| 1. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 2. |
- Ishizuka, O, et al.
(författare)
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Effect of apomorphine on intracavernous pressure and blood pressure in conscious, spinalized rats
- 2002
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Ingår i: International Journal of Impotence Research. - 1476-5489. ; 14:2, s. 128-132
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Tidskriftsartikel (refereegranskat)abstract
- Apomorphine, given subcutaneously (s.c.), induces erection and bladder overactivity in rats through stimulation of dopamine (D1- and D2-like) receptors in the central nervous system. In paraplegic patients, apomorphine was reported to cause bladder overactivity. This suggests that apomorphine may have a spinal site of action also for stimulation of erection. The present study was initiated to evaluate the effect of apomorphine on erectile function in spinalized rats. Apomorphine (100 mug/kg, s.c.) was given to awake. unrestrained male Sprague-Dawley rats (300 g) with or without spinal cord injure, made at the Th 8 level 2 weeks before the experiment. Intracavernous pressure changes from baseline were evaluated as time to first response to apomorphine (TFR; see), number of phasic pressure changes in the first 30 min (PP30), duration (113; see) of the phasic pressure changes, the amount of increase in tonic peak pressure (TPP; cmH(2)O), and burst peak pressure (BPP, cmH(2)O). Blood pressure (cmH(2)O) was recorded via an intra-arterial catheter. Apomorphine, 100 mug/kg, caused no significant differences in TFR (217.8 vs 271.2), PP30 (6.4 vs 6.5), D (38.9 vs 37.6.), TPP (51.0 vs 54.0) and BPP (128.9 vs 160.4) between normal (n = 8) and spinalized rats (n = 6). However, blood pressure decreased significantly more in spinalized than in normal animals (17.7 vs 43.3: P < 0.05). The results suggest that both in normal rats, and in rats with spinal cord injury, apomorphine given s.c., can produce erection. This finding supports the use of apomorphine for treatment of erectile dysfunction in paraplegia patients. However, due consideration should be given to possible decreases in blood pressure.
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| 3. |
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| 4. |
- Minikel, EV, et al.
(författare)
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Quantifying prion disease penetrance using large population control cohorts
- 2016
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 8:322, s. 322ra9-
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Tidskriftsartikel (refereegranskat)abstract
- Large genomic reference data sets reveal a spectrum of pathogenicity in the prion protein gene and provide genetic validation for a therapeutic strategy in prion disease.
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| 5. |
- Mizusawa, H, et al.
(författare)
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alpha-Melanocyte stimulating hormone and oxytocin induced penile erections, and intracavernous pressure increases in the rat
- 2002
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Ingår i: Journal of Urology. - : Elsevier. - 1527-3792 .- 0022-5347. ; 167:2, part 1, s. 757-760
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: alpha-Melanocyte stimulating hormone (alpha-MSH; Fluka Chemie AG, Geneva, Switzerland) and oxytocin induce erection in rats after intracerebroventricular administration. We studied possible interactions of alpha-melanocyte stimulating hormone with mechanisms pertaining to oxytocin or nitric oxide. Materials and Methods: We used 78 anesthetized male Sprague-Dawley rats. Catheters were implanted in the lateral cerebral ventricle or into the subarachnoid space at L6 to S1. Intracavernous pressure was documented and arterial blood pressure was directly measured. Results: Intracerebroventricular alpha-MSH (3 mug.) produced a mean of 2.6 +/- 0.6 erectile responses (P <0.05) with a mean duration of 3.4 +/- 1.1 minutes (p <0.05). Mean peak intracavernous pressure was 114 +/- 8 cm. water. An intracerebroventricular dose of 100 mug. N-nitro-L-argininemethyl ester HCl (Sigma Chemical Co., St. Louis, Missouri) given in intracerebroventricular fashion abolished alpha-MSH induced erectile responses, whereas intracerebroventricular administration of 500 ng. of the oxytocin receptor antagonist 1-deamino, 2-D-Tyr(Oet), 4-Thr, 8-Orn-OT (Ferring AB, Malmo, Sweden) had no effect. Intracerebroventricular oxytocin (30 ng.) induced a mean of 3.2 +/- 0.9 erectile responses (p <0.05) with a mean peak intracavernous pressure of 81 +/- 8 cm. water and a mean duration of 3.3 +/- 1. 1 minutes. Intrathecal alpha-MSH (3 mug.) did not produce any erectile responses, whereas a mean of 5.7 +/- 0.9 responses (p <0.001) with a mean peak intracavernous pressure of 142 +/- 8 cm. water and mean duration of 5.0 +/- 1.3 minutes was obtained with 30 ng. oxytocin intrathecally. Responses induced by intrathecal oxytocin were abolished by 100 mug. N-nitro-L-arginine-methyl ester HCl intrathecally. Conclusions: We confirmed by monitoring intracavernous pressure and blood pressure that supraspinal erectile responses induced by a-melanocyte stimulating hormone involve effects mediated by nitric oxide but are independent of oxytocinergic mechanisms. At the spinal level oxytocin produces erectile responses involving nitric oxide. alpha-Melanocyte stimulating hormone does not seem to have a spinal site of action.
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| 6. |
- Mizusawa, H, et al.
(författare)
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Nitric oxide independent activation of guanylate cyclase by YC-1 causes erectile responses in the rat.
- 2002
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Ingår i: Journal of Urology. - 1527-3792 .- 0022-5347. ; 167:5, s. 2276-2281
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Activation of soluble guanylate cyclase with a subsequent increase in intracellular levels of cyclic guanosine monophosphate is necessary for normal erection. In vascular tissue 3(5'-hydroxymethyl-2'-furyl-1-benzyl indazole (YC-1) (Abbott Laboratories, North Chicago, Illinois) has been shown to stimulate soluble guanylate cyclase independent of nitric oxide. We studied whether YC-1 modulates erectile responses in the rat. MATERIALS AND METHODS: The effects of YC-1 given intracavernously or intraperitoneally on intracavernous pressure were investigated in rats. Functional effects of YC-1 on neuronal and endothelial nitric oxide relaxations were studied in 3 x 10(-6) M. 1-noradrenaline contracted preparations of rat isolated corpus cavernosum. RESULTS: Intracavernous YC-1 (10 micromol. kg.-1) produced erectile responses with a mean intracavernous pressure plus or minus standard error of mean of 81 +/- 17 cm. water (p <0.001) and a mean duration of 7.1 +/- 3.3 minutes (p <0.001). YC-1 (10 micromol. kg.-1) given intraperitoneally also increased the amplitude and duration of erectile responses to cavernous nerve stimulation. Mean peak intracavernous pressure increased from 63 +/- 6 to 10(2) +/- 16 cm. water (p <0.05). Erections induced by a submaximal dose of 25 microg. kg.-1 apomorphine s.c. increased in number after 10 micromol. kg.-1 YC-1 intraperitoneally (p <0.05). In vitro nerve induced relaxant responses were enhanced by increasing concentrations of YC-1. Relaxations at 20 Hz. were increased from a mean of 9% +/- 5% to 52% +/- 5% at a YC-1 concentration of 10(-5) M. (p <0.001). At this concentration carbachol induced relaxations were enhanced from a mean of 19% +/- 3% to 40% +/- 9% (p <0.05). CONCLUSIONS: YC-1 can evoke erectile responses when given intracavernously and it enhances erections induced by cavernous nerve stimulation and apomorphine when given systemically. In vitro YC-1 enhances electrically evoked relaxations in rat corpus cavernosum. YC-1 represents an interesting pharmacological principle that may be useful for treating erectile dysfunction.
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