PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci

Baseline drinking water consumption and changes in body weight and waist circumference at 2-years of follow-up in a senior Mediterranean population

The PREDIMEDPlus trial was supported by the Spanish government's official funding agency for biomedical research, ISCIII, through the Fondo de Investigacion para la Salud (FIS) and cofunded by European Union ERDF/ESF, "A way to make Europe"/"Investing in your future" (five coordinated FIS projects led by JS-S and JVid, including the following: PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/00728, PI14/01722, PI14/00636, PI14/01206, PI14/01919, PI14/01374, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00366, PI17/00764, PI17/01827, PI17/01441, PI17/01732, PI17/00926, PI19/00309, PI19/01032, PI19/00576, PI19/00017, and PI19/00781) , the Special Action Project entitled: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant to JSS, the European Research Council (Advanced Research Grant 2013-2018, 340918) to MAMG, the Recercaixa Grant to JS-S (2013ACUP00194) , a grant from the Generalitat Valenciana (PROMETEO/2017/017) , a SEMER-GEN grant, and funds from the European Regional Development Fund (CB06/03) . Study resulting from the SLT006/17/00246 grant, funded by the Department of Health of the Generalitat de Catalunya by the call "Accio instrumental de programes de recerca orientats en l'ambit de la recerca i la innovacio en salut". We thank the CERCA Programme/Generalitat de Catalunya for institutional support. This publication has been possible with the support of the Ministerio de Ciencia, Innovacion y Universidades (MICINN) (FPU 17/01925) . Jordi SalasSalvado, senior author of this study, is partially supported by ICREA under the ICREA Academia programme. IP-G receives a grant from the Spanish Ministry of Education, Culture and Sports (FPU 17/01925) . Dr. NB-T is supported by a postdoctoral fellowship (Juan de la Cierva-Formacion, FJC2018-036016-I) . I.M GimenezAlba received an FPU grant from the Ministry of Science, Innovation and Universities (reference FPU 18/01703) . C.B. received a Fernando Tarongi Bauza PhD Grant.Background & aims: The association between drinking water consumption and adiposity has been poorly explored. Therefore, we aimed to analyse the associations between the frequency of drinking water consumption and body weight and waist circumference changes in an elderly Mediterranean cohort. Methods: A total of 1832 elderly participants (aged 55e75 years) with metabolic syndrome from the PREDIMED-Plus study with baseline data on drinking water and other beverages assessed by a validated 32-item Spanish fluid-intake questionnaire and with data on body weight (BW) and waist circumference (WC) at 1-year and 2-year were included in these prospective analyses. Multivariable linear regression models were fitted to assess the b-coefficients and 95% confidence interval (CI) for BWand WC changes in terms of categories of baseline drinking water consumption (tap water and bottled water). The theoretical effect on BWand WC of replacing several beverages with drinking water was assessed using mathematical models. Results: The baseline frequency of drinking water consumptionwas inversely associated with 1-year and 2- year changes in BW. b-coefficients (95%CI) across categories ofwater consumption (<2.5, 2.5 to <5, 5 to < 7.5, 7.5 servings/d) expressed in % of weight changes at 2 years of follow-up were 0.0, 0.80 ( 1.48, 0.12), 1.36 ( 2.18, 0.54), and 1.97 ( 3.09, 0.86), respectively. Individuals in the two highest categories of drinkingwater consumption (5 to < 7, and 7.5 servings/d) also showed a higher decrease inWC (expressed as % of change) after 2 years of follow-up: 1.11 ( 1.96, 0.25) and 1.45 ( 2.66, 0.24) compared to the reference intake (<2.5 servings/day), after adjustment for potential confounding factors. The theoretical replacement of soups, beers, spirits, hot beverages, dairy beverages, and other beverages group with drinking water was associated with greater reductions in BWat one- and two-years of follow-up. Conclusions: Drinking water consumption was inversely associated with 2-year adiposity changes in an elderly Mediterranean cohort at high cardiovascular risk. Our results also suggest that the consumption of drinking water instead of energy-containing beverages is associated with lower weight gain.Spanish Government European CommissionEuropean Union ERDF/ESF, "A way to make Europe"/"Investing in your future" PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/00728 PI14/01722 PI14/00636 PI14/01206 PI14/01919 PI14/01374 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00366Special Action Project entitled: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grantEuropean Research Council (ERC)European Commission 340918Recercaixa Grant 2013ACUP00194Generalitat Valenciana European Commission PROMETEO/2017/017SEMER-GEN grant European Commission CB06/03Department of Health of the Generalitat de Catalunya SLT006/17/00246Ministerio de Ciencia, Innovacion y Universidades (MICINN) FPU 17/01925ICREA under the ICREA Academia programmeSpanish Ministry of Education, Culture and Sports FPU 17/01925Juan de la Cierva-Formacion FJC2018-036016-IMinistry of Science, Innovation and Universities FPU 18/01703Fernando Tarongi Bauza PhD GrantThe European Union ERDF/ESF, "A way to make Europe"/"Investing in your future" PI17/00764 PI17/01827 PI17/01441 PI17/01732 PI17/00926 PI19/00309 PI19/01032 PI19/00576 PI19/00017 PI19/0078