Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms

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Original article

Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms Susceptibilité génétique aux maladies thyroïdiennes auto-immunes au sein de l’ethnie Han : rôle des polymorphismes génétiques du récepteur à la vitamine D Shuai Meng , Shuang-tao He , Wen-juan Jiang , Ling Xiao , Dan-feng Li , Jian Xu , Xiao-hong Shi , Jin-an Zhang ∗ Department of Endocrinology, Jinshan Hospital of Fudan University, 1508, Longhang Road, Shanghai 201508, China

Abstract Purpose. – Previous studies have found that some immune-related genes were associated with autoimmune thyroid diseases (AITDs). A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms and susceptibility to AITDs in different populations and found conflicting results. This case-control study was designed to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs in a Chinese Han population. Methods. – A total of 417 patients with Graves’ disease (GD), 250 patients with Hashimoto’s thyroiditis (HT) and 301 healthy subjects were enrolled. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was applied to detect four SNPs (rs1544410, rs2228570, rs731236 and rs7975232) in the VDR gene. Results. – In the rs7975232 allele A frequency showed a significant increase in GD patients (30.34% vs. 25.42% in controls; P = 0.041, OR = 1.278, 95%CI = 1.010–1.617). However, no relationship was found between clinical phenotypes and the four SNPs. Conclusions. – This result suggests that the VDR gene may be one susceptibility gene which contributes to the risk of GD. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Autoimmune thyroid disease (AITD); Graves’ disease (GD); Hashimoto’s thyroiditis (HT); Vitamin D receptor (VDR); Single nucleotide polymorphism (SNP)

Résumé Objectif. – Des études antérieures ont retrouvé que des gènes liés au système immunitaire étaient associés à des maladies auto-immunes de la thyroïde (AITD). Plusieurs études ont exploré l’association entre les polymorphismes génétiques du récepteur à la vitamine D (1,25-dihydroxyvitamine D3) (VDR) et la susceptibilité aux AITD dans différentes populations avec des résultats contradictoires. Cette étude cas-témoins a été conc¸ue pour évaluer le rôle des polymorphismes du gène du VDR dans la prédisposition aux AITD dans une population chinoise Han. Méthodes. – Un total de 417 patients atteints de la maladie de Basedow (Graves’ disease [GD]), 250 patients atteints de la thyroïdite de Hashimoto (HT) et 301 sujets sains a été recruté. La désorption-ionisation laser assistée par matrice-spectromètre de masse à temps de vol (MALDI-TOMS) a été utilisée pour détecter quatre polymorphismes de nucléotide unique (SNP) (rs1544410, rs2228570, rs731236 et rs7975232) dans le gène VDR. Résultats. – Dans les rs7975232, la fréquence de l’allèle A montrait une augmentation significative chez les patients GD (30,34 % contre 25,42 % chez les témoins ; p = 0,041 ; OR = 1,278 ; IC 95 % = 1,010–1,617). Cependant, aucune relation n’était retrouvée entre les phénotypes cliniques et les quatre SNP. Conclusions. – Les données suggèrent que les polymorphismes du gène VDR sont associés à une susceptibilité au GD et que le gène VDR est un gène de susceptibilité au GD. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Maladies thyroïdiennes auto-immunes (MAIT) ; Maladie de Basedow (GD) ; Thyroïdite de Hashimoto (HT) ; Récepteur à la vitamine D (VDR) ; Polymorphisme de nucléotide unique (SNP)

∗

Corresponding author. E-mail address: [email protected] (J.-a. Zhang).

http://dx.doi.org/10.1016/j.ando.2015.01.003 0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Meng S, et al. Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms. Ann Endocrinol (Paris) (2015), http://dx.doi.org/10.1016/j.ando.2015.01.003

