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PubMed1998

Variability of individual normal tissue radiation sensitivity. An international empirical evaluation of endogenous and exogenous response modifiers.

BACKGROUND: The variability of normal-tissue response is of major concern for radiation therapy. Multiple endogenous and exogenous factors are qualitatively known to alter the acute and late tissue response. Which of them are regarded most important by the European radiation oncologists and what is, empirically, their quantitative influence on the acute or late tissue tolerance? METHODS: In August 1997, we sent a questionnaire to 255 European radiation oncology departments. Among others, the questionnaire asked for endogenous and exogenous factors modifying the tissue response to radiation therapy and their quantitative influence on the acute and late radiation morbidity (TD 5/5). Fifty-five questionnaires (21.5%) were answered. RESULTS: Empirically, the most important endogenous factors to modify the acute tissue tolerance are a) metabolic/other diseases with macro- or microangiopathia (17 answers [a]/32% mean decrease of tissue tolerance), b) collagen diseases (9 a/37%) and c) immune diseases (5 a/53%). As endogenous response modifiers for the TD 5/5 are recognized a) metabolic or other diseases leading to macro- or microangiopathia (15 a/31%), b) collagen diseases (11 a/38%) and c) immune diseases (2 a/50%). Inflammations from any reason are assumed to alter the acute tissue tolerance by (6 a/26%) and the TD 5/5 by (10 a/24%). Exogenous modifiers of the acute tissue response mentioned are a) smoking (34 a/44%), b) alcohol (23 a/45%), c) nutrition/diets (16 a/45%), d) hygiene (9 a/26%) and e) medical therapies (10 a/37%). Exogenous factors assumed to influence the TD 5/5 are a) smoking (22 a/40%), b) alcohol (15 a/38%), c) nutrition/diets (9 a/48%), d) hygiene (5 a/34%) and e) medical therapies (10 a/30%). CONCLUSIONS: Exogenous factors are regarded more important by number and extent on the acute and late tissue response than endogenous modifiers. Both may have an important influence on the individual expression of normal tissue response.

Alcohol Drinking↗

PubMed2004

Rapid analysis of genetically modified organisms by in-house developed capillary electrophoresis chip and laser-induced fluorescence system.

A microfabricated, inexpensive, reusable glass capillary electrophoresis chip and a laser-induced fluorescence system were developed in-house for the rapid DNA-based analysis of genetically modified organisms (GMOs). The 35S promoter sequence of cauliflower mosaic virus and the terminator of the nopaline synthase (NOS) gene from Agrobacterium tumefaciens were both detected since they are present in most genetically modified organisms. The detection of genetically modified soybean in the presence of unaltered soybean was chosen as a model. Lectin, a plant-specific gene, was also detected for confirmation of the integrity of extracted DNA. The chip was composed of two glass plates, each 25 x 76 mm, thermally bonded together to form a closed structure. Photomasks with cross-topology were prepared rapidly by using polymeric material instead of chrome plates. The widths of the injection and separation channels were 30 and 70 microm, respectively, the effective separation length 4.5 cm. The glass slide was etched to a depth of 30 microm for both the injection and separation channel. The cost of the chip was less than 1 $ and required 2 days for photomask preparation and microfabrication. The separation and detection of polymerase chain reaction-amplified NOS, 35S, and lectin sequences (180, 195, and 181 bp, respectively) was completed in less than 60 s. As low as 0.1% GMO content was detectable by the proposed system after 35 and 40 amplification cycles for 35S and NOS, respectively, using 25 ng of extracted DNA as starting material. This corresponds to only 20 genome copies of genetically modified soybean.

Amino Acid Oxidoreductases↗

PubMed2006

Development and validation of a sensitive and fast chemiluminescent enzyme immunoassay for the detection of genetically modified maize.

