Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients

Abstract Background Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. Methods To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10− 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. Results In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (β = − 4.8%, P = 9.6 × 10− 9 for systolic and β = − 4.3%, P = 2.2 × 10− 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10− 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (β = − 0.8%, P = 0.4 for systolic and β = − 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (β = − 7.6 g/m2, P = 0.02). Conclusions rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology

High Risk Population Isolate Reveals Low Frequency Variants Predisposing to Intracranial Aneurysms

Peer reviewe

The human mitochondrial DNA depletion syndrome gene MPV17 encodes a non-selective channel that modulates membrane potential

Abstract The human MPV17-related mitochondrial DNA depletion syndrome is an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein MPV17. Although more than 30 MPV17 gene mutations were shown to be associated with mitochondrial DNA depletion syndrome, the function of MPV17 is still unknown. Mice deficient in Mpv17 show signs of premature aging. In the present study, we used electrophysiological measurements with recombinant MPV17 to reveal that this protein forms a non-selective channel with a pore diameter of 1.8 nm and located the channel’s selectivity filter. The channel was weakly cation-selective and showed several subconductance states. Voltage-dependent gating of the channel was regulated by redox conditions and pH and was affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17−/− mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions

Normaalipaineisen hydrokefaluksen kliininen kuva, diagnostiset tutkimukset ja hoito

Abstract Acute hydrocephalus is a life-threatening emergency. Primary diagnosis and suspected shunt malfunction requires immediate CT or MR imaging and neurosurgical consultation. Normal pressure hydrocephalus (NPH) is a chronic degenerative disease but requires prompt diagnosis and treatment due to progressive nature. Recent studies indicate apparent specific disease mechanisms of idiopathic NPH including potential genetic risk factors. CSF shunt may significantly improve gait, urinary incontinence and cognitive symptoms in selected patients. Noteworthy, iNPH seems to progress frequently despite of shunt emphasizing the need for active follow-up. Recognition and appropriate treatment of potential comorbid neurodegenerative diseases like vascular dementia and Alzheimer’s disease are needed in case of cognitive deterioration.Tiivistelmä Akuutti hydrokefalia on henkeä uhkaava tila kaikenikäisillä. Mikäli sunttiriippuvaisella potilaalla epäillään suntin toimintahäiriötä, on pään TT (tai MK) tehtävä viipymättä ja tarvitessa konsultoitava päivystävää neurokirurgista yksikköä välittömästi. Normaalipaineinen hydrokefalia (NPH) on harvoin päivystyksellinen ongelma, mutta tauti on selkeästi etenevä ja hoidon viivästyminen heikentää ennustetta. Tuoreet tutkimukset avaavat idiopaattisen NPH-taudin (iNPH) etiologiaa ja patofysiologisia mekanismeja sekä ennustetta. Osalla potilaista likvorisuntti voi merkittävästi lievittää oireita, erityisesti liikkumisvaikeuksia mutta myös inkontinenssia ja tiedonkäsittelyn ongelmia. Suntista huolimatta tauti pyrkii vuosien myötä etenemään, korostaen seurannan merkitystä. iNPH potilailla on usein myös samanaikainen vaskulaarinen kognitiivinen heikkenemä, Alzheimerin tauti tai muu aivorappeumasairaus, joka on myös diagnosoitava ja hoidettava