Mitochondrial haplogroups and polymorphisms reveal no association with sporadic prostate cancer in a southern European population

Background

It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer.

Methodology and Principal Findings

Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage.

Conclusions and Significance

Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results.     

Mitochondrial haplogroups, control region polymorphisms and malignant melanoma: a study in middle European Caucasians

Background

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.

Methodology and Principal Findings

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.

Conclusions and Significance

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.     

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 to be protective for AMD.     

Mitochondrial haplogroups h and j: risk and protective factors for ischemic cardiomyopathy

Background

Since mitochondria are the principal source of reactive oxygen species (ROS), these organelles may play an important role in ischemic cardiomyopathy (IC) development. The mitochondrial genome may influence this disease. The aim of the present study was to test the relationship between IC development and the impact of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) defining the mitochondrial haplogroups in a population study.

Methodology and principal findings

Ten major European haplogroups were identified by using the single base extension technique and by polymerase chain reaction-restriction fragment length polymorphism. Frequencies and Odds Ratios for the association between IC patients (n = 358) and healthy controls (n = 423) were calculated. No convincing associations between classical risk factors for ischemic cardiomyopathy development and haplogroups were found. However, compared to healthy controls, the prevalence of haplogroup H was significantly higher in IC patients (40.0% vs 50.0%, p-value  = 0.039) while the frequency of haplogroup J was significantly lower (11.1% vs 5.6%, p-value  = 0.048). The analysis of the SNPs characterizing the European mtDNA haplogroups showed that the m.7028C allele (40.0% vs 50.0%, p-value  = 0.005) and m.14766C allele (43.0% vs 54.2%, p-value  = 0.002) were overrepresented in IC patients, meanwhile the m.10398G allele (19.8% vs 13.1%, p-value  = 0.015) and m.4216C allele (22.2% vs 16.5%, p-value  = 0.044) were found as protective factors against IC.

Conclusions and significance

Our results showed that the haplogroups H and J were found as a risk and protective factors for ischemic cardiomyopathy development, respectively.     

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 Haplogroup T Is Associated with Obesity in Austrian Juveniles and Adults

Background

Recent publications have reported contradictory data regarding mitochondrial DNA (mtDNA) variation and its association with body mass index. The aim of the present study was to compare the frequencies of mtDNA haplogroups as well as control region (CR) polymorphisms of obese juveniles (n = 248) and obese adults (n = 1003) versus normal weight controls (n_juvenile = 266, n_adults = 595) in a well-defined, ethnically homogenous, age-matched comparative cohort of Austrian Caucasians.

Methodology and Principal Findings

Using SNP analysis and DNA sequencing, we identified the nine major European mitochondrial haplogroups and CR polymorphisms. Of these, only the T haplogroup frequency was increased in the juvenile obese cohort versus the control subjects [11.7% in obese vs. 6.4% in controls], although statistical significance was lost after adjustment for sex and age. Similar data were observed in a local adult cohort, in which haplogroup T was found at a significantly higher frequency in the overweight and obese subjects than in the normal weight group [9.7% vs. 6.2%, p = 0.012, adjusted for sex and age]. When all obese subjects were considered together, the difference in the frequency of haplogroup T was even more clearly seen [10.1% vs. 6.3%, p = 0.002, OR (95% CI) 1.71 (1.2–2.4), adjusted for sex and age]. The frequencies of the T haplogroup-linked CR polymorphisms C16294T and the C16296T were found to be elevated in both the juvenile and the adult obese cohort compared to the controls. Nevertheless, no mtDNA haplogroup or CR polymorphism was robustly associated with any of several investigated metabolic and cardiovascular parameters (e.g., blood pressure, blood glucose concentration, triglycerides, cholesterol) in all obese subjects.

Conclusions and Significance

By investigation of this large ethnically and geographically homogenous cohort of Middle European Caucasians, only mtDNA haplogroup T was identified as an obesity risk factor.     

Functional Differences between Mitochondrial Haplogroup T and Haplogroup H in HEK293 Cybrid Cells

Background

Epidemiological case-control studies have revealed associations between mitochondrial haplogroups and the onset and/or progression of various multifactorial diseases. For instance, mitochondrial haplogroup T was previously shown to be associated with vascular diseases, including coronary artery disease and diabetic retinopathy. In contrast, haplogroup H, the most frequent haplogroup in Europe, is often found to be more prevalent in healthy control subjects than in patient study groups. However, justifications for the assumption that haplogroups are functionally distinct are rare. Therefore, we attempted to compare differences in mitochondrial function between haplogroup H and T cybrids.

