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- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 2. |
- Rodriguez, Alexander J., et al.
(författare)
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Pain, Quality of Life, and Safety Outcomes of Kyphoplasty for Vertebral Compression Fractures : Report of a Task Force of the American Society for Bone and Mineral Research
- 2017
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 32:9, s. 1935-1944
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Tidskriftsartikel (refereegranskat)abstract
- The relative efficacy and harms of balloon kyphoplasty (BK) for treating vertebral compression fractures (VCF) are uncertain. We searched multiple electronic databases to March 2016 for randomized and quasi-randomized controlled trials comparing BK with control treatment (nonsurgical management [NSM], percutaneous vertebroplasty [PV], KIVA VCF treatment system [Benvenue Medical, Inc., Santa Clara, CA, USA], vertebral body stenting, or other) in adults with VCF. Outcomes included back pain, back disability, quality of life, new VCF, and adverse events (AEs). One reviewer extracted data, a second checked accuracy, and two rated risk of bias (ROB). Mean differences and 95% confidence intervals (CIs) were calculated using inverse-variance models. Risk ratios of new VCF and AE were calculated using Mantel-Haenszel models. Ten unique trials enrolled 1837 participants (age range, 61 to 76 years; 74% female), all rated as having high or uncertain ROB. Versus NSM, BK was associated with greater reductions in pain, back-related disability, and better quality of life (k = 1 trial) that appeared to lessen over time, but were less than minimally clinically important differences. Risk of new VCF at 3 and 12 months was not significantly different (k = 2 trials). Risk of any AE was increased at 1 month (RR = 1.73; 95% CI, 1.36 to 2.21). There were no significant differences between BK and PV in back pain, back disability, quality of life, risk of new VCF, or any AE (k = 1 to 3 trials). Limitations included lack of a BK versus sham comparison, availability of only one RCT of BK versus NSM, and lack of study blinding. Individuals with painful VCF experienced symptomatic improvement compared with baseline with all interventions. The clinical importance of the greater improvements with BK versus NSM is unclear, may be due to placebo effect, and may not counterbalance short-term AE risks. Outcomes appeared similar between BK and other surgical interventions. Well-conducted randomized trials comparing BK with sham would help resolve remaining uncertainty about the relative benefits and harms of BK.
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