The association between vitamin D receptor (
Autoimmune thyroid disease (AITD), mainly including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), is an organ-specific autoimmune disease and affects up to 5% of the general population [
Vitamin D is a fat-soluble vitamin and is activated in the liver and kidney [
All related articles were obtained by systematically searching PubMed, Embase, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI). The search keywords were as follows: “vitamin D receptor OR VDR,” “polymorphism OR genetic variation OR genetic variant,” and “autoimmune thyroid disease OR AITD OR thyroid.” There were no limitations on language and year of publication. The last search was updated on August 28, 2017. Furthermore, the references of all related articles were also retrieved to find other eligible studies.
All eligible studies must meet the following inclusion criteria: (a) case-control studies; (b) evaluation of the association between
Two authors independently reviewed the related articles and extracted the following data: first author’s name, year of publication, region, ethnicity, genotyping methods, the number of cases and controls, and genotype/allele frequency. Any disagreement was resolved by discussion with each other.
Hardy-Weinberg equilibrium (HWE) in the control group of each study was calculated by chi-square goodness-of-fit test, and
The flowchart for identifying eligible studies is shown in Figure
The flowchart for identifying eligible studies.
The main characteristics of all included articles.
First author | Year of publication | Region | Ethnicity | Cases | Controls | Genotyping method | Polymorphisms |
---|---|---|---|---|---|---|---|
Giovinazzo [ |
2016 | Italy | European | 100 HT | 100 | PCR–RFLP | rs731236, rs7975232, rs1544410 |
Guleryuz [ |
2016 | Turkey | Asian | 136 HT | 50 | PCR–RFLP | rs731236, rs2228570 |
Long [ |
2015 | China | Asian | 260 GD | 221 | PCR–RFLP | rs7975232 |
Meng [ |
2015 | China | Asian | 417 GD and 250 HT | 301 | MALDI-TOF-MS | rs731236, rs7975232, rs2228570, rs1544410 |
Djurovic [ |
2015 | Serbia | European | 44 HT | 32 | PCR–RFLP | rs731236, rs7975232, rs2228570 |
Inoue [ |
2014 | Japan | Asian | 139 GD and 116 HT | 76 | PCR–RFLP | rs731236, rs7975232, rs2228570, rs1544410 |
Yu [ |
2013 | China | Asian | 75 HT | 80 | PCR–RFLP | rs1544410 |
Yazici [ |
2013 | Turkey | Asian | 111 HT | 159 | PCR–RFLP | rs731236, rs7975232, rs2228570, rs1544410 |
El Gawad [ |
2012 | Egypt | African | 90 GD | 55 | PCR–RFLP | rs731236, rs7975232, rs1544410 |
Hong [ |
2011 | China | Asian | 82 HT | 80 | PCR–RFLP | rs2228570 |
Huo [ |
2010 | China | Asian | 120 GD and 115 HT | 120 | PCR–RFLP | rs1544410 |
Horst-Sikorska [ |
2008 | Poland | European | 75 GD | 163 | PCR–RFLP | rs731236, rs7975232, rs2228570, rs1544410 |
Maalej [ |
2008 | Tunisia | African | 100 AITD | 100 | PCR–RFLP | rs731236, rs2228570, rs1544410 |
Jing [ |
2008 | China | Asian | 115 HT | 120 | PCR–RFLP | rs1544410 |
Stefanić [ |
2008 | Croatia | European | 145 HT | 145 | PCR–RFLP | rs731236, rs7975232, rs1544410 |
Chen [ |
2007 | Taiwan | Asian | 88 GD | 90 | PCR–RFLP | rs2228570 |
Lin [ |
2006 | Taiwan | Asian | 109 HT | 90 | PCR–RFLP | rs2228570 |
Ramos-Lopez [ |
2005 | Germany, Poland, Serbia | European | 789 GD | 823 | PCR–RFLP | rs731236, rs7975232, rs2228570, rs1544410 |
Stefanić [ |
2005 | Croatia | European | 110 GD | 99 | PCR–RFLP | rs731236, rs7975232, rs1544410 |
Kang [ |
2005 | China | Asian | 102 GD | 120 | PCR–RFLP | rs7975232, rs1544410 |
Collins [ |
2004 | United Kingdom | European | 768 GD | 864 | PCR–RFLP | rs731236, rs7975232, rs2228570, rs1544410 |
Ban [ |
2000 | Japan | Asian | 180 GD | 195 | PCR–RFLP | rs7975232, rs2228570, rs1544410 |
PCR–RFLP: polymerase chain reaction-restriction fragment length polymorphism; MALDI-TOF-MS: matrix-assisted laser desorption ionization-time of flight mass spectrometry.