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1. Introduction Autoimmune thyroid diseases (AITDs) are organ-specific autoimmune diseases including mainly Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Although the causes for GD and HT are unclear, previous studies have found that genetic and environmental factors and their mutual interaction may contribute to the development of these diseases. Recent studies show that several immune-related genes, such as HLA class II gene, protein tyrosine phosphatase-22 (PTPN22) gene, CTLA4 gene, CD40 gene and other thyroid-specific genes encoding thyroid-stimulating hormone (TSH) receptor and thyroglobulin are associated with AITDs [1]. A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms using single nucleotide polymorphisms (SNPs) and susceptibility to AITDs in different populations and found conflicting results. Some studies show significant differences in VDR SNPs between GD patients and controls [2–4], while others indicate no significant correlation [5,6]. Meanwhile, studies in Taiwan and Croatia reveal that there is a significant association between VDR SNPs and susceptibility to HT [7,8]. In the circumstances of these conflicting results, we aimed to investigate the association of rs1544410, rs2228570, rs731236 and rs7975232 polymorphisms with AITDs in Chinese Han population. 2. Subjects and methods 2.1. Subjects All patients with AITDs (GD and HT) in this case-control study were recruited from the Endocrinology Department of the Jinshan Hospital of Fudan University. As Table 1 shows, Table 1 Clinical data of AITD patients and controls.

our study investigated a total of 667 AITD patients (24.44% men and 75.56% women) comprised of 417 GD (29.74% men and 70.26% women) and 250 HT patients (15.60% men and 84.40% women). Patients with GD were 32.31 ± 14.07 years old in average. Among them, 72 had family history of GD and 98 had ophthalmopathy. Patients with HT were 30.29 ± 13.05 in average. Among them, 54 had family history and 6 had ophthalmopathy. The diagnostic criteria for GD were mainly based on clinical manifestations, laboratory biochemical evidence of hyperthyroidism, and presence of diffuse goiter, circulating TSH receptor antibody (TRAb), thyroglobulin antibody (TGAb), or thyroid peroxidase antibody (TPOAb). HT was defined as enlarged thyroid, high level of either TPOAb or TgAb, with or without clinical and biochemical hypothyroidism. For suspicious HT cases, diagnosis was confirmed by fine needle aspiration biopsies (FNAC). A total of 301 controls without thyroid disease and other autoimmune diseases were selected from health examination in the Health Check-up Center of the same hospital. Also, all the normal individuals enrolled had no relative relationship with each other. Both AITD patients and controls were Han Chinese and an informed consent was signed by each individual. The research project was approved by the Ethics Committee of the hospital. 2.2. Genotyping method Peripheral venous blood of 2 ml from each subject was collected in a tube containing ethylene diamine tetraacetic acid (EDTA). The genomic DNA was extracted using Relax Gene Blood DNA System (Tiangen Biotech, Beijing, China) according to the manufactures’ protocol. Genotyping of rs1544410, rs2228570, rs731236 and rs7975232 was performed using matrix assisted laser desorption ionization-time of flight mass spectrometer (MALDI-TOF-MS) platform from Sequenom (San Diego, CA, USA). 2.3. Clinical phenotype analyses

GD

HT

Control

n

417

250

301

Gender Female Male

293 (70.26%) 124 (29.74%)

211 (84.40%) 39 (15.60%)

210 (69.77%) 91 (30.23%)

Age

34.48 ± 13.95

31.90 ± 13.10

33.60 ± 12.64

Age of onset

32.31 ± 14.07

30.29 ± 13.05

Thyroid size Normal size

26 (6.21%)

10 (4.13%)

I degree

41 (9.89%)

20 (7.80%)

II degree

272 (65.25%)

194 (77.52%)

III degree

78 (18.64%)

26 (10.55%)

Family history (+) (−)

72 (17.27%) 345 (82.73%)

54 (21.60%) 196 (78.40%)

Ophthalmopathy (+) (−)

98 (23.50%) 319 (76.50%)

6 (2.40%) 244 (97.60%)

Correlations between genotypes and clinical manifestations of GD or HT were separately investigated. The clinical manifestations include: • • • •

the age of symptom onset (≤18 years vs. ≥18 years [9,10]); thyroid size or goiter degree; presence or absence of AITD family history; presence or absence of ophthalmopathy.

