Association analysis of indel variants and gene expression identifies MDM4 as a novel locus for skeletal muscle hypertrophy and power athlete status.

Insertions and deletions (indels) are the second most common type of variation in the human genome. However, limited data on their associations with exercise-related phenotypes have been documented. The aim of the present study was to examine the association between 18,370 indel variants and power athlete status, followed by additional studies in 357,246 individuals. In the discovery phase, the D allele of the MDM4 gene rs35493922 I/D polymorphism was over-represented in power athletes compared with control subjects (P = 7.8 × 10-9) and endurance athletes (P = 0.0012). These findings were replicated in independent cohorts, showing a higher D allele frequency in power athletes compared with control subjects (P = 0.016) and endurance athletes (P = 0.031). Furthermore, the D allele was positively associated (P = 0.0013) with greater fat-free mass in the UK Biobank. MDM4 encodes a protein that inhibits the activity of p53, which induces muscle fibre atrophy. Accordingly, we found that MDM4 expression was significantly higher in the vastus lateralis of power athletes compared with endurance athletes (P = 0.0009) and was positively correlated with the percentage of fast-twitch muscle fibres (P = 0.0062) and the relative area occupied by fast-twitch muscle fibres (P = 0.0086). The association between MDM4 gene expression and an increased proportion of fast-twitch muscle fibres was confirmed in two additional cohorts. Finally, we found that the MDM4 DD genotype was associated with increased MDM4 gene expression in vastus lateralis and greater cross-sectional area of fast-twitch muscle fibres. In conclusion, MDM4 is suggested to be a potential regulator of muscle fibre specification and size, with its indel variant being associated with power athlete status. HIGHLIGHTS: What is the central question of this study? Which indel variants are functional and associated with sport- and exercise-related traits? What is the main finding and its importance? Out of 18,370 tested indels, the MDM4 gene rs35493922 I/D polymorphism was found to be the functional variant (affecting gene expression) and the most significant, with the deletion allele showing associations with power athlete status, fat-free mass and cross-sectional area of fast-twitch muscle fibres. Furthermore, the expression of MDM4 was positively correlated with the percentage of fast-twitch muscle fibres and the relative area occupied by fast-twitch muscle fibres.

Optimal breast cancer risk reduction policies tailored to personal risk level.

Depending on personal and hereditary factors, each woman has a different risk of developing breast cancer, one of the leading causes of death for women. For women with a high-risk of breast cancer, their risk can be reduced by two main therapeutic approaches: 1) preventive treatments such as hormonal therapies (i.e., tamoxifen, raloxifene, exemestane); or 2) a risk reduction surgery (i.e., mastectomy). Existing national clinical guidelines either fail to incorporate or have limited use of the personal risk of developing breast cancer in their proposed risk reduction strategies. As a result, they do not provide enough resolution on the benefit-risk trade-off of an intervention policy as personal risk changes. In addressing this problem, we develop a discrete-time, finite-horizon Markov decision process (MDP) model with the objective of maximizing the patient's total expected quality-adjusted life years. We find several useful insights some of which contradict the existing national breast cancer risk reduction recommendations. For example, we find that mastectomy is the optimal choice for the border-line high-risk women who are between ages 22 and 38. Additionally, in contrast to the National Comprehensive Cancer Network recommendations, we find that exemestane is a plausible, in fact, the best, option for high-risk postmenopausal women.

Warburg Micro Syndrome 1 due to Segmental Paternal Uniparental Isodisomy of Chromosome 2 Detected by Whole-Exome Sequencing and Homozygosity Mapping.

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.

Mitotic stability of small supernumerary marker chromosomes: a study based on 93 immortalized cell lines.

Small supernumerary marker chromosomes (sSMC) are known for being present in mosaic form as 47,+mar/46 in >50% of the cases with this kind of extra chromosomes. However, no detailed studies have been done for the mitotic stability of sSMC so far, mainly due to the lack of a corresponding in vitro model system. Recently, we established an sSMC-cell bank (Else Kröner-Fresenius-sSMC-cellbank) with >150 cell lines. Therefore, 93 selected sSMC cases were studied here for the presence of the corresponding marker chromosomes before and after Epstein-Barr virus-induced immortalization. The obtained results showed that dicentric inverted duplicated-shaped sSMC are by far more stable in vitro than monocentric centric minute- or ring-shaped sSMC. Simultaneously, a review of the literature revealed that a comparable shape-dependent mitotic stability can be found in vivo in sSMC carriers. Additionally, a possible impact of the age of the sSMC carrier on mitotic stability was found: sSMC cell lines established from patients between 10-20 years of age were predominantly mitotically unstable. The latter finding was independent of the sSMC shape. The present study shows that in vitro models can lead to new and exciting insights into the biology of this genetically and clinically heterogeneous patient group.

