| 11. |
- Dimas, Antigone S, et al.
(författare)
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:6, s. 2158-2171
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Tidskriftsartikel (refereegranskat)abstract
- Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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| 12. |
- Engesæter, Lars B, et al.
(författare)
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Low revision rate after total hip arthroplasty in patients with pediatric hip diseases.
- 2012
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Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 83:5, s. 436-41
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Tidskriftsartikel (refereegranskat)abstract
- Background The results of primary total hip arthroplasties (THAs) after pediatric hip diseases such as developmental dysplasia of the hip (DDH), slipped capital femoral epiphysis (SCFE), or Perthes' disease have been reported to be inferior to the results after primary osteoarthritis of the hip (OA). Materials and methods We compared the survival of primary THAs performed during the period 1995-2009 due to previous DDH, SCFE, Perthes' disease, or primary OA, using merged individual-based data from the Danish, Norwegian, and Swedish arthroplasty registers, called the Nordic Arthroplasty Register Association (NARA). Cox multiple regression, with adjustment for age, sex, and type of fixation of the prosthesis was used to calculate the survival of the prostheses and the relative revision risks. Results 370,630 primary THAs were reported to these national registers for 1995-2009. Of these, 14,403 THAs (3.9%) were operated due to pediatric hip diseases (3.1% for Denmark, 8.8% for Norway, and 1.9% for Sweden) and 288,435 THAs (77.8%) were operated due to OA. Unadjusted 10-year Kaplan-Meier survival of THAs after pediatric hip diseases (94.7% survival) was inferior to that after OA (96.6% survival). Consequently, an increased risk of revision for hips with a previous pediatric hip disease was seen (risk ratio (RR) 1.4, 95% CI: 1.3-1.5). However, after adjustment for differences in sex and age of the patients, and in fixation of the prostheses, no difference in survival was found (93.6% after pediatric hip diseases and 93.8% after OA) (RR 1.0, CI: 1.0-1.1). Nevertheless, during the first 6 postoperative months more revisions were reported for THAs secondary to pediatric hip diseases (RR 1.2, CI: 1.0-1.5), mainly due to there being more revisions for dislocations (RR 1.8, CI: 1.4-2.3). Comparison between the different diagnosis groups showed that the overall risk of revision after DDH was higher than after OA (RR 1.1, CI: 1.0-1.2), whereas the combined group Perthes' disease/SCFE did not have a significantly different risk of revision to that of OA (RR 0.9, CI: 0.7-1.0), but had a lower risk than after DDH (RR 0.8, CI: 0.7-1.0). Interpretation After adjustment for differences in age, sex, and type of fixation of the prosthesis, no difference in risk of revision was found for primary THAs performed due to pediatric hip diseases and those performed due to primary OA.
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| 13. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 19. |
- Ganna, Andrea, et al.
(författare)
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Multilocus Genetic Risk Scores for Coronary Heart Disease Prediction
- 2013
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 33:9, s. 2267-2272
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. Approach and Results-We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P<0.001) and improved risk classification beyond established risk factors (net reclassification improvement, 4.2% and 4.9%; P=0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. Conclusions-Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting.
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| 20. |
- Ganna, Andrea, 1985-, et al.
(författare)
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Risk prediction measures for case-cohort and nested case-control designs : an application to cardiovascular disease.
- 2012
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 175:7, s. 715-724
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Tidskriftsartikel (refereegranskat)abstract
- Case-cohort and nested case-control designs are often used to select an appropriate subsample of individuals from prospective cohort studies. Despite the great attention that has been given to the calculation of association estimators, no formal methods have been described for estimating risk prediction measures from these 2 sampling designs. Using real data from the Swedish Twin Registry (2004-2009), the authors sampled unstratified and stratified (matched) case-cohort and nested case-control subsamples and compared them with the full cohort (as "gold standard"). The real biomarker (high density lipoprotein cholesterol) and simulated biomarkers (BIO1 and BIO2) were studied in terms of association with cardiovascular disease, individual risk of cardiovascular disease at 3 years, and main prediction metrics. Overall, stratification improved efficiency, with stratified case-cohort designs being comparable to matched nested case-control designs. Individual risks and prediction measures calculated by using case-cohort and nested case-control designs after appropriate reweighting could be assessed with good efficiency, except for the finely matched nested case-control design, where matching variables could not be included in the individual risk estimation. In conclusion, the authors have shown that case-cohort and nested case-control designs can be used in settings where the research aim is to evaluate the prediction ability of new markers and that matching strategies for nested case-control designs may lead to biased prediction measures.
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