Proteins from the Cry 1 family, in particular Cry 1Ab, are commonly expressed in genetically modified Bt maize in order to control chewing insect pests. A sensitive chemiluminescent sandwich enzyme immunoassay for the detection of Cry1Ab protein from genetically modified Bt maize has been developed and validated. A Cry1Ab protein-specific antibody was immobilized on 96- or 384-well microtiter plates in order to capture the Cry1Ab toxin in the sample; the bound toxin was then detected by employing a second anti-Cry1Ab antibody and a horseradish peroxidase-labeled anti-antibody, followed by measurement of the enzyme activity with an enhanced chemiluminescent system. The chemiluminescent assay fulfilled all the requirements of accuracy and precision and exhibited limits of detection of a few pg mL(-1) Cry1Ab (3 or 5 pg mL(-1), depending on the assay format), which are significantly lower than that achievable using conventional colorimetric detection of peroxidase activity and also represent an improvement compared to previously developed Cry1Ab immunoassays. High-throughput analysis can be performed using the 384-well microtiter plate format immunoassay, which also allows one to reduce the consumption of samples and reagents. Validation of the assay, performed by analyzing certified reference materials, proved that the immunoassay is able to detect the presence of the Cry1Ab protein in certified reference samples containing as low as 0.1% of MON 810 genetically modified Bt maize. This value is below the threshold requiring mandatory labeling of foods containing genetically modified material according to the actual EU regulation.

Bacillus thuringiensis Toxins↗

PubMed1996

Modified 2S albumins with improved tryptophan content are correctly expressed in transgenic tobacco plants.

Brazil nut 2S albumins lack the essential amino acid tryptophan. In order to improve the protein's nutritional value and create a basis for structural investigations, three separate modified Brazil nut 2S albumin genes were constructed. The first mutant contains five consecutive tryptophan codons, while the other two modified genes encode proteins carrying single tryptophan residues at sites that will allow confirmation of the predicted protein structure through fluorescence quenching techniques. The modified genes, under the regulation of the CaMV 35S promoter, were introduced into Nicotiana tabacum. All three modified genes were correctly transcribed and the 2S albumin accumulated in the seeds of transgenic plants.

Agrobacterium tumefaciens↗

PubMed1992

Are modified radical mastectomies done for T1 breast cancers because of surgeon's advice or patient's choice?

Clinical trials show that T1 breast cancers are equally well treated with breast-conserving surgery as with modified radical mastectomy. However, the Colorado Central Cancer Registry indicates that, for the past 5 years, the majority of women (72%) with T1 breast cancer in Colorado have undergone modified radical mastectomies. A questionnaire was sent to 175 general surgeons to determine the reasons for the high number of modified radical mastectomies still being performed. The results indicate that one group of surgeons (34% of those responding) believes each type of surgery has equal survival rates but unknowingly influences the patient to choose modified radical mastectomy, with a subtly biased presentation. Education of both surgeons and patients is needed to increase the number of patients with T1 breast lesions who can benefit from breast-conserving therapy.

Attitude of Health Personnel↗

PubMed2002

Substantial equivalence--an appropriate paradigm for the safety assessment of genetically modified foods?

Safety assessment of genetically modified food crops is based on the concept of substantial equivalence, developed by OECD and further elaborated by FAO/WHO. The concept embraces a comparative approach to identify possible differences between the genetically modified food and its traditional comparator, which is considered to be safe. The concept is not a safety assessment in itself, it identifies hazards but does not assess them. The outcome of the comparative exercise will further guide the safety assessment, which may include (immuno)toxicological and biochemical testing. Application of the concept of substantial equivalence may encounter practical difficulties: (i) the availability of near-isogenic parental lines to compare the genetically modified food with; (ii) limited availability of methods for the detection of (un)intended effects resulting from the genetic modification; and (iii) limited information on natural variations in levels of relevant crop constituents. In order to further improve the methodology for identification of unintended effects, new 'profiling' methods are recommended. Such methods will allow for the screening of potential changes in the modified host organism at different integration levels, i.e. at the genome level, during gene expression and protein translation, and at the level of cellular metabolism.

Animals↗

PubMed2006

Evaluation of a non-targeted "omic" approach in the safety assessment of genetically modified plants.