Methodology/Principal Findings

Mitochondrial haplogroup H and T cybrids were generated by fusion of HEK293 cells devoid of mitochondrial DNA with isolated thrombocytes of individuals with the respective haplogroups. These cybrid cells were analyzed for oxidative phosphorylation (OXPHOS) enzyme activities, mitochondrial DNA (mtDNA) copy number, growth rate and susceptibility to reactive oxygen species (ROS). We observed that haplogroup T cybrids have higher survival rate when challenged with hydrogen peroxide, indicating a higher capability to cope with oxidative stress.

Conclusions/Significance

The results of this study show that functional differences exist between HEK293 cybrid cells which differ in mitochondrial genomic background.     

Association of Mitochondrial DNA Haplogroups with Exceptional Longevity in a Chinese Population

Background

Longevity is a multifactorial trait with a genetic contribution, and mitochondrial DNA (mtDNA) polymorphisms were found to be involved in the phenomenon of longevity.

Methodology/Principal Findings

To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population based case-control study was conducted in Rugao – a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged ≥95 yr (EL group). Control subjects include 926 individuals aged 60–69 years (elderly group) and 463 individuals aged 40–49 years (middle-aged group) randomly recruited from Rugao. We observed significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle-aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle-aged subjects (8.6%), elderly subjects (7.2%) and longevity subjects (4.8%) (p = 0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%) and longevity subjects (21.7%) in females (p = 0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%) and longevity subjects (1.7%) in females (p = 0.045).

Conclusions

Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population.     

Role of mtDNA Haplogroups in the Prevalence of Osteoarthritis in Different Geographic Populations: A Meta-Analysis

Background

Osteoarthritis (OA) is the most common form of arthritis and has become an increasingly important public-health problem. However, the pathogenesis of OA is still unclear. In recent years, its correlation with mtDNA haplogroups attracts much attention. We aimed to perform a meta-analysis to investigate the association between mtDNA haplogroups and OA.

Methods

Published English or Chinese literature from PubMed, Web of Science, SDOS, and CNKI was retrieved up until April 15, 2014. Case-control or cohort studies that detected the frequency of mtDNA haplogroups in OA patients and controls were included. The quality of the included studies was evaluated by the Newcastle-Ottawa Scale (NOS) assessment. A meta-analysis was conducted to calculate pooled odds ratio (OR) with 95% confidence interval (CI) through the random or fixed effect model, which was selected based on the between-study heterogeneity assessed by Q test and I² test. Subgroup analysis was performed to explore the origin of heterogeneity.

Results

A total of 6 case-control studies (10590 cases and 7161 controls) with an average NOS score of 6.9 were involved. For the analysis between mtDNA haplogroup J and OA, random model was selected due to high heterogeneity. No significant association was found initially (OR = 0.73, 95%CI: 0.52–1.03), however, once any study from UK population was removed the association emerged. Further subgroup analysis demonstrated that there was a significant association in Spain population (OR = 0.57, 95%CI: 0.46–0.71), but not in UK population. Also, subgroup analysis revealed that there was a significant correlation between cluster TJ and OA in Spain population (OR = 0.70, 95%CI: 0.58–0.84), although not in UK population. No significant correlation was found between haplogroup T/cluster HV/cluster KU and OA.

Conclusions

Our current meta-analysis suggests that mtDNA haplogroup J and cluster TJ correlate with the risk of OA in Spanish population, but the associations in other populations require further investigation.     

The Peopling of Korea Revealed by Analyses of Mitochondrial DNA and Y-Chromosomal Markers

Background

The Koreans are generally considered a northeast Asian group because of their geographical location. However, recent findings from Y chromosome studies showed that the Korean population contains lineages from both southern and northern parts of East Asia. To understand the genetic history and relationships of Korea more fully, additional data and analyses are necessary.