Impact of the COVID-19 Pandemic on Breast Cancer Mortality in the US: Estimates From Collaborative Simulation Modeling.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted breast cancer control through short-term declines in screening and delays in diagnosis and treatments. We projected the impact of COVID-19 on future breast cancer mortality between 2020 and 2030. METHODS: Three established Cancer Intervention and Surveillance Modeling Network breast cancer models modeled reductions in mammography screening use, delays in symptomatic cancer diagnosis, and reduced use of chemotherapy for women with early-stage disease for the first 6 months of the pandemic with return to prepandemic patterns after that time. Sensitivity analyses were performed to determine the effect of key model parameters, including the duration of the pandemic impact. RESULTS: By 2030, the models project 950 (model range = 860-1297) cumulative excess breast cancer deaths related to reduced screening, 1314 (model range = 266-1325) associated with delayed diagnosis of symptomatic cases, and 151 (model range = 146-207) associated with reduced chemotherapy use in women with hormone positive, early-stage cancer. Jointly, 2487 (model range = 1713-2575) excess breast cancer deaths were estimated, representing a 0.52% (model range = 0.36%-0.56%) cumulative increase over breast cancer deaths expected by 2030 in the absence of the pandemic's disruptions. Sensitivity analyses indicated that the breast cancer mortality impact would be approximately double if the modeled pandemic effects on screening, symptomatic diagnosis, and chemotherapy extended for 12 months. CONCLUSIONS: Initial pandemic-related disruptions in breast cancer care will have a small long-term cumulative impact on breast cancer mortality. Continued efforts to ensure prompt return to screening and minimize delays in evaluation of symptomatic women can largely mitigate the effects of the initial pandemic-associated disruptions.

Association of beta-1 and beta-2 adrenergic receptor gene polymorphisms with myocardial infarction.

Both beta(1)- and beta2-adrenergic receptors (beta(1)- and beta(2)-AR) have important roles in heart function mainly in response to catecholamines. Some specific polymorphisms in the beta(1)- and beta(2)-AR genes, named ADRB1 and ADRB2, respectively, have been implicated in several cardiovascular and noncardiovascular phenotypes. In this study, we aimed to investigate the possible relationship between Ser49Gly and Arg389Gly polymorphisms of the ADRB1 and Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene with ST elevation myocardial infarction (MI) in a Turkish population. One hundred patients with ST elevation MI and 100 healthy control subjects were genotyped using the PCR-RFLP method. Although the Arg389 allele of the ADRB1 gene was associated with an elevated risk of MI, the Glu27 allele of the ADRB2 gene was associated with a decreased risk of MI. Carriers of the ADRB1 Arg389 allele (heterozygotes+homozygotes) had an approximately 3.5-fold increased risk for MI than Gly389 homozygotes (OR=3.59, 95% CI=0.96-13.47, P=0.045). For the ADRB2 Gln27Glu polymorphism, subjects having one or two copies of the Glu27 allele showed a decreased risk of MI compared with Gln27 homozygote subjects (OR=0.48, 95% CI=0.24-0.94, P=0.03). Haplotype analysis of these polymorphisms showed no significant differences between groups. These results suggest that the Arg389Gly and Gln27Glu polymorphisms may be associated with an altered risk of MI in this Turkish population.

Cost-effectiveness of adjuvant paclitaxel and trastuzumab for early-stage node-negative, HER2-positive breast cancer.

OBJECTIVES: Adjuvant paclitaxel and trastuzumab has been shown to be an effective regimen with low risk of cancer recurrence and treatment-related toxicities in early-stage node-negative, HER2-positive breast cancer. We investigated the cost-effectiveness of this regimen. METHODS: A Markov-based microsimulation model with six health states is used to simulate four adjuvant therapy options for women with early-stage node-negative, HER2-positive breast cancer at different age groups. The four treatment arms are 1) adjuvant paclitaxel and trastuzumab (TH), 2) doxorubicin, cyclophosphamide, paclitaxel and trastuzumab (ACTH), 3) docetaxel, carboplatin and trastuzumab (TCH), and 4) no adjuvant trastuzumab (NT). Data from randomized trials were used to estimate treatment efficacy. Societal perspective was used in this cost-effectiveness analysis. Costs were measured in 2016 US dollars (US$) and quality-adjusted life-years (QALYs) was used for health outcomes. Sensitivity analyses were performed to evaluate the impact of uncertainty in parameter estimation. RESULTS: We found that 40-year-old women undergoing TH treatment would have an average of 16.17 QALYs for the cost of $178,650 when lifetime horizon is used. Compared to NT, TH has incremental cost-effectiveness ratios ranged from $10,584 (ages 40-49) to $84,981 (age 80+) per additional QALYs. The sensitivity analysis showed that TH is cheaper and leads to higher QALYs compared to both ACTH and TCH for all age groups and time horizons. CONCLUSIONS: TH is cost-effective for all age groups in the base case scenario and in the sensitivity analysis. In order to reduce the parameter uncertainty, clinical trials with longer follow-up times are needed.

