Citations

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1 –/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Abstract A unique and highly versatile technique, stress echocardiography (SE) is increasingly recognized for its utility in the evaluation of non-ischaemic heart disease. SE allows for simultaneous assessment of myocardial function and haemodynamics under physiological or pharmacological conditions. Due to its diagnostic and prognostic value, SE has become widely implemented to assess various conditions other than ischaemic heart disease. It has thus become essential to establish guidance for its applications and performance in the area of non-ischaemic heart disease. This paper summarizes these recommendations.

Background The early diastolic velocity of the mitral annulus (E′) is reduced in patients with diastolic dysfunction and increased filling pressures. Because transmitral inflow early velocity (E) increases progressively with higher filling pressures, E/E′ has been shown to have a strong positive relationship with pulmonary capillary wedge pressure (PCWP) and left ventricular end-diastolic pressure. However, previous studies have primarily involved patients without a pericardial abnormality. In constrictive pericarditis (CP), E′ is not reduced, despite increased filling pressures. This study evaluated the relationship between E/E′ and PCWP in patients with CP. Methods and Results We studied 10 patients (8 men; mean age, 64±7 years) with surgically confirmed CP. Doppler echocardiography was performed to measure early and late diastolic transmitral flow velocities. Tissue Doppler echocardiography was performed to measure E′. PCWP was measured with right heart catheterization. All patients were in sinus rhythm. Mean E and E′ were 91±15 cm/s and 11±4 cm/s, respectively. Mean PCWP was 25±6 mm Hg. E′ was positively correlated with PCWP ( r =0.69, P =0.027). There was a significant inverse correlation between E/E′ and PCWP ( r =−0.74, P =0.014). Despite high left ventricular filling pressures, E/E′ (mean, 9±4) was <15 in all but 1 patient. Conclusions Paradoxical to the positive correlation between E/E′ and PCWP in patients with myocardial disease, an inverse relationship was found in patients with CP.