Methodology and Results

We analyzed mitochondrial DNA (mtDNA) sequence variation in the hypervariable segments I and II (HVS-I and HVS-II) and haplogroup-specific mutations in coding regions in 445 individuals from seven east Asian populations (Korean, Korean-Chinese, Mongolian, Manchurian, Han (Beijing), Vietnamese and Thais). In addition, published mtDNA haplogroup data (N = 3307), mtDNA HVS-I sequences (N = 2313), Y chromosome haplogroup data (N = 1697) and Y chromosome STR data (N = 2713) were analyzed to elucidate the genetic structure of East Asian populations. All the mtDNA profiles studied here were classified into subsets of haplogroups common in East Asia, with just two exceptions. In general, the Korean mtDNA profiles revealed similarities to other northeastern Asian populations through analysis of individual haplogroup distributions, genetic distances between populations or an analysis of molecular variance, although a minor southern contribution was also suggested. Reanalysis of Y-chromosomal data confirmed both the overall similarity to other northeastern populations, and also a larger paternal contribution from southeastern populations.

Conclusion

The present work provides evidence that peopling of Korea can be seen as a complex process, interpreted as an early northern Asian settlement with at least one subsequent male-biased southern-to-northern migration, possibly associated with the spread of rice agriculture.     

The Druze: a population genetic refugium of the Near East

Background

Phylogenetic mitochondrial DNA haplogroups are highly partitioned across global geographic regions. A unique exception is the X haplogroup, which has a widespread global distribution without major regions of distinct localization.

Principal Findings

We have examined mitochondrial DNA sequence variation together with Y-chromosome-based haplogroup structure among the Druze, a religious minority with a unique socio-demographic history residing in the Near East. We observed a striking overall pattern of heterogeneous parental origins, consistent with Druze oral tradition, together with both a high frequency and a high diversity of the mitochondrial DNA (mtDNA) X haplogroup within a confined regional subpopulation. Furthermore demographic modeling indicated low migration rates with nearby populations.

Conclusions

These findings were enabled through the use of a paternal kindred based sampling approach, and suggest that the Galilee Druze represent a population isolate, and that the combination of a high frequency and diversity of the mtDNA X haplogroup signifies a phylogenetic refugium, providing a sample snapshot of the genetic landscape of the Near East prior to the modern age.     

The Enigmatic Origin of Bovine mtDNA Haplogroup R: Sporadic Interbreeding or an Independent Event of Bos primigenius Domestication in Italy?

Background

When domestic taurine cattle diffused from the Fertile Crescent, local wild aurochsen (Bos primigenius) were still numerous. Moreover, aurochsen and introduced cattle often coexisted for millennia, thus providing potential conditions not only for spontaneous interbreeding, but also for pastoralists to create secondary domestication centers involving local aurochs populations. Recent mitochondrial genomes analyses revealed that not all modern taurine mtDNAs belong to the shallow macro-haplogroup T of Near Eastern origin, as demonstrated by the detection of three branches (P, Q and R) radiating prior to the T node in the bovine phylogeny. These uncommon haplogroups represent excellent tools to evaluate if sporadic interbreeding or even additional events of cattle domestication occurred.

Methodology

The survey of the mitochondrial DNA (mtDNA) control-region variation of 1,747 bovine samples (1,128 new and 619 from previous studies) belonging to 37 European breeds allowed the identification of 16 novel non-T mtDNAs, which after complete genome sequencing were confirmed as members of haplogroups Q and R. These mtDNAs were then integrated in a phylogenetic tree encompassing all available P, Q and R complete mtDNA sequences.

Conclusions

Phylogenetic analyses of 28 mitochondrial genomes belonging to haplogroups P (N = 2), Q (N = 16) and R (N = 10) together with an extensive survey of all previously published mtDNA datasets revealed major similarities between haplogroups Q and T. Therefore, Q most likely represents an additional minor lineage domesticated in the Near East together with the founders of the T subhaplogroups. Whereas, haplogroup R is found, at least for the moment, only in Italy and nowhere else, either in modern or ancient samples, thus supporting an origin from European aurochsen. Haplogroup R could have been acquired through sporadic interbreeding of wild and domestic animals, but our data do not rule out the possibility of a local and secondary event of B. primigenius domestication in Italy.     

T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study 384

Introduction

Mitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. We previously reported an association between African mtDNA haplogroup L2 and less robust CD4 cell recovery on antiretroviral therapy (ART) in non-Hispanic black ACTG 384 subjects. We explored whether additional T cell parameters in this cohort differed by mtDNA haplogroup.