The association between
The association between
Comparison model | Subgroup | The number of studies | Sample size (cases/controls) | Effect model | OR (95% CI) | |||
---|---|---|---|---|---|---|---|---|
Homozygote comparison (CC versus TT) | AITD | 14 | 1930/1341 | 54% | 0.008 | Random | 0.02 | |
HT | 7 | 625/579 | 41% | 0.12 | Fixed | 0.005 | ||
GD | 9 | 1305/1087 | 53% | 0.03 | Random | 0.71 [0.49, 1.04] | 0.08 | |
European | 9 | 930/891 | 53% | 0.03 | Random | 0.75 [0.54, 1.05] | 0.09 | |
Asian | 4 | 942/424 | 47% | 0.13 | Fixed | 0.01 | ||
African | 1 | 58/26 | — | — | — | 0.02 | ||
Heterozygote comparison (CT versus TT) | AITD | 14 | 2674/1949 | 70% | <0.001 | Random | 0.82 [0.64, 1.05] | 0.11 |
HT | 7 | 827/778 | 72% | 0.002 | Random | 0.82 [0.52, 1.29] | 0.38 | |
GD | 9 | 1847/1546 | 65% | 0.004 | Random | 0.85 [0.65, 1.11] | 0.22 | |
European | 9 | 1471/1354 | 50% | 0.04 | Random | 0.97 [0.84, 1.13] | 0.71 | |
Asian | 4 | 1123/551 | 82% | <0.001 | Random | 0.69 [0.35, 1.35] | 0.27 | |
African | 1 | 80/44 | — | — | — | 0.007 | ||
Dominant model (CC + CT versus TT) | AITD | 14 | 2950/2254 | 75% | <0.001 | Random | 0.79 [0.61, 1.02] | 0.07 |
HT | 7 | 895/861 | 75% | <0.001 | Random | 0.81 [0.51, 1.29] | 0.38 | |
GD | 9 | 2055/1769 | 71% | <0.001 | Random | 0.81 [0.61, 1.07] | 0.13 | |
European | 9 | 1705/1615 | 62% | 0.007 | Random | 0.90 [0.70, 1.15] | 0.39 | |
Asian | 4 | 1155/584 | 84% | <0.001 | Random | 0.69 [0.34, 1.37] | 0.29 | |
African | 1 | 90/55 | — | — | — | 0.003 | ||
Recessive model (CC versus CT + TT) | AITD | 14 | 2950/2254 | 7% | 0.37 | Fixed | 0.01 | |
HT | 7 | 895/861 | 0% | 0.44 | Fixed | 0.71 [0.50, 1.01] | 0.06 | |
GD | 9 | 2055/1769 | 6% | 0.38 | Fixed | 0.84 [0.68, 1.03] | 0.09 | |
European | 9 | 1705/1615 | 26% | 0.21 | Fixed | 0.83 [0.68, 1.01] | 0.06 | |
Asian | 4 | 1155/584 | 0% | 0.61 | Fixed | 0.67 [0.39, 1.17] | 0.16 | |
African | 1 | 90/55 | — | — | — | 0.50 [0.20, 1.27] | 0.14 | |
Allele comparison (C versus T) | AITD | 15 | 3050/2354 | 73% | <0.001 | Random | 0.85 [0.71, 1.02] | 0.09 |
HT | 7 | 895/861 | 70% | 0.003 | Random | 0.85 [0.61, 1.19] | 0.35 | |
GD | 9 | 2055/1769 | 70% | <0.001 | Random | 0.83 [0.68, 1.02] | 0.08 | |
European | 9 | 1705/1615 | 66% | 0.003 | Random | 0.89 [0.74, 1.07] | 0.21 | |
Asian | 4 | 1155/584 | 79% | 0.003 | Random | 0.77 [0.47, 1.26] | 0.30 | |
African | 2 | 190/155 | 92% | <0.001 | Random | 0.84 [0.27, 2.54] | 0.75 | |
14 | 2950/2254 | 72% | <0.001 | Random | 0.04 |
Forest plot of the association of
rs731236
rs1544410
rs2228570
rs7975232
The association of
The association between