The size of thyroid is classified into normal volume and goiter by palpation. Goiter is subclassified into three degrees. I degree is defined as the goiter could not be seen but could be palpated; II degree was defined as the goiter could be seen and palpated, but still located in the sternocleidomastoid; III degree is defined as the goiter is beyond the exterior margin of sternocleidomastoid. In statistical analysis, we assigned all members into two groups according to the size of thyroid, and comparison was made between these two groups (≤I degree vs. ≥II degree). AITD family history is defined as AITD occurrence in the

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subjects’ first-degree relatives including parents, children and siblings or second-degree relatives such as grandparents, uncles and aunts. Ophthalmopathy is defined as distinctive inflammation and swelling of the extraocular muscles, orbital fat, eyelid retraction, periorbital edema, episcleral vascular injection, conjunctiva swelling and proptosis.

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95%CI = 1.010–1.617). Nevertheless, no significant difference was found between the cases and the controls in rs1544410, rs2228570 or rs731236. As Table 3 shows, there was no significant difference in AA genotype of rs7975232 between AITD patients and the controls. 3.2. Haplotype analysis

2.4. Statistical analysis The clinical data are expressed as M ± SD. The SNPs of patients and healthy controls were analyzed using HardyWeinberg equilibrium (HWE) tests (Haploview 4.2 [Broad Institute, Cambridge, MA, USA]) and haplotype frequency calculation and linkage disequilibrium (LD) test. LD among these SNPs was measured using the pairwise LD measures D and r2 . Haplotype blocks were generated using the default algorithm based on methods established by Gabriel et al. [11]. Allele and genotype frequencies between patients and healthy controls were compared using Chi2 test or Fisher’s exact test. Differences between groups were determined by the odds ratio (OR) and 95% confidence interval (95%CI). All statistical analyses were performed using the software SPSS version 13.0. A P value less than 0.05 was considered significant.

According to D’ value, we have detected one LD block containing rs7975232–rs1544410 (within intron 8) using the Haploview 4.2 (Broad Institute, Cambridge, MA, USA). Table 4 shows three common haplotypes (GG, AG and AA) with frequencies over 0.05 found in this block. Unfortunately, none of these three haplotypes were found to be associated with GD or HT (P > 0.05). 3.3. Genotype and clinical phenotype correlations Table 5 shows the comparison of alleles between thyroidassociated ophthalmopathy patients and non-ophthalmopathy ones in GD group, no significant genotype difference was found. Differences between family history (Table 6), age onset (Table 7), goiter degree (data not shown) and these SNPs were also not statistically significant.

3. Results 4. Discussion 3.1. Allele and genotyping results All of these 4 SNPs in both case and control groups were in HWE (P > 0.05). The allele frequencies and case-control association analysis for each SNP are shown in Table 2. GD patients had an increased frequency of allele A in rs7975232 compared with the controls (P = 0.041, OR = 1.278,

The etiology of GD appears to be complicated and involves in multiple genetic and environmental factors. The best known genes contributing to the susceptibility of GD are the human leukocyte antigen (HLA) class II genes and the cytotoxic Tlymphocyte antigen-4 (CTLA4). In addition, certain other genes are also likely to contribute to GD. In this study, we found an

Table 2 Allele and genotype frequencies in AITD patients and the controls. SNP

Alleles

Control (%)

AITD (%)

P

GD (%)

P

rs1544410

AA AG GG A G

0 (0) 31 (10.30) 270 (89.70) 31 (5.15) 571 (94.85)

1 (0.15) 72 (10.79) 594 (89.06) 74 (5.55) 1260 (94.45)

0.775

0 (0) 50 (11.99) 367 (88.01) 50 (6.00) 784 (94.00)