Methods

ACTG 384 randomized ART-naïve subjects to two different nucleoside regimens with efavirenz, nelfinavir, or both. CD4 and CD8 memory and activation markers were available at baseline and week 48 on most subjects. mtDNA sequencing was performed on whole blood DNA, and haplogroups were determined. We studied non-Hispanic black subjects with HIV RNA <400 copies/mL at week 48. Analyses included Wilcoxon ranksum test and linear regression.

Results

Data from 104 subjects were included. Major African mtDNA haplogroups included L1 (N = 25), L2 (N = 31), and L3 (N = 32). Baseline age, HIV RNA, and CD4 cells did not differ between L2 and non-L2 haplogroups. Compared to non-L2 haplogroups, L2 subjects had lower baseline activated CD4 cells (median 12% vs. 17%; p = 0.03) and tended toward lower activated CD8 cells (41% vs. 47%; p = 0.06). At 48 weeks of ART, L2 subjects had smaller decreases in activated CD4 cells (−4% vs. −11%; p = 0.01), and smaller CD4 cell increases (+95 vs. +178; p = 0.002). In models adjusting for baseline age, CD4 cells, HIV RNA, and naïve-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48-week change in (p = 0.01) activated CD4 cells.

Conclusions

Among ART-naïve non-Hispanic blacks, mtDNA haplogroup L2 was associated with baseline and 48-week change in T cell activation, and poorer CD4 cell recovery. These data suggest mtDNA variation may influence CD4 T cell dynamics by modulating T cell activation. Further study is needed to replicate these associations and identify mechanisms.     

Ashkenazi Jewish centenarians do not demonstrate enrichment in mitochondrial haplogroup J

Background

Association of mitochondrial haplogroup J with longevity has been reported in several population subgroups. While studies from northern Italy and Finland, have described a higher frequency of haplogroup J among centenarians in comparison to non-centenarian, several other studies could not replicate these results and suggested various explanations for the discrepancy.

Methodology/Principal Findings

We have evaluated haplogroup frequencies among Ashkenazi Jewish centenarians using two different sets of matched controls. No difference was observed in the haplogroup J frequencies between the centenarians or either matched control group, despite adequate statistical power to detect such a difference. Furthermore, the lack of association was robust to population substructure in the Ashkenazi Jewish population. Given this discrepancy with the previous reported associations in the northern Italian and the Finnish populations, we conducted re-analysis of these previously published data, which supported one of several possible explanations: i) inadequate matching of cases and controls; ii) inadequate adjustment for multiple comparison testing; iii) cryptic population stratification.

Conclusions/Significance

There does not exist a universal association of mitochondrial haplogroup J with longevity across all population groups. Reported associations in specialized populations may reflect genetic or other interactions specific to those populations or else cryptic confounding influences, such as inadequate matching attributable to population substructure, which are of general relevance to all studies of the possible association of mitochondrial DNA haplogroups with common complex phenotypes.     

Mitochondrial Control Region Alterations and Breast Cancer Risk: A Study in South Indian Population

Background

Mitochondrial displacement loop (D-loop) is the hot spot for mitochondrial DNA (mtDNA) alterations which influence the generation of cellular reactive oxygen species (ROS). Association of D-loop alterations with breast cancer has been reported in few ethnic groups; however none of the reports were documented from Indian subcontinent.

Methodology

We screened the entire mitochondrial D-loop region (1124 bp) of breast cancer patients (n = 213) and controls (n = 207) of south Indian origin by PCR-sequencing analysis. Haplotype frequencies for significant loci, the standardized disequilibrium coefficient (D′) for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software.

Principal Findings

We identified 7 novel mutations and 170 reported polymorphisms in the D-loop region of patients and/or controls. Polymorphisms were predominantly located in hypervariable region I (60%) than in II (30%) of D-loop region. The frequencies of 310‘C’ insertion (P = 0.018), T16189C (P = 0.0019) variants and 310‘C’ins/16189C (P = 0.00019) haplotype were significantly higher in cases than in controls. Furthermore, strong LD was observed between nucleotide position 310 and 16189 in controls (D′ = 0.49) as compared to patients (D′ = 0.14).