Comparison model | Subgroup | The number of studies | Sample size (cases/controls) | Effect model | OR (95% CI) | |||
---|---|---|---|---|---|---|---|---|
Homozygote comparison (AA versus GG) | AITD | 17 | 2405/2032 | 57% | 0.002 | Random | 0.74 [0.53, 1.02] | 0.07 |
HT | 8 | 763/837 | 34% | 0.15 | Fixed | 0.80 [0.55, 1.16] | 0.24 | |
GD | 12 | 1642/1631 | 68% | <0.001 | Random | 0.71 [0.46, 1.09] | 0.11 | |
European | 8 | 959/1076 | 65% | 0.005 | Random | 0.02 | ||
Asian | 8 | 1400/928 | 0% | 0.47 | Fixed | 1.51 [0.90, 2.55] | 0.12 | |
African | 1 | 46/28 | — | — | — | 0.002 | ||
13 | 1823/1539 | 62% | 0.001 | Random | 0.04 | |||
4 | 582/493 | 28% | 0.24 | Fixed | 1.06 [0.70, 1.61] | 0.79 | ||
Heterozygote comparison (AG versus GG) | AITD | 17 | 3180/2788 | 38% | 0.05 | Random | 0.99 [0.84, 1.18] | 0.93 |
HT | 8 | 925/984 | 0% | 0.63 | Fixed | 1.07 [0.84, 1.36] | 0.61 | |
GD | 12 | 2255/2285 | 60% | 0.004 | Random | 0.99 [0.78, 1.25] | 0.94 | |
European | 8 | 1432/1638 | 0% | 0.85 | Fixed | 0.02 | ||
Asian | 8 | 1666/1110 | 22% | 0.25 | Fixed | 0.008 | ||
African | 1 | 82/40 | — | — | — | 0.56 [0.25, 1.23] | 0.15 | |
13 | 2475/2103 | 22% | 0.22 | Fixed | 0.95 [0.82, 1.08] | 0.42 | ||
4 | 705/685 | 71% | 0.01 | Random | 1.32 [0.69, 2.54] | 0.41 | ||
Dominant model (AA + AG versus GG) | AITD | 17 | 3636/3373 | 61% | <0.001 | Random | 0.98 [0.80, 1.20] | 0.82 |
HT | 8 | 1009/1089 | 25% | 0.23 | Fixed | 1.03 [0.82, 1.29] | 0.82 | |
GD | 12 | 2627/2769 | 73% | <0.001 | Random | 0.97 [0.74, 1.27] | 0.81 | |
European | 8 | 1835/2177 | 3% | 0.41 | Fixed | 0.002 | ||
Asian | 8 | 1711/1141 | 44% | 0.09 | Random | 0.02 | ||
African | 1 | 90/55 | — | — | — | 0.02 | ||
13 | 2869/2593 | 56% | 0.008 | Random | 0.91 [0.74, 1.12] | 0.38 | ||
4 | 767/780 | 77% | 0.004 | Random | 1.39 [0.70, 2.76] | 0.34 | ||
Recessive model (AA versus AG + GG) | AITD | 17 | 3636/3373 | 58% | 0.002 | Random | 0.79 [0.59, 1.06] | 0.11 |
HT | 8 | 1009/1089 | 35% | 0.15 | Fixed | 0.82 [0.59, 1.13] | 0.22 | |
GD | 12 | 2627/2769 | 67% | <0.001 | Random | 0.77 [0.53, 1.12] | 0.17 | |
European | 8 | 1835/2177 | 71% | 0.001 | Random | 0.74 [0.53, 1.02] | 0.06 | |
Asian | 8 | 1711/1141 | 0% | 0.57 | Fixed | 1.42 [0.87, 2.33] | 0.16 | |
African | 1 | 90/55 | — | — | — | 0.005 | ||
13 | 2869/2593 | 63% | 0.001 | Random | 0.72 [0.51, 1.01] | 0.05 | ||
4 | 767/780 | 8% | 0.35 | Fixed | 1.18 [0.82, 1.72] | 0.37 | ||
Allele comparison (A versus G) | AITD | 18 | 3736/3473 | 72% | <0.001 | Random | 0.96 [0.81, 1.13] | 0.63 |
HT | 8 | 1009/1089 | 58% | 0.02 | Random | 1.08 [0.81, 1.44] | 0.60 | |
GD | 12 | 2627/2769 | 80% | <0.001 | Random | 0.97 [0.77, 1.21] | 0.76 | |
