RESUMO
Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
RESUMO
BACKGROUND: Venous thromboembolism (VTE) is a well-recognized and preventable complication of acute stroke. Although graduated compression stockings reduce the risk of VTE for patients undergoing operation, their benefit in acute stroke remains uncertain. METHODS: The relationship between symptomatic VTE (sVTE) and use of stockings using observational data from the Tinzaparin in Acute Ischemic Stroke Trial, which compared 10 days of treatment with tinzaparin (175 IU/kg(-1) or 100 IU/kg(-1)) with aspirin (300 mg), was assessed using logistic regression adjusted for known VTE risk factors and treatment. RESULTS: sVTE Occurred in 28 patients (1.9%; 18 with deep vein thrombosis and 13 with pulmonary embolism) within 15 days of enrollment in 1479 patients. Patients wearing one or two stockings for any period of time during the first 10 days (n = 803) had a nonsignificant increase (odds ratio 2.45, 95% confidence interval 0.95-6.32) in the risk of sVTE. In contrast, those wearing bilateral stockings for 10 days (n = 374) had a nonsignificant reduction in the odds of sVTE as compared with those who wore no stockings or wore them for less than 10 days (odds ratio 0.65, 95% confidence interval 0.26-1.65). Mild stroke and treatment with tinzaparin were associated with a reduced risk of VTE. CONCLUSIONS: Bilateral graduated compression stockings may reduce the incidence of VTE by one third for patients with acute ischemic stroke. However, the uncertainty in this finding, low frequency of sVTE, potential for stockings to cause harm, and cost of stockings highlight the need for a large randomized controlled trial to examine the safety and efficacy of stockings in acute stroke.