Strong associations of psoriasis with antigen processing LMP and transport genes TAP differ by gender and phenotype

Abstract

Psoriasis, a skin disease with autoimmune features, can be triggered and exacerbated by genetic and environmental factors. Chemicals can break tolerance to self-antigens by interfering with antigen processing and presentation; therefore, proteins involved in antigen processing may affect susceptibility. We test here whether variants of immunoproteasome subunits LMP2 and LMP7, or antigen peptide transport proteins TAP1 (transporters associated with antigen presentation) and TAP2 are associated with psoriasis. We analyzed 7 single-nucleotide polymorphisms in 321 Caucasian (German) psoriasis patients and 235 unrelated controls by time-of-flight mass spectrometry, using the Sequenom platform. We found strong associations of psoriasis with variant alleles of LMP and TAP (OR TAP_687 : 3.3, 95% CI: 1.9-5.7). Genotype effects were generally stronger for males and LMP effects were mainly seen for psoriasis arthropathica. Our results will help define behavioral or drug treatment suggestions to patients and contribute to a better understanding of the role of low molecular weight chemicals in genetic susceptibility to autoimmune diseases. Genes and Immunity (2007) Keywords: immunotoxicology; genetic susceptibility; proteasome; psoriasis arthropathica; environmental factors; SNP Psoriasis is a disease with autoimmune features, affecting about 2% of Caucasians, with major impact on patient's quality of life. Manifestations include red, heavily scaled pruritic plaques, and can affect joints as well. Several distinct but overlapping clinical phenotypes can be distinguished including psoriasis vulgaris and psoriasis arthropathica. Strong evidence suggests a multilocus model of inheritance in association with environmental factors. 1 The etiology of the disease is still unclear. In several cases, however, low molecular weight chemicals (LMWC), such as drugs, were identified as etiologic agents, and variants of genes responsible for metabolizing LMWC are risk factors. 2 A proven concept of immunotoxicology holds that LMWC can break tolerance by interfering with antigen processing and presentation, either exposing cryptic neo-antigens, or by haptenating and thus immunoconverting presented self-antigens.Self-antigen processing and presentation is an essential part of the autoimmune response. Consequently, presenting human leukocyte antigen (HLA) genes, notably HLA-Cw*0602, belong to the identified susceptibility genes of psoriasis. 3 Antigen presentation is essentially dependent on the proteasome, an intracellular protease complex catalyzing important steps in the breakdown of proteins to peptides to be presented as antigens. The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of four rings of 28 non-identical subunits; two rings are composed of seven a-subunits and two rings are composed of seven b-subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave cellular as well as foreign peptides in an ATP/u...

No association of TAP and LMP genetic polymorphism in human brucellosis and its complications

“…The patients and the controls were in Hardy-Weinberg equilibrium. The allele and genotype frequencies were similar to those reported previously in other white populations [13] and different from those reported for other ethnic populations, South American tribes [20] and Chinese persons [21]. In these populations the frequency of the LMP2H allele is high and that of the LMP2R allele is low compared with Spanish Caucasians, and in some populations there is absence of the LMP7-K/K genotype [20].…”

“…The frequency of TAP1*A, B, C, D, and E was similar to that previously reported by Spanish authors and in other white Caucasian populations [22,13], and different from that reported for other ethnic groups, black persons [23], South American tribes [24,25], and Chinese persons [26]. Significant differences are seen in the black race in the TAP1*0201 and TAP1*0401 alleles between Africans and non-Africans.…”

“…In addition, they have been related with autoimmune type disorders [11][12][13] and infectious diseases, such as leprosy and tuberculosis [14 -16].…”

A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat

“…The specificity of these reactions and their biological functions are affected by the 3D conformation of the peptide, HLA complexes, compatibility of the peptide sequence with its HLA class I binding pocket etc [62]. Interestingly, significant differences in the amino-acid signatures of the peptide-binding pockets of MHC class I α chains as well as class II β chains were observed between vitiligo patients and unaffected controls [15]. Though TAP1 SNP was not associated with vitiligo but the predominant presence of ‘G’ allele in combination with other SNPs in this region might affect the peptide selectivity in patients.…”

Molecular Mechanisms of Uterine Leiomyosarcomas: Involvement of Defect in LMP2 Expression

“…Overall, nearly 42.9% (6/14) of uterine LMS tissues had mutations in the ATP-binding region or kinase-active site of JAK1. Furthermore the genetic approach has already revealed that somatic mutations in the LMP2 molecule or its enhancer region correlate to the initiation of several cancer progressions and other disorders (Heward et al 1999; Satoh et al 2006; Krämer et al 2007; Liu et al 2007; Mehta et al 2007), 35.7% (5/14) of uterine LMS tissues had somatic mutations in the Lmp2 promoter region, which is required for transcriptional activation. In addition, genetic examination has already demonstrated that somatic mutations in the STAT1 molecule correlate to the initiation of several disorders (Dupuis et al 2001; Dupuis et al 2003; Chapgier et al 2006; Scarzello et al 2007).…”