European | 8 | 1835/2177 | 66% | 0.005 | Random | 0.02 | ||
Asian | 8 | 1711/1141 | 58% | 0.02 | Random | 0.02 | ||
African | 2 | 190/155 | 72% | 0.06 | Random | 0.64 [0.35, 1.15] | 0.14 | |
13 | 2969/2693 | 70% | <0.001 | Random | 0.89 [0.75, 1.06] | 0.21 | ||
4 | 767/780 | 79% | 0.002 | Random | 1.44 [0.78, 2.65] | 0.24 |
The association between
The association between
Comparison model | Subgroup | The number of studies | Sample size (cases/controls) | Effect model | OR (95% CI) | |||
---|---|---|---|---|---|---|---|---|
Homozygote comparison (TT versus CC) | AITD | 14 | 1713/1474 | 64% | <0.001 | Random | 0.76 [0.55, 1.04] | 0.09 |
HT | 7 | 509/440 | 27% | 0.22 | Fixed | 0.77 [0.55, 1.07] | 0.11 | |
GD | 9 | 1204/1224 | 73% | <0.001 | Random | 0.79 [0.54, 1.15] | 0.22 | |
European | 6 | 819/907 | 72% | 0.003 | Random | 0.93 [0.58, 1.49] | 0.76 | |
Asian | 8 | 894/567 | 45% | 0.08 | Random | 0.02 | ||
11 | 1409/1301 | 71% | <0.001 | Random | 0.78 [0.53, 1.14] | 0.20 | ||
3 | 304/173 | 0% | 0.89 | Fixed | 0.65 [0.42, 1.00] | 0.05 | ||
Heterozygote comparison (CT versus CC) | AITD | 14 | 2478/2123 | 72% | <0.001 | Random | 0.02 | |
HT | 7 | 665/600 | 77% | 0.001 | Random | 0.61 [0.35, 1.06] | 0.08 | |
GD | 9 | 1813/1832 | 65% | 0.004 | Random | 0.83 [0.64, 1.07] | 0.14 | |
European | 6 | 1145/1315 | 77% | <0.001 | Random | 0.78 [0.52, 1.16] | 0.22 | |
Asian | 8 | 1333/808 | 70% | 0.001 | Random | 0.68 [0.47, 1.00] | 0.05 | |
11 | 2008/1762 | 66% | 0.001 | Random | 0.84 [0.64, 1.10] | 0.21 | ||
3 | 470/361 | 32% | 0.23 | Fixed | <0.001 | |||
Dominant model (TT + CT versus CC) | AITD | 14 | 3174/2836 | 76% | <0.001 | Random | <0.001 | |
HT | 7 | 839/788 | 77% | <0.001 | Random | 0.60 [0.35, 1.02] | 0.06 | |
GD | 9 | 2335/2425 | 72% | <0.001 | Random | 0.81 [0.62, 1.06] | 0.12 | |
European | 6 | 1562/1795 | 80% | <0.001 | Random | 0.78 [0.52, 1.18] | 0.24 | |
Asian | 8 | 1612/1041 | 72% | <0.001 | Random | 0.02 | ||
11 | 2616/2416 | 74% | <0.001 | Random | 0.81 [0.60, 1.08] | 0.14 | ||
3 | 558/420 | 36% | 0.21 | Fixed | <0.001 | |||
Recessive model (TT versus CT + CC) | AITD | 14 | 3174/2836 | 54% | 0.008 | Random | 0.87 [0.68, 1.10] | 0.23 |
HT | 7 | 839/788 | 0% | 0.46 | Fixed | 0.79 [0.59, 1.06] | 0.11 | |
GD | 9 | 2335/2425 | 64% | 0.004 | Random | 0.90 [0.68, 1.19] | 0.46 | |
European | 6 | 1562/1795 | 60% | 0.03 | Random | 1.05 [0.76, 1.45] | 0.79 | |
Asian | 8 | 1612/1041 | 23% | 0.24 | Fixed | 0.005 | ||
11 | 2616/2416 | 64% | 0.002 | Random | 0.83 [0.62, 1.11] | 0.20 | ||
3 | 558/420 | 0% | 0.89 | Fixed | 1.02 [0.71, 1.48] | 0.91 | ||
Allele comparison (T versus C) | AITD | 15 | 3274/2936 | 75% | <0.001 | Random | 0.01 | |