0.480

CC CT TT C T

97 (32.23) 145 (48.17) 59 (19.60) 339 (56.31) 263 (43.69)

210 (31.49) 349 (52.32) 108 (16.19) 769 (57.65) 565 (42.35)

0.344

135 (32.37) 220 (52.76) 62 (14.87) 490 (58.75) 344 (41.25)

0.218

CC CT TT C T

1 (0.33) 34 (11.30) 266 (88.37) 36 (5.98) 566 (94.02)

3 (0.45) 78 (11.69) 586 (87.86) 84 (6.30) 1250 (93.70)

0.949

1 (0.24) 54 (12.95) 362 (86.81) 56 (6.71) 778 (93.29)

0.782

AA AC CC A C

20 (6.65) 113 (37.54) 168 (55.81) 153 (25.42) 449 (74.58)

57 (8.55) 279 (41.83) 331 (49.62) 393 (29.46) 941 (70.54)

0.180

39 (9.35) 175 (41.97) 203 (48.68) 253 (30.34) 581 (69.66)

0.127

rs2228570

rs731236

rs7975232

0.721

0.583

0.789

0.067

OR

95%CI

0.493

0.356

0.575

0.041

1.278

1.010–1.617

HT (%)

P

1 (0.40) 22 (8.80) 227 (90.80) 24 (4.80) 476 (95.20)

0.463

75 (30.00) 129 (51.60) 46 (18.40) 279 (55.80) 221 (44.20)

0.725

2 (0.80) 24 (9.60) 224 (89.60) 28 (5.60) 472 (94.40)

0.623

18 (7.20) 104 (41.60) 128 (51.20) 140 (28.00) 360 (72.00)

0.556

0.791

0.865

0.788

0.334

The bold means the frequency of allele A of rs7975232 was increased in GD patients (P = 0.041).

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Table 3 Genotype distributions of rs1544410, rs2228570, rs731236 and rs7975232 in AITD patients and the controls. SNP

Genotype

Control (%)

AITD (%)

P

GD (%)

rs1544410

AA AG + GG AG AA + GG GG AA + AG CC CT + TT CT CC + TT TT CC + CT CC CT + TT CT CC + TT TT CC + CT AA AC + CC AC AA + CC CC AA + AC

0 (0) 301 (100.00) 31 (10.30) 270 (89.70) 270 (89.70) 31 (10.30) 97 (32.23) 204 (67.77) 145 (48.17) 156 (51.83) 59 (19.60) 242 (80.40) 1 (0.33) 300 (99.67) 34 (11.30) 267 (88.70) 266 (88.37) 35 (11.63) 20 (6.65) 281 (93.35) 113 (37.54) 188 (62.46) 168 (55.81) 133 (44.19)

1 (0.15) 666 (99.85) 72 (10.79) 595 (89.21) 594 (89.06) 73 (10.94) 210 (31.49) 457 (68.51) 349 (52.32) 318 (47.68) 108 (16.19) 559 (83.81) 3 (0.45) 664 (99.55) 78 (11.69) 589 (88.31) 586 (87.86) 81 (12.14) 57 (8.55) 610 (91.45) 279 (41.83) 388 (58.17) 331 (49.62) 336 (50.38)

0.502

0 (0) 417 (100.00) 50 (11.99) 367 (88.01) 367 (88.01) 50 (11.99) 135 (32.37) 282 (67.63) 220 (52.76) 197 (47.24) 62 (14.87) 355 (85.13) 1 (0.24) 416 (99.76) 54 (12.95) 363 (87.05) 362 (86.81) 55 (13.19) 39 (9.35) 378 (90.65) 175 (41.97) 242 (58.03) 203 (48.68) 214 (51.32)

rs2228570

rs731236

rs7975232

0.817 0.764 0.818 0.232 0.194 0.792 0.858 0.819 0.312 0.208 0.075

P

OR

0.480

1.187

0.480

0.843

0.967

1.007

0.225

1.201

0.095

0.716

0.817

0.721

0.505

1.168

0.533

0.866

0.192

1.450

0.233

1.203

0.059

0.751

HT (%)