Genetically modified plants must be approved before release in the European Union, and the approval is generally based upon a comparison of various characteristics between the transgenic plant and a conventional counterpart. As a case study, focusing on safety assessment of genetically modified plants, we here report the development and characterisation of six independently transformed ARABIDOPSIS THALIANA lines modified in the flavonoid biosynthesis. Analyses of integration events and comparative analysis for characterisation of the intended effects were performed by PCR, quantitative Real-time PCR, and High Performance Liquid Chromatography. Analysis by cDNA microarray was used as a non-targeted approach for the identification of potential unintended effects caused by the transformation. The results revealed that, although the transgenic lines possessed different types of integration events, no unintended effects were identified. However, we found that the majority of genes showing differential expression were identified as stress-related genes and that environmental conditions had a large impact on the expression of several genes, proteins, and metabolites. We suggest that the microarray approach has the potential to become a useful tool for screening of unintended effects, but state that it is crucial to have substantial information on the natural variation in traditional crops in order to be able to interpret "omics" data correctly within the framework of food safety assessment strategies of novel plant varieties, including genetically modified plant varieties.

Arabidopsis↗

PubMed2005

Altered microtubule dynamics by expression of modified alpha-tubulin protein causes right-handed helical growth in transgenic Arabidopsis plants.

The proper organization of cortical microtubule arrays is essential for anisotropic growth in plants but how distinct array patterns are formed is not understood. Here, we report a relationship between microtubule dynamics and array organization using transgenic plants expressing modified tubulins. When green fluorescent protein (GFP) or a hemaglutinin epitope tag was fused to the N-terminus of tubulins and expressed in Arabidopsis plants, these tubulins were incorporated into microtubules along with endogenous tubulins. Plants expressing the modified beta-tubulins were phenotypically normal and possessed transversely oriented cortical arrays in the epidermal cells of the root elongation zone; however, the expression of modified alpha-tubulins caused right-handed helical growth, increased trichome branching, and a shallow left-handed (S-form) helical array organization. In cells expressing the modified alpha-tubulins, microtubule dynamicity was suppressed and polymerization was promoted, and GFP-EB1 (End Binding 1) labeled larger regions of the microtubule end more frequently, when compared with control cells. We propose that the N-terminal appendage introduced into alpha-tubulin inhibits GTP hydrolysis, thus producing polymerization-prone microtubules with an extended GTP cap. Consistent with this interpretation, plants expressing an alpha-tubulin mutated in the GTPase-activating domain exhibited similar microtubule properties, with regard to dynamics and the localization of GFP-EB1, and showed right-handed helical growth.

Arabidopsis↗

PubMed2001

Evaluation of interactions of human cytomegalovirus immediate-early IE2 regulatory protein with small ubiquitin-like modifiers and their conjugation enzyme Ubc9.

The human cytomegalovirus (HCMV) major immediate-early protein IE2 is a nuclear phosphoprotein that is believed to be a key regulator in both lytic and latent infections. Using yeast two-hybrid screening, small ubiquitin-like modifiers (SUMO-1, SUMO-2, and SUMO-3) and a SUMO-conjugating enzyme (Ubc9) were isolated as IE2-interacting proteins. In vitro binding assays with glutathione S-transferase (GST) fusion proteins provided evidence for direct protein-protein interaction. Mapping data showed that the C-terminal end of SUMO-1 is critical for interaction with IE2 in both yeast and in vitro binding assays. IE2 was efficiently modified by SUMO-1 or SUMO-2 in cotransfected cells and in cells infected with a recombinant adenovirus expressing HCMV IE2, although the level of modification was much lower in HCMV-infected cells. Two lysine residues at positions 175 and 180 were mapped as major alternative SUMO-1 conjugation sites in both cotransfected cells and an in vitro sumoylation assay and could be conjugated by SUMO-1 simultaneously. Although mutations of these lysine residues did not interfere with the POD (or ND10) targeting of IE2, overexpression of SUMO-1 enhanced IE2-mediated transactivation in a promoter-dependent manner in reporter assays. Interestingly, many other cellular proteins identified as IE2 interaction partners in yeast two-hybrid assays also interact with SUMO-1, suggesting that either directly bound or covalently conjugated SUMO moieties may act as a bridge for interactions between IE2 and other SUMO-1-modified or SUMO-1-interacting proteins. When we investigated the intracellular localization of SUMO-1 in HCMV-infected cells, the pattern changed from nuclear punctate to predominantly nuclear diffuse in an IE1-dependent manner at very early times after infection, but with some SUMO-1 protein now associated with IE2 punctate domains. However, at late times after infection, SUMO-1 was predominantly detected within viral DNA replication compartments containing IE2. Taken together, these results show that HCMV infection causes the redistribution of SUMO-1 and that IE2 both physically binds to and is covalently modified by SUMO moieties, suggesting possible modulation of both the function of SUMO-1 and protein-protein interactions of IE2 during HCMV infection.