HT | 7 | 839/788 | 72% | 0.001 | Random | 0.03 | ||
GD | 9 | 2335/2425 | 76% | <0.001 | Random | 0.87 [0.73, 1.05] | 0.15 | |
European | 6 | 1562/1795 | 79% | <0.001 | Random | 0.90 [0.70, 1.16] | 0.41 | |
Asian | 8 | 1612/1041 | 69% | 0.002 | Random | 0.008 | ||
African | 1 | 100/100 | — | — | — | 0.86 [0.53, 1.39] | 0.54 | |
11 | 2716/2516 | 77% | <0.001 | Random | 0.83 [0.68, 1.01] | 0.06 | ||
3 | 558/420 | 38% | 0.20 | Fixed | 0.01 |
For
The association between
Comparison model | Subgroup | The number of studies | Sample size (cases/controls) | Effect model | OR (95% CI) | |||
---|---|---|---|---|---|---|---|---|
Homozygote comparison (CC versus AA) | AITD | 16 | 1899/1606 | 76% | <0.001 | Random | 1.16 [0.84, 1.61] | 0.37 |
HT | 6 | 396/434 | 33% | 0.19 | Fixed | 1.11 [0.80, 1.55] | 0.52 | |
GD | 12 | 1503/1403 | 81% | <0.001 | Random | 1.22 [0.81, 1.83] | 0.34 | |
European | 9 | 983/1016 | 71% | <0.001 | Random | 1.10 [0.76, 1.60] | 0.62 | |
Asian | 6 | 876/561 | 80% | <0.001 | Random | 1.02 [0.55, 1.92] | 0.94 | |
African | 1 | 40/29 | — | — | — | 0.001 | ||
12 | 1714/1439 | 76% | <0.001 | Random | 1.14 [0.81, 1.61] | 0.45 | ||
4 | 185/167 | 82% | 0.001 | Random | 1.19 [0.39, 3.64] | 0.75 | ||
Heterozygote comparison (CA versus AA) | AITD | 16 | 2436/2287 | 61% | <0.001 | Random | 1.04 [0.83, 1.31] | 0.71 |
HT | 6 | 504/538 | 30% | 0.21 | Fixed | 1.11 [0.84, 1.47] | 0.45 | |
GD | 12 | 1932/1926 | 67% | <0.001 | Random | 1.03 [0.79, 1.36] | 0.81 | |
European | 9 | 1468/1585 | 43% | 0.08 | Random | 1.02 [0.82, 1.27] | 0.86 | |
Asian | 6 | 904/654 | 71% | 0.004 | Random | 0.91 [0.56, 1.47] | 0.70 | |
African | 1 | 64/48 | — | — | — | 0.008 | ||
12 | 2152/1976 | 66% | <0.001 | Random | 1.06 [0.83, 1.37] | 0.63 | ||
4 | 284/311 | 55% | 0.09 | Random | 0.96 [0.53, 1.75] | 0.90 | ||
Dominant model (CC + CA versus AA) | AITD | 16 | 3544/3117 | 73% | <0.001 | Random | 1.08 [0.84, 1.38] | 0.56 |
HT | 6 | 757/812 | 37% | 0.16 | Fixed | 1.08 [0.83, 1.40] | 0.56 | |
GD | 12 | 2787/2681 | 78% | <0.001 | Random | 1.09 [0.80, 1.49] | 0.57 | |
European | 9 | 1884/2011 | 61% | 0.009 | Random | 1.04 [0.81, 1.34] | 0.73 | |
Asian | 6 | 1570/1051 | 79% | <0.001 | Random | 0.94 [0.55, 1.60] | 0.81 | |
African | 1 | 90/55 | — | — | — | 0.001 | ||
12 | 3159/2727 | 75% | <0.001 | Random | 1.10 [0.84, 1.45] | 0.50 | ||
4 | 385/390 | 71% | 0.02 | Random | 0.97 [0.48, 1.96] | 0.94 | ||
Recessive model (CC versus CA + AA) | AITD | 16 | 3544/3117 | 59% | 0.001 | Random | 1.10 [0.90, 1.33] | 0.36 |
HT | 6 | 757/812 | 18% | 0.29 | Fixed | 0.97 [0.77, 1.21] | 0.78 | |
