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1.  No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing 
Easton, Douglas F | Lesueur, Fabienne | Decker, Brennan | Michailidou, Kyriaki | Li, Jun | Allen, Jamie | Luccarini, Craig | Pooley, Karen A | Shah, Mitul | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Ahmad, Jamil | Thompson, Ella R | Damiola, Francesca | Pertesi, Maroulio | Voegele, Catherine | Mebirouk, Noura | Robinot, Nivonirina | Durand, Geoffroy | Forey, Nathalie | Luben, Robert N | Ahmed, Shahana | Aittomäki, Kristiina | Anton-Culver, Hoda | Arndt, Volker | Baynes, Caroline | Beckman, Matthias W | Benitez, Javier | Van Den Berg, David | Blot, William J | Bogdanova, Natalia V | Bojesen, Stig E | Brenner, Hermann | Chang-Claude, Jenny | Chia, Kee Seng | Choi, Ji-Yeob | Conroy, Don M | Cox, Angela | Cross, Simon S | Czene, Kamila | Darabi, Hatef | Devilee, Peter | Eriksson, Mikael | Fasching, Peter A | Figueroa, Jonine | Flyger, Henrik | Fostira, Florentia | García-Closas, Montserrat | Giles, Graham G | Glendon, Gord | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A | Hall, Per | Hart, Steven N | Hartman, Mikael | Hooning, Maartje J | Hsiung, Chia-Ni | Ito, Hidemi | Jakubowska, Anna | James, Paul A | John, Esther M | Johnson, Nichola | Jones, Michael | Kabisch, Maria | Kang, Daehee | Kosma, Veli-Matti | Kristensen, Vessela | Lambrechts, Diether | Li, Na | Lindblom, Annika | Long, Jirong | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Matsuo, Keitaro | Meindl, Alfons | Mitchell, Gillian | Muir, Kenneth | Nevelsteen, Ines | van den Ouweland, Ans | Peterlongo, Paolo | Phuah, Sze Yee | Pylkäs, Katri | Rowley, Simone M | Sangrajrang, Suleeporn | Schmutzler, Rita K | Shen, Chen-Yang | Shu, Xiao-Ou | Southey, Melissa C | Surowy, Harald | Swerdlow, Anthony | Teo, Soo H | Tollenaar, Rob A E M | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Vachon, Celine | Verhoef, Senno | Wong-Brown, Michelle | Zheng, Wei | Zheng, Ying | Nevanlinna, Heli | Scott, Rodney J | Andrulis, Irene L | Wu, Anna H | Hopper, John L | Couch, Fergus J | Winqvist, Robert | Burwinkel, Barbara | Sawyer, Elinor J | Schmidt, Marjanka K | Rudolph, Anja | Dörk, Thilo | Brauch, Hiltrud | Hamann, Ute | Neuhausen, Susan L | Milne, Roger L | Fletcher, Olivia | Pharoah, Paul D P | Campbell, Ian G | Dunning, Alison M | Le Calvez-Kelm, Florence | Goldgar, David E | Tavtigian, Sean V | Chenevix-Trench, Georgia
Journal of medical genetics  2016;53(5):298-309.
BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.
We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
PMCID: PMC4938802  PMID: 26921362
2.  SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival 
Oncotarget  2015;6(35):37979-37994.
In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P = 1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.
PMCID: PMC4741978  PMID: 26317411
breast cancer; survival analysis; SNP-SNP interaction; NF-κB pathway
3.  ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome 
Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.
This study was performed in LDL-receptor (LDLR−/−) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR−/−, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during β-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp.
In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and β-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to β-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+.
Cardiomyocyte contractility and β-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to β-adrenergic stimulation in MS.
PMCID: PMC3729821  PMID: 23848952
Metabolic syndrome; Cardiomyocyte contractility; β-adrenergic stimulation; Hypocaloric diet; ACE-inhibition
4.  Angiotensin-converting enzyme inhibition and food restriction restore delayed preconditioning in diabetic mice 
Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential.
Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student’s t-test or one-way ANOVA followed by a Fisher’s LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher’s LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant.
Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob.
Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.
PMCID: PMC3598767  PMID: 23432808
Myocardial protection; Preconditioning; Ischemia/reperfusion injury; Diabetes mellitus; Metabolic syndrome
5.  Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury 
The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.
C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student’s t-test or factorial ANOVA followed by a Fisher’s LSD post hoc test.
Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.
ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.
PMCID: PMC3444392  PMID: 22853195
Ischemia/reperfusion; Diabetes mellitus; Metabolic syndrome; In vivo contractility; Infarct size

Results 1-5 (5)