Amino Acid Sequence↗

PubMed2004

Expression of modified Cry1Ac gene of Bacillus thuringiensis in transgenic tobacco plants.

Several mutations were introduced into the Cry1Ac toxin gene, resulting in four variants with altered sequences that were responsible for low expression of the toxin in transgenic plants. These variants were as follows: V1, with modified three A/T-rich regions, including the first signal of transcription termination; V2, with modified five putative polyadenylation signals (polyadenylation signals PAS) and the second signal of transcription termination; V3, with four initial AUUUA motifs; V4, with modification of six PASs, four AUUUA motifs, as well as the first and the second signals of transcription termination. The modified variants and the initial WT gene were cloned into the binary vector pBI121 and introduced into tobacco plants (Nicotiana tabacum) by Agrobacterium tumefaciens-mediated transformation. The presence of transgenes in the tobacco plants was confirmed by the polymerase chain reaction (PCR) method. The expression of particular variants of the Cry1Ac gene in tobacco was assayed using Western blotting with antibodies against the domain II of the Cry1Ac toxin. The average expression of WT was estimated to be 0.0025% of soluble proteins, and the expression levels of modified variants were 0.004%, 0.0098%, 0.0125%, and 0.0043% for V1, V2, V3, and V4, respectively. In this article we described the construction of a variant of the Cry1Ac gene (V3) with 12 point mutations leading to an average level of expression in transgenic plants five times higher than that observed in the case of the WT gene. Our results have shown for the first time that the modification of AUUUA sequences has a significant effect on the expression of the Cry1Ac gene in transgenic plants.

Amino Acid Motifs↗

PubMed2000

Effect of fibrin glue on lymphatic drainage after modified radical mastectomy: a prospective randomized trial.

Fibrin as a tissue sealant has been used since the turn of the century for hemostasis. The development of cryoprecipitate and the resultant availability of higher concentrations of fibrinogen have led to a resurgence of interest in this material. Fibrin glue has since been shown to be effective for numerous applications throughout the field of surgery. Animal studies have shown fibrin glue to be effective at reducing drain output after mastectomy. Human studies, however, have been equivocal. Our objectives were to determine whether the use of fibrin glue would decrease lymphatic drainage after modified radical mastectomy and subsequently reduce time to drain removal. A prospective randomized trial was conducted consisting of 27 women. All women received modified radical mastectomy. At the completion of the mastectomy they were randomized to receive either standard closure or the application of fibrin glue before standard closure. Patients were then monitored for daily drain output, time to drain removal, and wound complications. A total of 14 women received fibrin glue and 13 received no glue. Those patients receiving fibrin glue had a significantly higher average drain output than patients who did not receive glue (1308 vs 754 cm3; P = 0.012). Time to drain removal was also increased by 4 days, although this did not reach statistical significance. The overall complication rate was higher for the fibrin glue group, although again, this did not reach significance. The application of fibrin glue significantly increased drain total drain output after modified radical mastectomy. Time to drain removal was increased as was the complication rate. On the basis of these data fibrin glue cannot be recommended for routine use in modified radical mastectomy.

Breast Neoplasms↗

PubMed2003

[Progress on biosafety assessment of marker genes in genetically modified foods].

Marker genes are useful in facilitating the detection of genetically modified organisms(GMO). These genes play an important role during the early identification stage of GMO development, but they exist in the mature genetically modified crops. So the safety assessment of these genes could not be neglected. In this paper, all the study on the biosafety assessment of marker genes were reviewed, their possible hazards and risks were appraised, and the marker genes proved safe were list too. GMO Labeling the is one important regulations for the development of genetically modified foods in the market. The accurate detecting techniques for GMO are the basis for setting up labeling regulation. In addition, some methods used to remove marker genes in genetically modified foods were introduced in the paper, which can eliminate their biosafety concern thoroughly.