GD | 12 | 2787/2681 | 67% | <0.001 | Random | 1.13 [0.89, 1.42] | 0.31 | |
European | 9 | 1884/2011 | 58% | 0.02 | Random | 1.06 [0.81, 1.40] | 0.65 | |
Asian | 6 | 1570/1051 | 62% | 0.02 | Random | 1.06 [0.79, 1.42] | 0.71 | |
African | 1 | 90/55 | — | — | — | 0.03 | ||
12 | 3159/2727 | 52% | 0.02 | Random | 1.06 [0.87, 1.28] | 0.57 | ||
4 | 385/390 | 77% | 0.005 | Random | 1.25 [0.58, 2.68] | 0.57 | ||
Allele comparison (C versus A) | AITD | 16 | 3544/3117 | 75% | <0.001 | Random | 1.06 [0.91, 1.24] | 0.44 |
HT | 6 | 757/812 | 33% | 0.19 | Fixed | 1.01 [0.87, 1.17] | 0.88 | |
GD | 12 | 2787/2681 | 81% | <0.001 | Random | 1.09 [0.90, 1.32] | 0.37 | |
European | 9 | 1884/2011 | 70% | <0.001 | Random | 1.04 [0.86, 1.25] | 0.69 | |
Asian | 6 | 1570/1051 | 78% | <0.001 | Random | 1.00 [0.77, 1.31] | 0.98 | |
African | 1 | 90/55 | — | — | — | <0.001 | ||
12 | 3159/2727 | 76% | <0.001 | Random | 1.06 [0.90, 1.25] | 0.47 | ||
4 | 385/390 | 79% | 0.002 | Random | 1.04 [0.65, 1.66] | 0.88 |
A sensitivity analysis showed that the pooled OR values were not substantially changed after one study deletion each time, which suggests that results of this meta-analysis were stable. As shown in Figure
Funnel plot of the association of
rs731236
rs1544410
rs2228570
rs7975232
Egger’s test results for the publication bias of
Comparison model | ||||
---|---|---|---|---|
rs731236 | rs1544410 | rs2228570 | rs7975232 | |
Homozygote comparison | 0.516 | 0.626 | 0.125 | 0.258 |
Heterozygote comparison | 0.271 | 0.521 | 0.07 | 0.274 |
Dominant model | 0.287 | 0.444 | 0.07 | 0.283 |
Recessive model | 0.381 | 0.933 | 0.092 | 0.130 |
Allele comparison | 0.307 | 0.422 | 0.062 | 0.186 |
As an immune modulator, vitamin D is involved in the onset and development of AITD [
Heterogeneity was observed in the current meta-analysis. We tried to investigate the sources of heterogeneity by a stratification analysis based on clinical types, ethnicity, and HWE, but the investigation results were not satisfactory and could not provide a reasonable explanation for the sources of heterogeneity. In view of factors affecting vitamin D levels and methodological issues, heterogeneity may result from differences in economic and public health indexes among different countries, variations in environment and climate, age and gender mismatch in published studies, and variations in diagnostic criteria for GD/HT.
Although the current results showed the statistically significant associations of
In conclusion, the present study suggested that
The authors declare that they have no competing interests.
Table S1: genotype and allele frequency distributions of