Conclusions

Mitochondrial D-loop alterations may constitute inherent risk factors for breast cancer development. The analysis of genetic alterations in the D-loop region might help to identify patients at high risk for bad progression, thereby helping to refine therapeutic decisions in breast cancer.     

Frequency of Chromosomally-Integrated Human Herpesvirus 6 in Children with Acute Lymphoblastic Leukemia

Introduction

Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen infecting nearly 100% of the human population. Of these individuals, between 0.2% and 1% of them carry chromosomally-integrated HHV-6 (ciHHV-6). The biological consequences of chromosomal integration by HHV-6 remain unknown.

Objective

To determine and compare the frequency of ciHHV-6 in children with acute lymphoblastic leukemia to healthy blood donors.

Methodology

A total of 293 DNA samples from children with pre-B (n = 255), pre-pre-B (n = 4), pre-T (n = 26) and undetermined (n = 8) leukemia were analyzed for ciHHV-6 by quantitative TaqMan PCR (QPCR) using HHV-6 specific primers and probe. As control, DNA samples from 288 healthy individuals were used. Primers and probe specific to the cellular GAPDH gene were used to estimate integrity and DNA content.

Results

Out of 293 DNA samples from the leukemic cohort, 287 contained amplifiable DNA. Of these, only 1 (0.35%) contained ciHHV-6. Variant typing indicates that the ci-HHV-6 corresponds to variant A. None of the 288 DNA samples from healthy individuals contained ciHHV-6.

Conclusion

The frequency of ciHHV-6 in children with acute lymphoblastic leukemia is similar (p = 0.5) to that of healthy individuals. These results suggest that acute lymphoblastic leukemia does not originate as a consequence to integration of HHV-6 within the chromosomes.     

Evolutionary Pressure on Mitochondrial Cytochrome b Is Consistent with a Role of CytbI7T Affecting Longevity during Caloric Restriction

Background

Metabolism of energy nutrients by the mitochondrial electron transport chain (ETC) is implicated in the aging process. Polymorphisms in core ETC proteins may have an effect on longevity. Here we investigate the cytochrome b (cytb) polymorphism at amino acid 7 (cytbI7T) that distinguishes human mitochondrial haplogroup H from haplogroup U.

Principal Findings

We compared longevity of individuals in these two haplogroups during historical extremes of caloric intake. Haplogroup H exhibits significantly increased longevity during historical caloric restriction compared to haplogroup U (p = 0.02) while during caloric abundance they are not different. The historical effects of natural selection on the cytb protein were estimated with the software TreeSAAP using a phylogenetic reconstruction for 107 mammal taxa from all major mammalian lineages using 13 complete protein-coding mitochondrial gene sequences. With this framework, we compared the biochemical shifts produced by cytbI7T with historical evolutionary pressure on and near this polymorphic site throughout mammalian evolution to characterize the role cytbI7T had on the ETC during times of restricted caloric intake.

Significance

Our results suggest the relationship between caloric restriction and increased longevity in human mitochondrial haplogroup H is determined by cytbI7T which likely enhances the ability of water to replenish the Q_i binding site and decreases the time ubisemiquinone is at the Q_o site, resulting in a decrease in the average production rate of radical oxygen species (ROS).     

Genetic Polymorphisms of the Glycine N-Methyltransferase and Prostate Cancer Risk in the Health Professionals Follow-Up Study

Purpose

Glycine N-methyltransferase (GNMT) affects genetic stability by regulating the ratio of S-adenosylmethionine to S-adenosylhomocysteine, by binding to folate, and by interacting with environmental carcinogens. In Taiwanese men, GNMT was found to be a tumor susceptibility gene for prostate cancer. However, the association of GNMT with prostate cancer risk in other ethnicities has not been studied. It was recently reported that sarcosine, which is regulated by GNMT, increased markedly in metastatic prostate cancer. We hereby explored the association of GNMT polymorphisms with prostate cancer risk in individuals of European descent from the Health Professionals Follow-up Study (HPFS).

Methods

A total of 661 incident prostate cancer cases and 656 controls were identified from HPFS. The GNMT short tandem repeat polymorphism 1 (STRP1), 4-bp insertion/deletion polymorphisms (INS/DEL) and the single nucleotide polymorphism rs10948059 were genotyped to test for their association with prostate cancer risk.

