Molecular genetic studies of psoriasis susceptibility in 6p21.3
Psoriasis is a common and chronic skin disease with multifactorial background. It affects approximately 2% of the Swedish population and is characterized by inflammatory and scaly lesions. The aetiology of psoriasis is not yet known, however, the genetic contribution to the disease is strong. Several loci have been identified and among these, psoriasis susceptibility 1 (PSORS1) in chromosome region 6p21.3 is consistently described in populations of different ethnic background. A major factor involved in disease susceptibility is therefore believed to reside at this locus.
Studies in this region are complicated by strong linkage disequilibrium and the previously identified associating allele of human leukocyte antigen C (HLA-C), HLACw*0602, was therefore believed to be a marker of a disease gene located nearby. The purpose of the studies that make up the main body of this thesis work is to characterize alternative candidate genes for association to psoriasis in the Swedish population. Each new candidate was compared to HLA-Cw*0602 and their relationship to this allele was also investigated.
The HCR gene was characterized and found to be a very polymorphic gene and to be strongly associated to psoriasis. However, when compared to the level of association of HLACw*0602, variations in HCR appeared to be in linkage disequilibrium with this allele. Three new genes were identified upon further characterization of the region; psoriasis susceptibility 1 candidate 1-3 (PSORS1C1-C3). Several variants were identified and tested for association, but after comparison, the observed associations appeared to be dependent on the presence of HLA-Cw*0602. HLC-A therefore remains the strongest candidate in the region. The biological function of this molecule is to signal our immune system for self-recognition, and its main interacting partners are specific killer immunoglobulin like receptors (KIR) on natural killer (NK) cells.
The presence and absence of these KIR genes and HLA-C alleles were investigated. KIR2DS1 showed association to psoriasis vulgaris. Furthermore, when combining HLA-C and KIR in potential NK cell responses, a clear difference was observed in guttate psoriasis. This group showed an increased potential for inhibition and had less individuals with an undetermined NK cell response. When adding HLA-Cw*0602 to these combinations the effect was even more pronounced. From this analysis HLA-Cw*0602 appears to play an important role in potential thresholds of NK cell responses associated to psoriasis. Continued functional studies on HLA-C and its interaction partners are needed in order to elucidate the involvement of this gene in psoriasis pathogenesis.
List of scientific papers
I. OBrien KP, Holm SJ, Nilsson S, Carlen L, Rosenmuller T, Enerback C, Inerot A, Stahle-Backdahl M (2001). The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene. J Invest Dermatol. 116(5): 750-4.
https://doi.org/10.1046/j.0022-202x.2001.01323.x
II. Holm SJ, Carlen LM, Mallbris L, Stahle-Backdahl M, OBrien KP (2003). Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Exp Dermatol. 12(4): 435-44.
https://doi.org/10.1034/j.1600-0625.2003.00048.x
III. Holm SJ, Sanchez F, Carlen LM, Mallbris L, Stahle M, OBrien KP (2005). Associates more strongly to psoriasis in the Swedish population than variants of the novel 6p21.3 gene PSOR1C3. Acta Dermato-Venereologica. [Accepted]
https://doi.org/10.1080/00015550410023527
IV. Holm SJ, Sakuraba K, Mallbris L, Wolk K, Granath F, Stahle M, Sanchez F (2005). HLA-C and KIR genotype combinations and their potential functional effect among Swedish psoriasis patients. [Manuscript]
History
Defence date
2005-03-11Department
- Department of Medicine, Solna
Publication year
2005Thesis type
- Doctoral thesis
ISBN-10
91-7140-225-XNumber of supporting papers
4Language
- eng