P

OR

1 (0.40) 249 (99.60) 22 (8.80) 228 (91.20) 227 (90.80) 23 (9.20) 75 (30.00) 175 (70.00) 129 (51.60) 121 (48.40) 46 (18.40) 204 (81.60) 2 (0.80) 248 (99.20) 24 (9.60) 226 (90.40) 224 (89.60) 26 (10.40) 18 (7.20) 232 (92.80) 104 (41.60) 146 (58.40) 128 (51.20) 122 (48.80)

0.272

1.004

0.552

0.840

0.666

1.133

0.575

0.901

0.423

1.147

0.721

0.925

0.458

2.419

0.518

0.834

0.647

1.134

0.798

1.090

0.332

1.185

0.280

0.831

Table 4 Haplotype analysis in AITD patients and the controls. Haplotypes

Control (Frequency)

GD (Frequency)

P

HT (Frequency)

P

Block 1 CG AG AA

449 (0.746) 122 (0.203) 31 (0.051)

585 (0.720) 199 (0.224) 50 (0.056)

0.064 0.107 0.493

360 (0.734) 116 (0.216) 24 (0.050)

0.334 0.239 0.791

Table 5 The allele frequencies of rs2228570, rs731236, rs7975232 and rs1544410 in ophthalmopathy and non-ophthalmopathy GD patients. SNP

Alleles

Ophthalmopathy (%)

Non-ophthalmopathy (%)

P

rs2228570

C T

114 (58.16) 82 (41.84)

377 (59.09) 261 (40.91)

0.817

rs731236

C T

13 (6.63) 183 (93.37)

43 (6.74) 595 (93.26)

0.958

rs7975232

A C

57 (29.08) 139 (70.92)

192 (30.09) 446 (69.91)

0.786

rs1544410

A G

13 (6.63) 183 (93.37)

37 (5.80) 601 (94.20)

0.667

Table 6 The allele frequencies of rs2228570, rs731236, rs7975232 and rs1544410 in patients with and without AITD family history. SNP

Alleles

Family history (+) (%)

Family history (−) (%)

P

rs2228570

C T

143 (56.75) 109 (43.25)

627 (57.95) 455 (42.05)

0.728

rs731236

C T

10 (3.97) 242 (96.03)

74 (6.84) 1008 (93.16)

0.091

rs7975232

A C

65 (25.79) 187 (74.21)

324 (29.94) 758 (70.06)

0.192

rs1544410

A G

10 (3.97) 242 (96.03)

64 (5.91) 1018 (94.09)

0.224

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Table 7 The allele frequencies of rs2228570, rs731236, rs7975232 and rs1544410 in patients whose age of onset was above and below 18 years old. SNP

Alleles

≤18 years (%)

>18 years (%)

P

rs2228570

C T

137 (53.52) 119 (46.48)

633 (58.72) 445 (41.28)

0.130

rs731236

C T

21 (8.20) 235 (91.80)

63 (5.84) 1015 (94.16)

0.162

rs7975232

A C

76 (29.69) 180 (70.31)

313 (29.04) 765 (70.96)

0.836

rs1544410

A G

17 (6.64) 239 (93.36)

57 (5.29) 1021 (94.71)

