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【bio-news】研究发现银屑病和系统性红斑狼疮的遗
Jacquelyn K. Beals, PhD
December 3, 2007 — Two independent studies published online December 2 in Nature Genetics clarify the genetic variations underlying psoriasis and systemic lupus erythematosus (SLE). One study establishes an association between psoriasis and increased copy number of a gene cluster on chromosome 8. The second report links susceptibility to SLE with increased expression of a gene in the tumor necrosis factor (TNF) superfamily.
Psoriasis and Copy Number Variation
Psoriasis, an inflammatory disorder affecting about 2% of the population in developed countries, occurs when healthy skin cells are perceived as foreign substances and are attacked by the immune system.
First author Edward J. Hollox, PhD, lecturer, Department of Genetics, University of Leicester, United Kingdom, told Medscape Pathology via email: "There are 8 beta-defensin [DEFB] genes in the 8p23.1 cluster, and we do not know which one, or ones, is responsible for the increase in risk. The best candidate is DEFB4, because it is highly expressed in psoriatic lesions."
The initial study of Dutch patients with psoriasis (n = 179) and control patients (n = 272) found that increased copy number in a cluster of 8 DEFB genes was significantly associated with psoriasis (P = .01). DEFB gene products are small antimicrobial proinflammatory peptides, and copy number variation (CNV) could reasonably influence susceptibility to infection and inflammation.
Independent replication in German patients with psoriasis (n = 305) and control patients (n = 319) confirmed the association between increased beta-defensin copy number and psoriasis (P = 2.95 × 10−5).
"Many DEFB genes encode proteins that have been shown to be antimicrobial — they directly destroy bacteria (and possibly yeasts) by disrupting the cell membrane," said Dr. Hollox. This has been shown for 3 of the genes in the cluster on chromosome 8. The report notes that beta-defensins "have cytokine-like properties" and play a major role in the "innate immune system of the skin." Thus, increased levels could cause inflammation characteristic of psoriasis.
"Quite often, gene clusters have similar functions because they have similar DNA sequence, and hence [their products have] similar protein sequence," Dr. Hollax continued. "All the evidence we have shows that it is an entire cluster that varies in copy number." Apparently the beta-defensin CNV is inherited in a Mendelian manner, "as seems to be the case with other well-studied copy number variations around the genome. I've yet to see any good evidence of non-Mendelian inheritance of CNV," Dr. Hollox noted.
A large number of gene loci show variations in copy number, and many may be associated with disease susceptibility. Coincidentally, the psoriasis paper mentioned a recent study that linked SLE to low copy number of complement C4 genes. However, the current Nature Genetics report associates SLE with a polymorphism at gene TNFSF4.
SLE and TNFSF4 Polymorphism
There are few reports of psoriasis and SLE in the same patient (eg, from 1950 through 1975, the Mayo Clinic reported only 27 patients — roughly 1 a year — with coexistent psoriasis and SLE), although both involve abnormal immune responses that attack healthy cells and lead to inflammation.
The current SLE study investigated single nucleotide polymorphisms (SNPs) from 472 nuclear families in the United Kingdom. Investigators focused on gene TNFSF4 (TNF superfamily member 4) and the receptor gene TNFRSF4, both on chromosome 1.
Among TNFRSF4 variants, none of the SNPs or haplotypes was significantly associated with SLE. However, the upstream region of TNFSF4 contained a haplotype associated with increased susceptibility to SLE. This correlated with greater expression of TNFSF4 (overall P = .0020). Replicating the study in 263 SLE parental-affected trios in Minnesota confirmed the significant association (overall P = .0057).
"The genetic data do tell us very important things about the role of the immune system in SLE," said senior author Timothy J. Vyse, MD, PhD, professor of rheumatology, Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, London, United Kingdom, in an email to Medscape Pathology.
Statistical analysis established that "no single genotyped variant is responsible for the association in the upstream region of TNFSF4," Dr. Vyse and colleagues report. Rather, the upstream variants may increase the expression of TNFSF4 and the TNFSF4 on the surface of lymphoblastoid cells through TNFRSF4 increasing stimulation of CD4+ T cells; CD4+ T cell activation is characteristic of SLE.
Asked to comment on the psoriasis/CNV article, Dr. Vyse replied: "I have heard about this paper. I think this is fascinating data in psoriasis." However, he expressed reservations about the role of C4 in SLE: "The role of low copy number of C4 in SLE has not been established. C4 deletions are carried on extended haplotypes that show association with SLE...but neither we nor anyone else has clearly shown that the gene effect...is due to C4."
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作者:admin@医学,生命科学 2011-09-07 17:14
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