Food, Genetically Modified↗

PubMed1993

A comparison between scalpel and electrocautery in modified radical mastectomy.

OBJECTIVE: To compare the effects of a conventional cold scalpel and electrocautery in modified radical mastectomy. DESIGN: A non-randomised controlled trial. SETTING: Teaching hospital in Southern Taiwan. SUBJECTS: 101 consecutive patients with primary breast cancer who underwent modified radical mastectomy between July 1987 and June 1989. INTERVENTIONS: The 44 patients during the first year were allocated to have skin flaps fashioned conventionally with a cold scalpel and the 57 patients during the second year, by electrocautery. MAIN OUTCOME MEASURES: Morbidity and mortality among the 101 patients who underwent modified radical mastectomy. RESULTS: The groups were comparable in regard to age, menopause, cancer stage, weight of specimen and histological type of cancer. The mean blood loss was 567 ml when scalpel was used and 150 ml when electrocautery was used (p < 0.001). The postoperative fall in packed cell volume was significantly greater in the scalpel group (0.75 [0.26] compared with 0.28 [0.15], p < 0.001) and more patients in this group required transfusion (9 compared with 0, p < 0.01). There were no deaths in either group. There were no significant differences in operation time, total post-operative Hemovac drainage, postoperative hospital stay, the number of lymph nodes removed, the number of metastatic lymph nodes, and postoperative complications between the groups. CONCLUSION: Electrocautery is a safe, convenient and rational method for constructing skin flaps in modified radical mastectomy, and patients do not need blood transfusions.

Breast Neoplasms↗

PubMed1998

Comparative study of 2 variants of a modified esophageal transection in the Sugiura-Futagawa operation.

OBJECTIVE: To compare 2 techniques of esophageal transection in our modification of the Sugiura-Futagawa procedure for the treatment of bleeding portal hypertension in low-risk patients who cannot undergo surgery to have shunts placed. DESIGN: A prospective controlled trial comparing 2 variants of transection (classic, complete section of the anterior muscularis externa and whole mucosa; modified, placement of a circumferential running suture without opening the mucosa). SETTING: Academic university hospital. PATIENTS: Eighty-three low-risk patients (Child-Pugh score A and B) with a history of bleeding portal hypertension were operated on (35 classic, 48 modified transections) between 1989 and 1996. Both groups were comparable. MAIN OUTCOME MEASURES: Postoperative dehiscence of the transection was evaluated as well as fistulization, postoperative stenosis, rebleeding, postoperative endoscopic findings, survival, and mortality. RESULTS: Fistulization was observed in 1 (2%) of the patients in the modified group, and dehiscence in 1 patient (2%). In the classic group, 3 (8%) of the patients had dehiscence (relative risk, 2.6) and 1 (2%) of the patients, fistulization. No differences were observed regarding rebleeding (6 patients [6%] vs 5 patients [7%]), postoperative stenosis (4 patients [8%] vs 5 patients [10%]), postoperative endoscopic findings, survival, and mortality (early and late). CONCLUSION: The modified variant of the transection has a lower frequency of postoperative dehiscence, with the same long-term results.

Esophageal and Gastric Varices↗

PubMed1998

Papillary thyroid carcinoma: modified radical neck dissection improves prognosis.

OBJECTIVE: To ascertain whether modified radical neck dissection offers a survival advantage for some subsets of patients with papillary cancer of the thyroid. DESIGN: A retrospective cohort study of 2966 patients curatively treated at the Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan, between 1946 and 1991. SETTING: A center for the treatment of thyroid disease, where about 1400 thyroid operations are performed per year. PATIENTS: Between 1946 and 1991, patients with papillary cancer whose primary tumor was 1 cm or larger and who were curatively treated were studied. Of the 2859 patients, 72.1% underwent modified radical neck dissection, 8.5% underwent partial node excision, and 19.4% underwent no node excision. RESULTS: A univariate analysis revealed a subset of patients who benefited from modified radical neck dissection. A multivariate analysis revealed that sex (P<.001), age at the time of the operation (P<.001), size of the primary tumor (P<.001), extrathyroidal invasion (P<.001), and the presence of nodal metastasis (P<.01) are significant risk factors. CONCLUSION: Patients with nodal metastasis, patients in whom the primary tumor invades beyond the thyroid capsule, and women older than 60 years can benefit from modified radical neck dissection.

