Mitochondrial Haplogroups, Control Region Polymorphisms and Malignant Melanoma: A Study in Middle European Caucasians

Because mitochondria play an essential role in energy metabolism, generation of reactive oxygen species (ROS), and apoptosis, sequence variation in the mitochondrial genome has been postulated to be a contributing factor to the etiology of multifactorial age-related diseases, including cancer. The aim of the present study was to compare the frequencies of mitochondrial DNA (mtDNA) haplogroups as well as control region (CR) polymorphisms of patients with malignant melanoma (n = 351) versus those of healthy controls (n = 1598) in Middle Europe.Using primer extension analysis and DNA sequencing, we identified all nine major European mitochondrial haplogroups and known CR polymorphisms. The frequencies of the major mitochondrial haplogroups did not differ significantly between patients and control subjects, whereas the frequencies of the one another linked CR polymorphisms A16183C, T16189C, C16192T, C16270T and T195C were significantly higher in patients with melanoma compared to the controls. Regarding clinical characteristics of the patient cohort, none of the nine major European haplogroups was associated with either Breslow thickness or distant metastasis. The CR polymorphisms A302CC-insertion and T310C-insertion were significantly associated with mean Breslow thickness, whereas the CR polymorphism T16519C was associated with metastasis.Our results suggest that mtDNA variations could be involved in melanoma etiology and pathogenesis, although the functional consequence of CR polymorphisms remains to be elucidated

The Mitochondrial T16189C Polymorphism Is Associated with Coronary Artery Disease in Middle European Populations

BACKGROUND: The pivotal role of mitochondria in energy production and free radical generation suggests that the mitochondrial genome could have an important influence on the expression of multifactorial age related diseases. Substitution of T to C at nucleotide position 16189 in the hypervariable D-loop of the control region (CR) of mitochondrial DNA (mtDNA) has attracted research interest because of its suspected association with various multifactorial diseases. The aim of the present study was to compare the frequency of this polymorphism in the CR of mtDNA in patients with coronary artery disease (CAD, n = 482) and type 2 diabetes mellitus (T2DM, n = 505) from two study centers, with healthy individuals (n = 1481) of Middle European descent in Austria. METHODOLOGY AND PRINCIPAL FINDINGS: CR polymorphisms and the nine major European haplogroups were identified by DNA sequencing and primer extension analysis, respectively. Frequencies and Odds Ratios for the association between cases and controls were calculated. Compared to healthy controls, the prevalence of T16189C was significantly higher in patients with CAD (11.8% vs 21.6%), as well as in patients with T2DM (11.8% vs 19.4%). The association of CAD, but not the one of T2DM, with T16189C remained highly significant after correction for age, sex and body mass index (BMI) and was independent of the two study centers. CONCLUSIONS AND SIGNIFICANCE: Our results show for the first time a significant association of T16189C with CAD in a Middle European population. As reported in other studies, in patients with T2DM an association with T16189C in individuals of European decent remains questionable

Mitochondrial Haplogroups and Control Region Polymorphisms in Age-Related Macular Degeneration: A Case-Control Study

Background: Onset and development of the multifactorial disease age-related macular degeneration (AMD) are highly interrelated with mitochondrial functions such as energy production and free radical turnover. Mitochondrial dysfunction and overproduction of reactive oxygen species may contribute to destruction of the retinal pigment epithelium, retinal atrophy and choroidal neovascularization, leading to AMD. Consequently, polymorphisms of the mitochondrial genome (mtDNA) are postulated to be susceptibility factors for this disease. Previous studies from Australia and the United States detected associations of mitochondrial haplogroups with AMD. The aim of the present study was to test these associations in Middle European Caucasians. Methodology/Principal Findings: Mitochondrial haplogroups (combinations of mtDNA polymorphisms) and mitochondrial CR polymorphisms were analyzed in 200 patients with wet AMD (choroidal neovascularization, CNV), in 66 patients with dry AMD, and in 385 controls from Austria by means of multiplex primer extension analysis and sequencing, respectively. In patients with CNV, haplogroup H was found to be significantly less frequent compared to controls, and haplogroup J showed a trend toward a higher frequency compared to controls. Five CR polymorphisms were found to differ significantly in the two study populations compared to controls, and all, except one (T152C), are linked to those haplogroups. Conclusions/Significance: It can be concluded that haplogroup J is a risk factor for AMD, whereas haplogroup H seems t

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

<p>Abstract</p> <p>Background</p> <p>There is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy.</p> <p>Methods</p> <p>This study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease.</p> <p>Results</p> <p>Haplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046).</p> <p>Conclusion</p> <p>Our data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.</p

Mast Cells Are Abundant in Primary Cutaneous T-Cell Lymphomas: Results from a Computer-Aided Quantitative Immunohistological Study.

