor (VDR) and the vitamin D binding protein (DBP) have been reported to modify the influence of vitamin D deficiency on susceptibility to active tuberculosis (TB) in the UK, but this phenomenon has not been investigated in settings with a high TB burden. SNPs in CYP2R1, which encodes a vitamin D 25-hydroxylase enzyme, are known to influence vitamin D status, but their potential role in determining ...[more]

PMID: 27160686

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Project description:Abstract Vitamin D binding protein (DBP) is one of regulators of vitamin D serum levels. rs4588 and rs7041 polymorphisms of the DBP gene constitute the genetic basis of the three major isoforms of circulating DBP, called GC1s, GC1f and GC2. We evaluated the association between the rs4588, rs7041, rs2282679 SNPs and of DBP isoforms with DBP and 25(OH)D serum levels and investigated whether these gene variants influence on the presence of vitamin D deficiency in a non-selected women sample. In this cross-sectional study, bio-repository samples of 443 apparently healthy women aged 20 to 72 years were analyzed. Most of the participants were ppostmenopausal (n=359). Sufficient circulating levels of 25(OH)D was considered as ≥20ng/mL and deficiency as <20ng/mL. Clinical and biochemical profile were collected. Participants were genotyped for rs4588, rs7041, and rs2282679 polymorphisms by RT-PCR. BDP isoforms were constructed from the combination of the rs4588 and rs7041 polymorphisms, where GC1s= rs4588CC and rs7041GG; GC1f= rs4588CC and rs7041TT and Gc2= rs4588AA and rs7041TT. Mean age and BMI were 53.4±9.4 years and 27.8±5.8, respectively. 25(OH)D levels in total sample was 22.8±8.3ng/mL and 60% had adequate circulating 25(OH)D levels. rs4588, rs2282679 SNPs and the GC2 isoforms were associated with lower DBP levels (rs4588: CC=203.0±28.3; CA=196.5±29.9; AA=184.0±36.9; linear p trend<0.001, B=-8.4; rs2282679: AA=203.1±27.9; AC=196.4±30.0; CC=180.9±38.2; linear p trend<0.001, B=-9.3; and DBP isoforms: GC1s=199.4±29.9; GC1f=204.8±31.6; GC2=180.8±37.6; linear p trend=0.012, B=-7.7) and rs2282689 as well as GC2 isoform were associated with lower 25(OH)D levels (rs2282679: AA=23.4±8.8; AC=22.8±7.8; CC=19.7±7.2; linear p trend=0.034, B=-1.3; and DBP isoforms: GC1s=23.8±9.2; GC1f=20.6±8.3; GC2=20.3±7.4; linear p trend=0.015, B=-1.9). CC genotype of rs2282679 (PR 1.74; 95%CI 1.30;2.24; p<0.001), GC2 isoform (PR 1.66; 95%CI 1.17; 2.38; p=0.005), time since menopause (PR 1.02; 95%CI 1.003;1.03, p= 0.016) and HOMA-IR (PR 1.02; 95%CI 1.01;1.03, p= 0.004) were associated with higher prevalence ratios for 25(OH)D deficiency. DBP levels (per 30 ug/mL of DBP increase, PR 0.89; 95%CI 0.80;0.99; p=0.027) were related to lower prevalence ratios for 25(OH)D deficiency. Except for HOMA-IR, these PR remained significant after adjustment for age and BMI. In conclusion, the present results suggest that rs2282679 and the GC2 isoform of DBP are related to lower DBP serum levels and with the susceptibility to 25(OH)D deficiency in adult and postmenopausal women. Support: CNPq, FAPERGS and FIPE/HCPA

Project description:Objective: Vitamin D receptor (VDR) mediates vitamin D activity. We examined whether VDR expression in excised melanoma tissues is associated with VDR gene (VDR) polymorphisms.Methods: We evaluated VDR protein expression (by monoclonal antibody immunostaining), melanoma characteristics, and carriage of VDR-FokI-rs2228570 (C>T),VDR-BsmI-rs1544410 (G>A),VDR-ApaI-rs7975232 (T>G), andVDR-TaqI-rs731236 (T>C) polymorphisms (by restriction fragment length polymorphism). Absence or presence of restriction site was denoted by a capital or lower letter, respectively: " F" and " f" for FokI, " B" and " b" for BsmI, " A" and " a" for ApaI, and " T" and " t" for TaqI endonuclease. Seventy-four Italian cutaneous primary melanomas (52.1±12.7 years old) were studied; 51.4% were stage I, 21.6% stage II, 13.5% stage III, and 13.5% stage IV melanomas. VDR expression was categorized as follows: 100% positivevs. <100%; over the median 20% (high VDR expression) vs. ≤20% (low VDR expression); absence vs. presence of VDR-expressing cells.Results: Stage I melanomas, Breslow thickness of <1.00 mm, level II Clark invasion, Aa heterozygous genotype, and AaTT combined genotype were more frequent in melanomas with high vs. low VDR expression. Combined genotypes BbAA, bbAa, AATt, BbAATt, and bbAaTT were more frequent in 100% vs. <100% VDR-expressing cells. Combined genotype AATT was more frequent in melanomas lacking VDR expression (odds ratio=14.5; P=0.025). VDR expression was not associated with metastasis, ulceration, mitosis >1, regression, tumor-infiltrating lymphocytes, tumoral infiltration of vascular tissues, additional skin and non-skin cancers, and melanoma familiarity.Conclusions: We highlighted that VDR polymorphisms can affect VDR expression in excised melanoma cells. Low VDR expression in AATT carriers is a new finding that merits further study. VDR expression possibly poses implications for vitamin D supplementation against melanoma. VDR expression and VDR genotype may become precise medicinal tools for melanoma in the future.

Dataset Information

Vitamin D deficiency associates with susceptibility to tuberculosis in Pakistan, but polymorphisms in VDR, DBP and CYP2R1 do not.

Publications

Vitamin D deficiency associates with susceptibility to tuberculosis in Pakistan, but polymorphisms in VDR, DBP and CYP2R1 do not.

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