Allelic Variants of Drug Metabolizing Enzymes as Risk Factors in Psoriasis

Abstract

The onset or exacerbation of psoriasis, a T-cell-dependent skin disease with autoimmune features, can be triggered by drugs such as antimalarials and beta-blockers. Xenobiotics may also play a role in idiopathic psoriasis. It has been hypothesized that different metabolic efficiencies caused by variant alleles of xenobiotic metabolizing enzymes could lead to the accumulation of xenobiotics or their reactive metabolites in target organs. Subsequently, neoantigens or cryptic peptides could be presented and initiate an aggressive T cell response. In this context, we analyzed a broad array of xenobiotic metabolizing enzymes in up to 327 Caucasian psoriasis patients and compared them to 235 control persons. Alleles tested include four phase I and three phase II enzymes. Significantly more carriers of the variant alleles of CYP1A1 (alleles *2A and *2C) were found in healthy controls than in patients, suggesting a protective role for these alleles. No significant difference between patients and controls could be found, however, for the other phase I alleles 1B1*1 and 1B1 *3, 2C19*1A and 2C19*2A, and 2E1*1A and 2E1*5B. Of the variant alleles coding for phase II enzymes only GSTM1, but not GSTT1 or NQOR, correlated with a risk to contract psoriasis. Some combinations of phase I and phase II enzymes suggested protective or risk-associated effects. Interestingly, heterozygosity for CYP2C19 alleles *1A and *2A was associated with increased risk for "late onset" psoriasis, whereas this genotype was protective for psoriatic arthritis. This is the first large-scale study on these enzymes and the results obtained support the concept that different activities of metabolizing enzymes can contribute to disease etiology and progression.

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

“…The majority of all patients suffered from early onset of psoriasis. 2 This finding might indicate again that gene effects can be assimilated by the environment or simply by age. Owing to a recombination hot spot, a second independent Genotyping analyses were carried out by using the MassARRAY system (Sequenom, San Diego, CA, USA).…”

“…2 In short, 50% of the psoriasis cases were female, mean age was 48.5 years with a range of 11-84 years. Controls were slightly younger (45.7 years).…”

“…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.…”

“…2 We chose seven coding singlenucleotide polymorphisms (SNPs), already investigated in some other studies (LMP2_60/rs17587, TAP1_637/ rs1800453, LMP7_49/rs2071543, TAP2_565, TAP2_651/ rs4148876, TAP2_665/rs241447, TAP2_687/rs241448), to investigate the association between genetic variations in cytosolic antigen processing and transport genes, and psoriasis. All SNPs lead to amino-acid exchanges in the encoded protein.…”

Gene-environment interactions in sarcoidosis: challenge and opportunity

“…Epidemiologic studies of psoriasis had suggested a potential role for several environmental exposures, including tobacco consumption, alcohol, infections and medications, however the results were anecdotal and inconclusive. Richter-Hintz et al conducted a case-control association study for a panel of polymorphisms among xenobiotic metabolizing enzymes [31]. The results suggested that a common (hypoactive) CYP1A1 variant conferred disease susceptibility.…”