| 1. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 2. |
- Coviello, Andrea D, et al.
(författare)
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A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p=1.8×10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4×10(-11)), GCKR (rs780093, 2p23.3, p=2.2×10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4×10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1×10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9×10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3×10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5×10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1×10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3×10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7×10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5×10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p=2.5×10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
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| 4. |
- Wood, Kirkham B., et al.
(författare)
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Effectiveness of Spinal Fusion Versus Structured Rehabilitation in Chronic Low Back Pain Patients With and Without Isthmic Spondylolisthesis : A Systematic Review
- 2011
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Ingår i: Spine. - 0362-2436 .- 1528-1159. ; 36:21, s. S110-S119
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Tidskriftsartikel (refereegranskat)abstract
- Study Design. Systematic review. Objective. To determine if the presence of isthmic spondylolisthesis modifies the effect of treatment (fusion vs. multidimensional supervised rehabilitation) in patients with chronic low back pain (CLBP). Summary of Background Data. Results of spinal surgery for CLBP are variable. It is unclear whether patients with CLBP and isthmic spondylolisthesis have more success with surgery versus a multidimensional supervised rehabilitation program when compared with those with CLBP but without spondylolisthesis. Methods. A systematic search was conducted in MEDLINE and the Cochrane Collaboration Library for articles published through January 2011. Randomized controlled trials (RCTs) were included that compared spine fusion versus multidimensional supervised rehabilitation in patients with and without isthmic spondylolisthesis. Standardized mean differences (SMDs) and risk differences were calculated for common outcomes, and then compared to determine potential heterogeneity of treatment effect. The final strength of the body of literature was expressed as "high," "moderate," or "low" confidence that the evidence reflects the true effect. Results. No studies were found that directly compared the two subgroups. Three RCTs compared fusion with supervised nonoperative care in patients with CLBP without isthmic spondylolisthesis; one RCT evaluated these treatments in patients with isthmic spondylolisthesis. There were study differences in patient characteristics, type of fusion, the nature of the rehabilitation, outcomes assessed, and length of follow-up. The SMDs for pain in favor of fusion were modest at 2 years for those without isthmic spondylolisthesis, but large in favor of fusion for those with isthmic spondylolisthesis compared with rehabilitation. Similarly, the SMDs for function in patients without isthmic spondylolisthesis compared with rehabilitation was small at 2 years, but appreciably higher in favor of fusion in patients with isthmic spondylolisthesis. Conclusion. The overall strength of evidence evaluating whether the presence of isthmic spondylolisthesis modifies the effect of fusion compared with rehabilitation patients with CLBP is "low." Fusion should be considered for patients with low back pain and isthmic spondylolisthesis who have failed nonoperative treatment. Clinical Recommendations. We recommend considering fusion for patients with isthmic spondylolisthesis and lower back pain who have failed nonoperative treatment. Recommendation: Weak.
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