Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations

Additional file 1. Complementary data on primer sequences, SKI amplification and survival analyses

Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant

Transplantation and immunomodulatio

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

Background: The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective: We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design: We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results: Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions: Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD

Pheochromocytoma presenting as takotsubo-like cardiomyopathy following delivery

Item does not contain fulltextOBJECTIVE: Diagnosis of pheochromocytoma during pregnancy can be difficult, and the tumor carries an unfavorable prognosis if not diagnosed and treated in a timely manner. METHODS: To present a case of Takotsubo-like cardiomyopathy characterized by transient left ventricular apical ballooning due to pheochromocytoma following delivery. RESULTS: A few hours after Caesarean section, a 32-year-old Caucasian female presented with pulmonary edema followed by cardiac arrest with echocardiographic and ventriculographic evidence of reversible acute myocardial failure characteristic of Takotsubo-like cardiomyopathy. A previously unrecognized adrenal pheochromocytoma was found during her clinical work-up. Left ventricle (LV) function normalized after surgical removal of the tumor, which was carried out after implementing an alpha-adrenoreceptor blockade. Hemorrhagic necrosis of the pheochromocytoma was seen on histopathologic analysis; this may have triggered the sequence of events leading to the development of Takotsubo-like cardiomyopathy and hemodynamic collapse. CONCLUSION: To the best of our knowledge, this is the first reported case of Takotsubo-like cardiomyopathy related to pheochromocytoma following delivery. This emphasizes the increased cardiovascular risk if pheochromocytoma is not diagnosed and treated in a timely manner, especially during pregnancy

Czy kompleksowa ocena polimorfizmów może być przydatna w ocenie rokowania po zabiegach angioplastyki wieńcowej: badanie prospektywne