0.395

association between VDR polymorphisms and individual’s susceptibility to GD. Our data revealed increased frequency of allele A in rs7975232 for GD patients compared to controls. Therefore, we suggest that VDR gene could be used as a screening indicator to predict the susceptibility to GD. VDR is a member of the nuclear receptor superfamily and able to modulate the transcription of target genes in response to 1,25(OH)2 D3 [12], a potent immunomodulatory hormone. VDR gene has eight coding exons and three alternative 5 -noncoding exons spanning over 75 kb of DNA on chromosome 12q12–12q14 [13]. Four different SNPs of VDR had been genotyped using the methods of restriction fragment length polymorphism (RFLP) in the Vincent Medical Center between 2001 and 2010 [14], and named by the four restriction enzymes: FokI C > T (rs2228570, at exon 2), BsmI G > A (rs1544410, at intron 8), ApaI C > A (rs7975232, at intron 8), and TaqI T > C (rs731236, at exon 9) [15–17]. Recent studies described the molecular basis of the immunomodulatory activity of 1,25(OH)2 D3 , the active biological form of vitamin D [18–20]. 1,25(OH)2 D3 inhibits T cell activation both in vitro and in vivo, and suppresses the production of interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor and interferon-␥ [18]. These cytokines play important roles in the development of T helper 1 cells, which are believed to be involved in the pathogenesis of chronic inflammatory autoimmune diseases [19]. Kawakami-Tani et al. [20] demonstrated a beneficial effect of treatment with 1,25(OH)2 D3 on serum thyroid hormone concentrations in hyperthyroid patients with untreated GD, suggesting that 1,25(OH)2 D3 may contribute to the treatment of hyperthyroidism in these patients. Associations of VDR-BsmI polymorphisms with osteoporosis [13,15], primary hyperparathyroidism (pHPT) [21,22] and some autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM) [23] and multiple sclerosis (MS) [24], have been reported. To confirm the genetic susceptibility to GD and to improve GD treatment strategies, we examined VDR gene polymorphisms in Chinese Han patients with GD and in controls. Our results are similar to those of some previous studies which showed significant differences in the allele distribution of VDR-APaI between patients and controls [2,25,26]. However, several other reports showed that the frequency of VDR-ApaI (rs7975232) polymorphisms does not significantly different between GD patients and controls [5,6]. One study in Japan found an association between VDR-ApaI/VDR-BsmI

polymorphism and GD, but not between this polymorphism and the VDR-FokI polymorphism in patients [2]. A study in Eastern Croatian population showed that the ApaI and BsmI “AA” and “BB” genotypes, respectively, as well as combined “BBAAtt” genotype, appear to confer protection against GD, whereas ApaI “aa” and TaqI “TT” genotypes are associated with an increased risk for GD [25]. An investigation in Egypt suggested that BsmI, ApaI, and TaqI polymorphisms in VDR gene are associated with susceptibility to GD [26]. In contrast, studies in UK Caucasians indicated that these polymorphisms do not contribute to GD susceptibility [5]. Similarly, a study in Tunisians suggested a lack of association between VDR gene polymorphisms and susceptibility to thyroid autoimmune diseases [6]. In conclusion, our study demonstrate the A allele of rs7975232 in APaI is related to GD in Chinese Han population. This result suggests the VDR gene may be the susceptibility gene which contributes to the risk of GD. In consideration of the conflicting results of VDR gene polymorphisms in different ethnic groups, further studies should be done to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments This study was supported by grants from the National Nature Science Foundation of China (No.81070627 and No.81270871) and Key Disciplines Development of Shanghai Jinshan District (No.2012-23). References [1] Baretic M. 100 years of Hashimoto thyroiditis, still an intriguing disease. Acta Med Croatica 2011;65(5):453–7 [Case Reports; English Abstract]. [2] Ban Y, Taniyama M, Ban Y. Vitamin D receptor gene polymorphism is associated with Graves’ disease in the Japanese population. J Clin Endocrinol Metab 2000;85(12):4639–43 [Clinical Trial; Research Support, Non-U.S. Gov’t]. [3] Chen RH, Chang CT, Chen HY, Chen WC, Tsai CH, Tsai FJ. Association between vitamin-D receptor gene FokI polymorphism and Graves’ disease among Taiwanese Chinese. J Clin Lab Anal 2007;21(3):173–7 [Research Support, Non-U.S. Gov’t].

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Please cite this article in press as: Meng S, et al. Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms. Ann Endocrinol (Paris) (2015), http://dx.doi.org/10.1016/j.ando.2015.01.003