VITAMIN D RECEPTOR GENE POLYMORPHISM IN PATIENTS WITH SARCOIDOSIS

To the Editor :

With great interest we read the report showing a significant association with a vitamin D receptor gene polymorphism (allele B of the BsmI polymorphism) and sarcoidosis in Japanese patients (1). Because of the undisputed importance of vitamin D levels in the pathogenesis of sarcoidosis and the reported association of gene polymorphisms of the vitamin D receptor (VDR) with serum calcitriol levels (2), we had also investigated the Taq1 gene polymorphism of the vitamin D receptor gene, which is in strong linkage disequilibrium with the BsmI polymorphism (97% concordance) (2), in 85 unrelated patients with pulmonary sarcoidosis and in 80 unrelated healthy control subjects. We have described other gene polymorphisms in these groups (3), and genotyping of the VDR was carried out by polymerase chain reaction of genomic DNA with subsequent Taq1 restriction analysis (4). The statistical evaluation (² test with Yates correction) of the genotype distribution (sarcoidosis: 51% TT, 41% Tt, 8% tt; controls: 46% T/t, 44% Tt, 10% tt) revealed no significant difference between the patient and control group. Likewise, statistical analysis of the allele frequency (T/t; sarcoidosis: 0.71/0.29; controls: 0.68/0.32) showed no significant association of a VDR Taq1 allele with sarcoidosis. Interethnic differences of the VDR polymorphisms in healthy cohorts have been described (4, 5), and reports on the influence of ethnicity on genetic associations in sarcoidosis are numerous (for an example involving a Scandinavian and a Japanese patient group see [6]). Owing to our results and the data reported by Niimi and colleague (1), we thus conclude that the VDR polymorphism constitutes a further genetic trait showing differences in significant association with sarcoidosis depending on the ethnic background of the patient group.

National Centre of Radiobiology, Sofia, Bulgaria

Ulrike Seitzer

Division of Molecular Immunology, Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany

1. Niimi, T., H. Tomita, S. Sato, H. Kawaguchi, K. Akita, H. Maeda, Y. Sugiura, and R. Ueda. 1999. Vitamin D receptor gene polymorphism in patients with sarcoidosis. Am. J. Respir. Crit. Care Med. 160: 1107-1109 [Abstract/Free Full Text].

2. Morrison, N. A., J. C. Qi, A. Tokita, P. J. Kelly, L. Crofts, T. V. Nguyen, P. N. Sambrook, and J. A. Eisman. 1994. Prediction of bone density from vitamin D receptor alleles. Nature 367: 284-287 [Medline].

3. Seitzer, U., C. Swider, F. Stüber, K. Suchnicki, A. Lange, E. Richter, P. Zabel, J. Müller-Quernheim, H.-D. Flad, and J. Gerdes. 1997. Tumor necrosis factor alpha promoter gene polymorphism in sarcoidosis. Cytokine 9: 787-790 [Medline].

4. Taylor, J. A., A. Hirvonen, M. Watson, G. Pittman, J. L. Mohler, and D. A. Bell. 1996. Association of prostrate cancer with vitamin D receptor gene polymorphism. Cancer Res. 56: 4108-4110 [Abstract/Free Full Text].

5. Hustmyer, F. G., H. F. DeLuca, and M. Peacock. 1993. ApaI, BsmI, EcoRV and TaqI polymorphisms at the human vitamin D receptor gene locus in Caucasians, Blacks and Asians. Hum. Mol. Gen. 2: 487 [Free Full Text].

6. Grunewald, J., M. Shigematsu, S. Nagai, T. Mikuniya, H. Wigzell, T. Izumi, and A. G. Eklund. 1995. T-cell receptor V gene expression in HLA-typed Japanese patients with pulmonary sarcoidosis. Am. J. Respir. Crit. Care Med. 151: 151-156 [Abstract].

From the Authors:

We read the letter by Dr. Seitzer and colleagues with great interest. However, we would like to point out that other investigators have reported influences of vitamin D receptor gene polymorphism on tuberculosis and leprosy (1, 2). We think their studies and our own investigation (3) suggest that vitamin D receptor gene polymorphism does indeed play a role in granulomatous diseases. Although Dr. Seitzer and colleagues obtained opposite data from our own, we could not investigate Caucasian subjects, so we regret that we cannot make a direct comment. However, we agree that a racial bias is conceivable; therefore, we think further investigations are necessary to determine if our results are universally valid or not.

TAKASHI NIIMI

Second Department of Internal Medicine

Nagoya City University Medical School

Nagoya, Japan

1. Roy, S., A. Frodsham, B. Sara, S. K. Hazra, C. G. N. Mascie-Taylor, and A. V. S. Hill. 1999. Association of vitamin D receptor genotype with leprosy type. J. Infect. Dis. 179: 187-191 [Medline].

2. Bellamy, R., C. Ruwende, T. Corrah, K. P. W. J. McAdam, M. Thusz, H. C. Whittle, and A. V. S. Hill. 1999. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J. Infect. Dis. 179: 721-724 [Medline].

3. Niimi, T., H. Tomita, S. Sato, H. Kawaguchi, K. Akita, H. Maeda, Y. Sugiura, and R. Ueda. 1999. Vitamin D receptor gene polymorphism in patients with sarcoidosis. Am. J. Respir. Crit. Care Med. 160: 1107-1109 .