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- Zeggini, Eleftheria, et al.
(author)
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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
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Journal article (peer-reviewed)abstract
- Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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| 3. |
- Weedon, Michael N., et al.
(author)
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A common variant of HMGA2 is associated with adult and childhood height in the general population
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 39:10, s. 1245-1250
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Journal article (peer-reviewed)abstract
- Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P= 4x10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P= 3x10(-11), overall P= 4x10(-16), including the genome-wide association data). We also observed the association in children (P=1x 10(-6), N= 6,827) and a tall/short case-control study (P= 4x10(-6), N=3,207). We estimate that rs1042725 explains similar to 0.3% of population variation in height (similar to 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitative traits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.
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| 6. |
- Tennis, M, et al.
(author)
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p53 Mutation analysis in breast tumors by a DNA microarray method
- 2006
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In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1055-9965. ; 15:1, s. 80-85
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Journal article (peer-reviewed)
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| 7. |
- Alm, Albert, et al.
(author)
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Side effects associated with prostaglandin analog therapy
- 2008
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In: Survey of ophthalmology. - : Elsevier BV. - 0039-6257 .- 1879-3304. ; 53:Suppl. 1, s. S93-S105
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Research review (peer-reviewed)abstract
- Topical prostaglandin analogs, which have become first-line therapy in the medical management of glaucoma, have an excellent safety profile with regard to systemic side effects, but are associated with several ocular side effects. Some of these are common, with no apparent serious consequences other than cosmetic, whereas others are much less common but represent potentially sight-threatening side effects. The former group includes conjunctival hyperemia, elongation and darkening of eyelashes, induced iris darkening, and periocular skin pigmentation. The latter group of side effects, which are relatively rare and lack definitive causal relationship to prostaglandin analog therapy, includes iris cysts, cystoid macular edema, anterior uveitis, and reactivation of herpes simplex keratitis. Most of the literature regarding side effects associated with prostaglandin analogs involves the use of latanoprost, probably because it was the first to be studied. There is no evidence, however, aside from less conjunctival hyperemia with latanoprost, that the commercially available prostaglandin analogs differ significantly with regard to side effects.
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| 10. |
- Willmore, L James, et al.
(author)
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Vigabatrin: 2008 update.
- 2009
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In: Epilepsia. - 1528-1167. ; 50:2, s. 163-73
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Research review (peer-reviewed)abstract
- Vigabatrin (VGB) is a structural analogue of gamma-aminobutyric acid (GABA) that irreversibly inhibits GABA-transaminase (GABA-T), increasing brain levels of GABA. VGB is under assessment for treatment of infantile spasms (IS) and refractory complex partial seizures (CPS). Response can be rapid with spasm cessation following approximately 2 weeks of therapy. Patients with symptomatic tuberous sclerosis (TS) and other patients have achieved spasm cessation. Comparison with ACTH has been performed. Patients with refractory CPS have responded as well. Adverse effects and structural findings on imaging occur with VGB treatment. T2 hyperintensities within brain have been observed. Psychotic disorders or hallucinations have occurred rarely. A specific adverse effects is associated VGB, with a peripheral visual field defect (VFD) detected in some patients. Prevalence and incidence of the VGB-induced peripheral VFD varied depending on the age of the patient and the extent of exposure to VGB, with 25% to 50% prevalence in adults; the prevalence in children was 15% and retinal defect in infants ranged from 15% to 31%. A bilateral nasal defect may be the first clinical indication and may progress to a concentric, bilateral field defect observed in many affected patients; central visual acuity is almost always preserved. The earliest finding of the first abnormal field examination in adults was after 9 months of treatment; with a mean duration of VGB exposure of 4.8 years. In children, the earliest onset of a first abnormal field examination was after 11 months, with a mean time to onset of 5.5 years. The earliest sustained onset of the VGB-induced retinal defect in infants was 3.1 months. RECOMMENDATION: Cognitive, age-appropriate visual field testing is required at baseline and then repeated at intervals in patients who continue therapy. Infants are tested at baseline and at 3-month intervals for the first 18 months of treatment, and then every 6 months thereafter. Adults with CPS are tested at baseline and at 6-month intervals. To select patients who are appropriate for VGB therapy, physicians must consider the benefits of fewer seizures and improved quality of life versus the potential risk of developing a VGBinduced peripheral VFD. Effectiveness of VGB can be detected within 12 weeks of initiating therapy. There appears to be minimal risk associated with a 2- to 3-month trial of VGB to evaluate effectiveness before there is a demonstrable risk of developing the VGB-induced peripheral VFD. If patients do not have a clinical benefit from VGB within 12 weeks of treatment initiation, VGB should be discontinued. If patients have a meaningful reduction in seizures or achieve seizure freedom, then the physician and patient or caregiver must determine if the benefits outweigh the potential risk of developing a peripheral VFD. When VGB is prescribed, the patient must be closely monitored for visual field changes. In cases where spasm or seizure improvement is not achieved within 12 weeks of initiation, VGB should be discontinued. In cases where complete spasm cessation, seizure control, or meaningful improvement is achieved within 12 weeks, continued treatment with VGB is warranted; subsequent periodic monitoring for the peripheral VFD is necessary and should be used to mitigate the risk of the defect. The risk of developing the peripheral VFD with short-term exposure seems to be low, therefore, VGB is an appropriate option for patients with IS or refractory CPS who receive a clinical benefit from its effectiveness, given the clinical consequences of uncontrolled seizures and spasms.
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