Results

The rs10948059 T/T genotype was associated with a 1.62-fold increase in prostate cancer risk (95% confidence interval (CI): 1.18, 2.22) when compared with the C/C genotype. The STRP1 ≥16GAs/≥16GAs genotype was associated with decreased risk of prostate cancer when compared with the <16GAs/<16GAs genotype (odds ratio (OR) = 0.68; 95% CI: 0.46, 1.01). INS/DEL was not associated with prostate cancer risk. Haplotypes containing the rs10948059 T allele were significantly associated with increased prostate cancer risk.

Conclusion

In men of European descent, the GNMT rs10948059 and STRP1 were associated with prostate cancer risk. Compared to the study conducted in Taiwanese men, the susceptibility GNMT alleles for prostate cancer had a reverse relationship. This study highlights the differences in allelic frequencies and prostate cancer susceptibility in different ethnicities.     

Improved Resolution Haplogroup G Phylogeny in the Y Chromosome,Revealed by a Set of Newly Characterized SNPs

Background

Y-SNP haplogroup G (hgG), defined by Y-SNP marker M201, is relatively uncommon in the United States general population, with only 8 additional sub-markers characterized. Many of the previously described eight sub-markers are either very rare (2–4%) or do not distinguish between major populations within this hg. In fact, prior to the current study, only 2% of our reference Caucasian population belonged to hgG and all of these individuals were in sub-haplogroup G2a, defined by P15. Additional Y-SNPs are needed in order to differentiate between individuals within this haplogroup.

Principal Findings

In this work we have investigated whether we could differentiate between a population of 63 hgG individuals using previously uncharacterized Y-SNPs. We have designed assays to test these individuals using all known hgG SNPs (n = 9) and an additional 16 unreported/undefined Y-SNPS. Using a combination of DNA sequence and genetic genealogy databases, we have uncovered a total of 15 new hgG SNPs that had been previously reported but not phylogenetically characterized. Ten of the new Y-SNPs are phylogenetically equivalent to M201, one is equivalent to P15 and, interestingly, four create new, separate haplogroups. Three of the latter are more common than many of the previously defined Y-SNPs. Y-STR data from these individuals show that DYS385*12 is present in (70%) of G2a3b1-U13 individuals while only 4% of non-G2a3b1-U13 individuals posses the DYS385*12 allele.

Conclusions

This study uncovered several previously undefined Y-SNPs by using data from several database sources. The new Y-SNPs revealed in this paper will be of importance to those with research interests in population biology and human evolution.     

High Prevalence of Human Cytomegalovirus Proteins and Nucleic Acids in Primary Breast Cancer and Metastatic Sentinel Lymph Nodes

Background

Breast cancer is a leading cause of death among women worldwide. Increasing evidence implies that human cytomegalovirus (HCMV) infection is associated with several malignancies. We aimed to examine whether HCMV is present in breast cancer and sentinel lymph node (SLN) metastases.

Materials and Methods

Formalin-fixed paraffin-embedded tissue specimens from breast cancer and paired sentinel lymph node (SLN) samples were obtained from patients with (n = 35) and without SLN metastasis (n = 38). HCMV immediate early (IE) and late (LA) proteins were detected using a sensitive immunohistochemistry (IHC) technique and HCMV DNA by real-time PCR.

Results

HCMV IE and LA proteins were abundantly expressed in 100% of breast cancer specimens. In SLN specimens, 94% of samples with metastases (n = 34) were positive for HCMV IE and LA proteins, mostly confined to neoplastic cells while some inflammatory cells were HCMV positive in 60% of lymph nodes without metastases (n = 35). The presence of HCMV DNA was confirmed in 12/12 (100%) of breast cancer and 10/11 (91%) SLN specimens from the metastatic group, but was not detected in 5/5 HCMV-negative, SLN-negative specimens. There was no statistically significant association between HCMV infection grades and progesterone receptor, estrogen receptor alpha and Elston grade status.

Conclusions

The role of HCMV in the pathogenesis of breast cancer is unclear. As HCMV proteins were mainly confined to neoplastic cells in primary breast cancer and SLN samples, our observations raise the question whether HCMV contributes to the tumorigenesis of breast cancer and its metastases.