Common NOD2 polymorphisms in Hong Kong Chinese patients with systemic lupus erythematosus

W. P. Chong, W. K. Ip, C. S. Lau1, T. M. Chan1, L. Padyukov2 and Y. L. Lau

Departments of Paediatrics and Adolescent Medicine and 1Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China and 2Department of Clinical Immunology, University of Göteborg, Göteborg and Unit of Rheumatology, Karolinska Institutet, Stockholm, Sweden

Correspondence to: Y. L. Lau, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China. E-mail: lauylung{at}hkucc.hku.hk

SIR, The chromosomal region 16q12 is linked with several autoimmune diseases, such as systemic lupus erythematosus (SLE) [1], Crohn's disease (CD) [2] and rheumatoid arthritis (RA) [3]. Hugot et al. [4] reported the association of nucleotide oligomerization domain (NOD) 2 gene, which is located on 16q12, with CD. NOD2 is a cytosolic protein that acts as an activator of nuclear factor (NF)-{kappa}B by bacterial lipopolysaccharide stimulation in vitro [5] and is believed to play a role in inflammatory and autoimmune diseases. Among several single nucleotide polymorphisms (SNPs) in NOD2, SNP8, SNP12 and SNP13 are associated with CD in several Caucasian populations [4, 6, 7]. The rare allele of SNP13 contains a cytosine insertion in the leucine-rich region (LRR) and causes a frame-shift mutation that generates a truncated NOD2 protein, which results in decreased activation of NF-{kappa}B [7]. The rare alleles of SNP8 and SNP12 may also have functional significance because they cause amino acid substitutions in the proximal adjacent region (R702W) and in the LRR domain (G908R), respectively [4].

Since NOD2 is the candidate gene that accounts for the linkage between 16q12 and CD, it may also account for the linkage of SLE with 16q12. Therefore, we investigated the frequencies of these three SNPs of NOD2 in Hong Kong Chinese healthy blood donors and patients with SLE. Since CD is of low prevalence in the Hong Kong Chinese population [8], which may be accounted for by the ethnic difference in allelic frequencies of these three NOD2 polymorphisms, we also investigated these polymorphisms in Chinese and Swedish healthy blood donors.

The study included 561 Hong Kong Chinese healthy blood donors, 188 SLE patients and 97 Swedish healthy blood donors. All SLE patients met the revised American College of Rheumatology criteria for systemic lupus [9]. The study was approved by the Ethics Committee of the Faculty of Medicine, The University of Hong Kong and all patients gave informed consent according to the declaration of Helsinki.

By the TaqMan system that was described previously [7], the three NOD2 SNPs were genotyped. Since there was no single subject who had two or more rare alleles of the three SNPs, the haplotype frequencies were calculated by direct counting and the results are shown in Table 1. We found no rare alleles of SNP12 or SNP13 in our Chinese healthy blood donors and SLE patients, and only one Chinese healthy blood donor carried the rare allele of SNP8. We concluded that these rare alleles are not associated with SLE in Hong Kong Chinese and probably not responsible for the linkage observed between SLE and 16q12 in Asian populations [1].


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TABLE 1. Frequencies of haplotypes of NOD2 in Hong Kong Chinese blood donors, Hong Kong Chinese SLE patients and Swedish blood donors

 
Analysis of NOD2 polymorphisms in our Swedish healthy blood donors showed similar frequencies of the haplotypes to other Caucasians [7], but very different from our Chinese population (Table 1). We propose the lack of common NOD2 polymorphisms in Chinese subjects may partially explain the ethnic difference in the prevalence of CD between Caucasian and Chinese populations [8].

However, we cannot entirely exclude the role of NOD2 as a susceptibility gene in SLE. Association studies of SLE with these three SNPs of NOD2 in other populations, in which these rare alleles are present, are required to ascertain whether they may be responsible for the linkage between 16q12 and SLE. Also, apart from NOD2, there are other genes that are located in 16q12 which may be involved in susceptibility to SLE. A systematic search of novel NOD2 polymorphisms in our population is warranted and a finer mapping of 16q12 should be performed to identify susceptibility genes to SLE.

The authors have declared no conflicts of interest.

References

  1. Tsao BP, Cantor RM, Grossman JM et al. Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to SLE. Arthritis Rheum 2002;46:2929–36.
  2. Hugot JP, Laurent-Puig P, Gower-Rousseau C et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 1999;379:821–3.
  3. Jawaheer D, Seldin MF, Amos CI et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 2001;68:927–36.[CrossRef][ISI][Medline]
  4. Hugot JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001;411:599–603.[CrossRef][ISI][Medline]
  5. Inohara N, Ogura Y, Chen FF, Muto A, Nunez G. Human Nod1 confers responsiveness to bacterial lipopolysacchaides. J Biol Chem 2001;276:2551–4.[Abstract/Free Full Text]
  6. Ogura Y, Bonen DK, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001;411:603–6.[CrossRef][ISI][Medline]
  7. Hampe J, Grebe J, Nikolaus S et al. Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study. Lancet 2002;359:1661–5.[CrossRef][ISI][Medline]
  8. Sung JJ, Hsu RK, Chan FK, Liew CT, Lau JW, Li AK. Crohn's disease in the Chinese population. An experience from Hong Kong. Dis Colon Rectum 1984;37:1307–9.
  9. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
Accepted 29 April 2003





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