Abstract
Mitochondrial dysfunction could contribute to the pathogenesis of psoriasis (Ps) and Ps-arthritis (PsA). Several common mtDNA polymorphisms/haplogroups have been linked to differences in the production of reactive oxygen species and mitochondrial oxidative damage. To test the hypothesis of an association between mtDNA variants and Ps/PsA, we studied the single-nucleotide polymorphisms that define the common European haplogroups in a total of 325 patients and 300 controls from Spain. No allele/haplogroup was significantly associated with the risk for Ps. However, haplogroup J was significantly less frequent among patients with PsA, suggesting a protective effect in our population (p=0.04; odds ratio=0.39). We concluded that mtDNA may have a role in Ps and PsA.
Introduction
P
An imbalance between pro- and antioxidant mechanisms could also play an important role in the pathogenesis of Ps (Bickers et al., 2006; Zhou et al., 2009). To diminish the deleterious effect of reactive oxygen species (ROS), the skin cells are equipped with efficient antioxidant mechanisms that could be increased in psoriatic patients. Mitochondria are the main source of ROS, and an imbalance in the oxidant-antioxidant mitochondrial system could have a role in the pathogenesis of Ps. Mitochondria are also the target of some drugs used to treat Ps, such as anthralin and psoralen (McGill et al., 2005; Caffieri et al., 2007).
The mitochondrion contains its own DNA (mtDNA) in a single circular chromosome that encodes 13 subunits of the electron-transfer chain, 2 ribosomal RNAs, and 22 transfer RNAs. The mtDNA is inherited from the mother and is highly polymorphic. Mitochondrial haplogroups are defined by alleles at several mtDNA single-nucleotide polymorphisms (SNPs) (Torroni et al., 1996). These haplogroups have been linked to the risk of developing common diseases, such as neurodegenerative and cardiovascular diseases and several types of cancer (Huerta et al., 2005; Raule et al., 2007; Abu-Amero et al., 2010; Palacin et al., 2011). These effects on disease susceptibility could be partially explained by differences in ROS production and mitochondrial oxidative damage (mtOD) between the haplogroups (Gómez-Durán et al., 2010; Martinez-Redondo et al., 2010). Based on the evidence, we hypothesized that the variation at the mtDNA that defines the common European haplogroups could influence the risk for developing Ps or act as modifier of the main clinical outcomes in these patients.
Methods
Patients and controls
We studied 325 Ps patients (55% men, mean age 47±15 years) and 300 healthy controls (54% men, mean age 47±13 years), all Caucasians from the region of Asturias (Northern Spain). The Psoriasis Area and Severity Index (PASI) was calculated for all the patients, and the disease was considered as severe in patients with a PASI score ≥10 at any time of the disease. Patients were considered to have “early onset” Ps if the onset was at an age <40 years. Patients who had at least one first-degree relative also affected by the disease were considered to have “familial” Ps. Patients with PsA were assessed by a rheumatologist according to the Classification Criteria for Psoriatic Arthritis. Written informed consent was obtained from each participant, under the protocols approved by the Ethical Committee of Hospital Universitario Central de Asturias.
Controls were from the same Caucasian population and were recruited through the Dermatology Department and the blood bank of Hopital Universitario Central Asturias. Controls were matched to patients for age and gender, and none of them had been diagnosed with Ps or autoimmune processes.
Mitochondrial polymorphisms and haplogroup classification
Six mtDNA SNPs were determined through a real-time polymerase chain reaction (PCR) Taqman assay (C7028T) or digestion with a restriction enzyme of a PCR fragment (PCR-restriction fragment length polymorphism (RFLP); SNPs G4580A, G9055A, A12308G, G13368A, and G13708A) (Supplementary Table S1; Supplementary Data are available online at www.liebertonline.com/gtmb). The analytical procedure was previously reported and is available upon request (Huerta et al., 2005; Coto et al., 2011; Palacin et al., 2011). Haplogroups were defined for each patient and control (Supplementary Table S2; see also www.mitomap.org for haplogroup definition).
Statistical analysis
The chi-squared test was used to compare the allele and haplogroup frequencies between the different groups (http://faculty.vassar.edu/lowry/odds2x2.html). We used a previously reported approach consisting in the comparison of the H-frequency (the most common haplogroup H) with the frequency of the other haplogroups pooled into one group, and of each haplogroup frequency with the frequency of haplogroup H (Van der Walt et al., 2003, 2004; Gaweda-Walerych et al., 2008; Palacín et al., 2011). The statistical power of the comparisons was calculated online (http://statpages.org/proppowr.html).
Results and Discussion
Table 1 summarizes the haplogroup frequencies in patients and controls, and in patients according to the family history of Ps, disease onset age, disease severity, presence of arthritis, and the Cw6 status. None of the haplogroups was associated with Ps risk. Compared with H (the most common haplogroup), J was significantly less frequent among the patients with PsA (7% vs. 14%; p=0.04), with an odds ratio=0.39 (Table 1).
Frequencies are presented as n (%).
J versus H: p=0.04, odds ratio=0.39 (95% CI=0.15-0.98) arthritis versus no arthritis.
To our knowledge, this is the first study that afforded the effect of common mtDNA polymorphisms/haplogroups on the risk of developing Ps and the main outcomes of the disease. Overall, our results did not support a significant role for common mtDNA variants on Ps risk. An effect of mtDNA variants on Ps risk was plausible based on the reported effect of ROS and mitochondrial activity/dysfunction in the skin of these patients. In addition, functional differences between the haplogroups have been published. For instance, a recent research with cellular “cybrids” described that mtDNA and mtRNA levels, mitochondrial protein synthesis, cytochrome oxidase amount and activity, mitochondrial inner membrane potential and oxygen consumption, and growth capacity differed between cybrids with different haplogroups (Gómez-Durán et al., 2010). This could explain the reported differences in ROS production and mtOD found among individuals with different haplogroups (Martinez-Redondo et al., 2010).
Some studies indicated that the mitochondrion was implicated in osteoarthritis, and haplogroups U and J have been linked to higher and lower risk for knee osteoarthritis, respectively (Rego-Pérez et al., 2008). We also found a significantly lower frequency of J among patients with PsA. This haplogroup has been linked to lower VO2 max and reduced efficiencies of electron transport chain, ATP, and ROS production (Martínez Redondo et al., 2010). Interestingly, serum levels of biomarkers increased in patients with arthritis (i.e., collagen type II markers and matrix metalloproteases) should be lower in patients with J compared with H (Rego-Pérez et al., 2010, 2011).
Haplogroup J is defined by a missense SNP in the ND5 gene (G13708A and Ala458Thr) that could be directly responsible for the observed association. Alternatively, this haplogroup might contain some mtDNA functional variant linked to a reduced ROS production compared with other haplogroups and this would explain the protective effect against PsA. The sequencing of the whole mitochondrial chromosome in PsA with this haplogroup should be necessary to identify these putative mtDNA variants.
We are well aware that our work was based on a limited number of patients with PsA. Additional studies with larger series of patients and from other populations should be required to confirm or refute the protective effect of haplogroup J.
Footnotes
Disclosure Statement
All the authors declare no conflicts of interest related to this work. In addition, all the authors contributed to this work and have read and approved the submission of the manuscript.
References
Supplementary Material
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