The relationship of the ESR1 gene polymorphisms with the presence of coronary artery disease determined by coronary angiography.

Effects of estrogen on the cardiovascular system, mediated mainly by estrogen receptor type alpha (ER alpha), have been well-defined and specific polymorphisms in the ER alpha gene (ESR1) have been associated with several coronary heart diseases including coronary artery disease (CAD) in studies covering different populations. In the present study, we aimed to investigate whether there is an association between two of the known polymorphisms in the ESR1, named c.454-397T>C and c.454-351A>G, and CAD in a Turkish population. One hundred sixty eight patients with CAD and 99 patients without CAD were included in the study. The ESR1 c.454-397T>C and c.454-351A>G polymorphisms were studied by the conventional polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. While no association was found between the c.454-351A>G polymorphism and CAD, the c.454-397T>C genotype distributions were statistically significant independent of known risk factors between CAD-positive (CAD+) and CAD-negative (CAD-) groups (p = 0.001). TT genotype was more frequent in CAD- group than in CAD+ group, 22.2% and 4.8%, respectively. CC genotype was associated with increased risk of CAD (p = 0.001) compared to the TT genotype. When comparing the distribution of CC + TC genotypes to that of TT genotype in CAD+ and CAD- groups, the frequency of CC + TC genotypes showed a significant increase independent of known CAD risk factors in CAD+ subjects (p = 0.001). As a conclusion, a statistically significant relationship between the ESR1 c.454-397T>C polymorphism and CAD were found independent of known CAD risk factors in a Turkish population.

Using Collaborative Simulation Modeling to Develop a Web-Based Tool to Support Policy-Level Decision Making About Breast Cancer Screening Initiation Age.

BACKGROUND: There are no publicly available tools designed specifically to assist policy makers to make informed decisions about the optimal ages of breast cancer screening initiation for different populations of US women. OBJECTIVE: To use three established simulation models to develop a web-based tool called Mammo OUTPuT. METHODS: The simulation models use the 1970 US birth cohort and common parameters for incidence, digital screening performance, and treatment effects. Outcomes include breast cancers diagnosed, breast cancer deaths averted, breast cancer mortality reduction, false-positive mammograms, benign biopsies, and overdiagnosis. The Mammo OUTPuT tool displays these outcomes for combinations of age at screening initiation (every year from 40 to 49), annual versus biennial interval, lifetime versus 10-year horizon, and breast density, compared to waiting to start biennial screening at age 50 and continuing to 74. The tool was piloted by decision makers (n = 16) who completed surveys. RESULTS: The tool demonstrates that benefits in the 40s increase linearly with earlier initiation age, without a specific threshold age. Likewise, the harms of screening increase monotonically with earlier ages of initiation in the 40s. The tool also shows users how the balance of benefits and harms varies with breast density. Surveys revealed that 100% of users (16/16) liked the appearance of the site; 94% (15/16) found the tool helpful; and 94% (15/16) would recommend the tool to a colleague. CONCLUSIONS: This tool synthesizes a representative subset of the most current CISNET (Cancer Intervention and Surveillance Modeling Network) simulation model outcomes to provide policy makers with quantitative data on the benefits and harms of screening women in the 40s. Ultimate decisions will depend on program goals, the population served, and informed judgments about the weight of benefits and harms.

An unexpected finding in a child with neurological problems: mosaic ring chromosome 18.

Major neurological disorders may accompany rare chromosomal abnormalities. As an example of this rare condition, we present a case with microcephaly, mental retardation, developmental delay, hyperactivity, stereotypic movements, seizures and dysmorphic facial appearance in whom a mosaic ring chromosome 18 was found [45,XX,-18/46,XX,r(18)/46,XX,dicr(18)]. Although ring chromosome 18 phenotype has been known for a long time, this is the third reported patient with a dicentric ring chromosome 18 mosaicism. The presented case will contribute to the identification of the genotype-phenotype correlation in chromosome 18 anomalies.