Background: Coronary artery disease (CAD) is a complex disorder accounting for the majority of cardiovascular deaths and morbidity. It is believed that genetic factors explain part of the excessive risk of major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI). Aim: To evaluate the influence on long-term prognosis of some genetic polymorphisms affecting renin–angiotensin system, inflammatory response, beta-2 adrenergic receptor, nitric oxide and platelets activity in patients with stable CAD undergoing routine PCI. Methods: The study population consisted of 110 consecutive male patients with stable angina undergoing elective, single- -vessel PCI. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism-based techniques. Follow-up data were obtained by postal questionnaires regarding survival, myocardial infarction and revascularisation procedures. The control group consisted of 78 healthy males. Results: Compared to controls, the distribution of polymorphisms among patients differed with regard to interleukin-1 receptor antagonist and CD14 variants. Patients who had PCI during follow-up in comparison with the remaining patients had a similar genetic profile, but higher triglycerides (1.9 vs 1.5 mmol/L, p = 0.01) and atherogenic index (3.8% vs 3.1%, p = 0.03) and lower percentage of HDL (21.8% vs 25.0%, p = 0.02). Among subjects with any revascularisation procedures, a similar clinical profile was observed. However, they differed from those without any procedures regarding the distribution of angiotensinogen M235T variants (MM%/TM%/TT%) 28%/64%/8% vs 19%/50%/31%, p = 0.048. Stratification for myocardial infarction showed association with selectin E variants (AA%/AC%/CC%) 57.1%/28.6%/14.3% vs 78.8%/21.2%/0%, p = 0.055 and higher triglycerides (2.11 vs 1.57 mmol/L, p = 0.055). Conclusions: Although we cannot exclude the role of polymorphism in angiotensinogen and selectin E genes, the prognosis of patients post-PCI in our study was mainly influenced by risk factors related to lipid metabolisms. Kardiol Pol 2011; 69, 9: 881–888Wstęp: Choroba wieńcowa (CAD) jest złożonym zespołem odpowiedzialnym za większość zgonów i nowych przypadków zachorowań na choroby sercowo-naczyniowe. Na podstawie danych z piśmiennictwa nie można wykluczyć, że predyspozycje genetyczne są odpowiedzialne za podwyższone ryzyko wystąpienia głównych powikłań sercowo-naczyniowych po zabiegach angioplastyki (PCI). Cel: Głównym celem badania była ocena wpływu wybranych polimorfizmów modyfikujących aktywność układu renina– –angiotensyna–aldosteron, receptora beta-2 adrenergicznego, tlenku azotu i aktywność płytek, a także nasilenie odpowiedzi przeciwzapalnej u pacjentów ze stabilną CAD, u których wykonuje się rutynowy zabieg angioplastyki wieńcowej. Metody: Badaniem objęto grupę 110 kolejnych mężczyzn ze stabilną CAD, u których przeprowadzono zabieg PCI pojedynczego naczynia (które nie było odpowiedzialne za zawał z załamkiem Q i miało średnicę > 2 mm). Genotypowanie wykonano metodą amplifikacji znanych regionów genomu, połączoną z analizą restrykcyjną (PCR-RFLP). Dane dotyczące zdarzeń w trakcie obserwacji odległej uzyskiwano drogą pocztową i dotyczyły one przeżywalności, wystąpienia zawału serca i zabiegów rewaskularyzacji. Wyniki: Grupa badana różniła się od grupy kontrolnej w odniesieniu do rozkładu polimorfizmów antagonisty receptora interleukiny-1 oraz CD14. W grupie osób badanych pacjenci, u których w trakcie dalszej obserwacji było konieczne wykonanie PCI, nie różnili się pod względem polimorfizmów wybranych genów, natomiast mieli wyjściowo wyższe stężenia triglicerydów (1,9 v. 1,5 mmol/l; p = 0,01) i wyższy wskaźnik aterogenności (3,8% v. 3,1%; p = 0,03), a niższy odsetek HDL (21,8% v. 25,0%; p = 0,02). Natomiast pacjenci z jakimkolwiek przebytym zabiegiem rewaskularyzacji w porównaniu z resztą chorych w trakcie obserwacji różnili się rozkładem polimorfizmów genu dla angiotensynogenu M235T (MM%/TM%/TT%: 28%/64%/8% v. 19%/50%/31%; p = 0,048). Dodatkowo osoby, u których wystąpił zawał serca, różniły się w porównaniu z pozostałymi badanymi chorymi rozkładem polimorfizmów dla selektyny E (AA%/AC%/CC%) 57,1%/28,6%/14,3% v. 78,8%/21,2%/0%; p = 0,055), a także stwierdzano u nich wyższe stężenia triglicerydów (2,11 v. 1,57 mmol/l; p = 0,055). Wnioski: Na podstawie przedstawionych danych należy zwrócić uwagę na potencjalną rolę prognostyczną polimorfizmu genów dla angiotensynogenu i selektyny E, jednak w niniejszym materiale główne znacznie miały zaburzenia lipidowe związane z nieprawidłowym stężeniem triglicerydów i cholesterolem frakcji HDL. Kardiol Pol 2011; 69, 9: 881–88

Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias – Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene

PubMed ID: 28336205Background Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. Methods This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0 ± 17.3 years, female n = 31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats > 2000/24 h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. Results In KCNJ2 mutation carriers vs non-carriers (n = 25 vs n = 19) significant differences were observed in U-wave manifestations in V2–V4, Tpeak - Tend duration, QTUc duration (p < 0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n = 9), in those with arrhythmias and/or syncope and/or CA (n = 16) micrognathia (p = 0.004), periodic paralysis (p = 0.019), palpitation (p = 0.005), U-wave n V2–V4 (p = 0.049) were more frequent; QTU (p = 0.045) and Tpeak - Tend (p = 0.014) were also longer (n = 9). In the subgroup of carriers with syncope and/or cardiac arrest (n = 10, 90% women), K897T-KCNH2 polymorphism (p = 0.02), periodic paralysis (p = 0.004), muscle weakness (p = 0.04), palpitations (p = 0.04), arrhythmias (biventricular VT, p = 0.003; polymorphic VT, p = 0.009) were observed more frequently. Tpeak - Tend duration was longer (p = 0.007) and the percentage of patients with premature ventricular contraction >2000/24 h was higher (p = 0.005). Conclusion A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged Tpeak - Tend time. Our findings suggest that K897T may contribute to the occurrence of syncope. © 2017 Japanese College of Cardiolog