Mast cells (MC) are bone marrow derived haematopoetic cells playing a crucial role not only in immune response but also in the tumor microenvironment with protumorigenic and antitumorigenic functions. The role of MC in primary cutaneous T-cell lymphomas (CTCL), a heterogeneous group of non-Hodgkin lymphomas with initial presentation in the skin, is largely unknown.To gain more accurate information about presence, number, distribution and state of activation (degranulated vs. non-degranulated) of MC in CTCL variants and clinical stages.We established a novel computer-aided tissue analysis method on digitized skin sections. Immunohistochemistry with an anti-MC tryptase antibody was performed on 34 biopsies of different CTCL subtypes and on control skin samples. An algorithm for the automatic detection of the epidermis and of cell density based CTCL areas was developed. Cells were stratified as being within the CTCL infiltrate, in P1 (a surrounding area 0-30 μm away from CTCL), or in P2 (30-60 μm away from CTCL) area.We found high MC counts within CTCL infiltrates and P1 and a decreased MC number in the surrounding dermis P2. Higher MC numbers were found in MF compared to all other CTCL subgroups. Regarding different stages of MF, we found significantly higher mast cell counts in stages IA and IB than in stages IIA and IIB. Regarding MC densities, we found a higher density of MC in MF compared to all other CTCL subgroups. More MC were non-degranulated than degranulated.Here for the first time an automated method for MC analysis on tissue sections and its use in CTCL is described. Eliminating error from investigator bias, the method allows for precise cell identification and counting. Our results provide new insights on MC distribution in CTCL reappraising their role in the pathophysiology of CTCL

Mitochondrial Haplogroups and Control Region Polymorphisms Are Not Associated with Prostate Cancer in Middle European Caucasians

Background: Besides being responsible for energy production in the cell, mitochondria are central players in apoptosis as well as the main source of harmful reactive oxygen species. Therefore, it can be hypothesised that sequence variation in the mitochondrial genome is a contributing factor to the etiology of diseases related to these different cellular events, including cancer. The aim of the present study was to assess the frequency of haplogroups and polymorphisms in the control region (CR) of mitochondrial DNA of peripheral blood mononuclear cells from patients with prostate carcinoma (n = 304) versus patients screened for prostate disease but found to be negative for cancer on biopsy (n = 278) in a Middle European population. Methodology/Principal Findings: The nine major European haplogroups and the CR polymorphisms were identified by means of primer extension analysis and DNA sequencing, respectively. We found that mitochondrial haplogroup frequencies and CR polymorphisms do not differ significantly between patients with or without prostate cancer, implying no impact of inherited mitochondrial DNA variation on predisposition to prostate carcinoma in a Middle European population. Conclusions/Significance: Our results contrast with a recent report claiming an association between mtDNA haplogroup

Frequencies (%) of control region polymorphisms >5% in patients with CNV and in controls as well as the corresponding odds ratios and 95% confidence intervals.

a<p>mtDNA = mitochondrial DNA.</p>b<p>CNV = choroidal neovascularisation.</p>c<p>n: number of individuals with the respective polymorphism.</p>d<p>P-value: Pearson chi-square or Fisher's exact test.</p>e<p>CI = confidence interval.</p>f<p>adjusted for age and sex by logistic regression analysis.</p

Comparison of age-related macular degeneration case-control studies in the literature with the present study.

a<p>mtDNA = mitochondrial DNA.</p>b<p>According to PhyloTree.org <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030874#pone.0030874-vanOven1" target="_blank">[21]</a>.</p>c<p>P-values: present study: adjusted for age and sex. Jones et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030874#pone.0030874-Jones1" target="_blank">[12]</a>: adjusted for age, sex and current smoking. Canter et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030874#pone.0030874-Canter1" target="_blank">[13]</a>: adjusted for sex and three nuclear polymorphisms (CFH-Complement Factor H gene, rs1061170; LOC387715, rs10490924; APOE, ApoE2 allele). Udar et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030874#pone.0030874-Udar1" target="_blank">[14]</a>: no adjustment. SanGiovanni et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030874#pone.0030874-SanGiovanni1" target="_blank">[15]</a>: adjusted for age, sex and smoking.</p>d<p>CI = confidence interval.</p

Characteristics of the study populations.

a<p>CNV = choroidal neovascularization.</p>b<p>AMD = age-related macular degeneration.</p>c<p>SD = standard deviation.</p