Adult↗

PubMed2000

Indications for bilateral modified radical neck dissection in patients with papillary carcinoma of the thyroid.

HYPOTHESES: After subtotal thyroidectomy with modified radical neck dissection of the affected side, nodal recurrence at the contralateral cervical side indicates a poor prognosis for patients with papillary thyroid cancer. Bilateral modified radical neck dissection is beneficial for patients at high risk for contralateral nodal recurrence. DESIGN AND SETTING: Retrospective study of patients with papillary cancer who were treated surgically from January 1, 1970, through December 31, 1995, at the Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan. PATIENTS: Patients (N = 1776) had primary tumors greater than 10 mm in maximum diameter and underwent thyroidectomy and ipsilateral modified radical neck dissection with curative intent. RESULTS: Thirty-two patients (1.8%) developed contralateral lymph node metastases during the mean follow-up period of 12.1 years. The risk factors for contralateral nodal recurrence were male sex, large primary tumor, tumor extension over the isthmus, extracapsular adhesion or invasion to surrounding tissues, and the presence of gross nodal metastasis at initial surgery. These patients had a greater number of distant metastases (31.1% vs 0.7%; P<.001) and a lower 10-year survival rate (83.7% vs 99.3%; P<.001) than patients without nodal recurrence. CONCLUSION: Bilateral modified radical neck dissection should be considered for patients with papillary carcinoma who show risk factors for contralateral nodal recurrence, as it could prevent a second operation and may improve their outcome.

Adult↗

PubMed2003

Long-term follow-up of the modified Delorme procedure for rectal prolapse.

HYPOTHESIS: The modified Delorme operation is a safe, effective, and durable treatment for complete rectal prolapse. DESIGN: Retrospective analysis of outcomes in adult patients undergoing the modified Delorme operation. SETTING: Community-based tertiary referral center with a 5-year general surgery residency program. PATIENTS: A total of 52 consecutive patients undergoing surgery for the treatment of complete rectal prolapse during the 26-year period ending December 2001. INTERVENTIONS: Modified Delorme operation. Main Outcomes Measured Method of anesthesia, morbidity, mortality, recurrence rates, length of follow-up, and incontinence. RESULTS: In the 52 patients, the mean length of prolapse was 8.2 cm. The mean operating time was 75 minutes. Forty-five patients were administered general anesthesia, 4 were administered spinal anesthesia, and 3 were administered local anesthesia. The mean postoperative stay was 4.9 days for 1975 through 2001 and 2.8 days for 1990 through 2001. No patients died as a result of the procedure. Patients were followed up for 61.4 months. Major medical comorbidities occurred in 40 patients. Preoperative incontinence was present in 12 patients, 10 of whom improved after the procedure, and postoperative incontinence in 8. The recurrent postoperative prolapse rate at 5 years was 6% (3/52) and the recurrent postoperative prolapse rate to the end of the study was 10% (5/52). Two patients (4%) had complications that required operative intervention in the postoperative period. CONCLUSIONS: The modified Delorme operation is a safe and effective surgical treatment for complete rectal prolapse. The risk of recurrent prolapse is low, and the procedure may be safely performed in patients with significant medical comorbidities.

Adult↗

PubMed2024

Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3.

IMPORTANCE: The genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM. OBJECTIVE: To interrogate the clinical traits and diseases associated with BAG3 coding variation. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System's clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study. EXPOSURES: Carrier status for BAG3 coding variants. MAIN OUTCOMES AND MEASURES: Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. RESULTS: In PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358). CONCLUSIONS AND RELEVANCE: BAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

Humans↗