Abstract. Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m 2 . A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors.The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.Chronic kidney disease (CKD) is a major public health problem. On the basis of clinical practice guidelines established by the National Kidney Foundation,~20 million adults in the United States have CKD, with 8 million of these classified as having moderate or severe kidney disease (1).In dialysis patients, cardiovascular disease (CVD) mortality rates are 10 to 30 times higher than in the general population (2). In high-risk patients, defined by the presence of either CVD or cardiovascular risk factors, less severe kidney disease is also an independent risk factor for CVD outcomes (3-12). However, in more representative community-based populations that were not selected for being at increased risk for CVD, there have been less consistent findings. Data from some studies suggest the absence of an independent association between the presence of CKD and CVD (13,14), whereas other data suggest that CKD is an independent risk factor for CVD outcomes (15-18). Previous studies may have been limited by insufficient power to examine subgroup relationships, in particular race, which may have caused discrepancies in these results.The purpose of the present study was to pool the findings from several large community-based cohort studies to evaluate more systematically whether CKD, as quantified by estimated GFR, ...
WW domains are protein modules that mediate protein-protein interactions through recognition of prolinerich peptide motifs and phosphorylated serine/threonine-proline sites. To pursue the functional properties of WW domains, we employed mass spectrometry to identify 148 proteins that associate with 10 human WW domains. Many of these proteins represent novel WW domain-binding partners and are components of multiprotein complexes involved in molecular processes, such as transcription, RNA processing, and cytoskeletal regulation. We validated one complex in detail, showing that WW domains of the AIP4 E3 proteinubiquitin ligase bind directly to a PPXY motif in the p68 subunit of pre-mRNA cleavage and polyadenylation factor Im in a manner that promotes p68 ubiquitylation. The tested WW domains fall into three broad groups on the basis of hierarchical clustering with respect to their associated proteins; each such cluster of bound proteins displayed a distinct set of WW domain-binding motifs. We also found that separate WW domains from the same protein or closely related proteins can have different specificities for protein ligands and also demonstrated that a single polypeptide can bind multiple classes of WW domains through separate prolinerich motifs. These data suggest that WW domains provide a versatile platform to link individual proteins into physiologically important networks.Many signaling proteins contain modular domains that mediate specific protein-protein interactions, frequently through the recognition of short peptide motifs in their binding partners (56). In many cases these interactions are regulated by posttranslational modifications, such as phosphorylation. Interaction domains can thereby control the subcellular localization, enzymatic activity, and substrate specificity of regulatory proteins and the assembly of multiprotein complexes, and thus the flow of information through signaling pathways.WW domains comprise a family of protein-protein interaction modules that are found in many eukaryotes and are present in approximately 50 human proteins (6; see Fig. 1). Within these polypeptides, WW domains are joined to a number of distinct interaction modules, including phosphotyrosinebinding domains (i.e., in the FE65 protein) and FF domains (CA150 and FBP11), as well as protein localization domains, such as C2 (NEDD4 family proteins) and pleckstrin homology domains (PLEKHA5). WW domains are also linked to a variety of catalytic domains, including HECT E3 protein-ubiquitin ligase domains (in NEDD4 family proteins), rotomerase/peptidyl prolyisomerase domains (Pin1), and Rho GTPase-activating protein domains. Consequently, WW domain-containing proteins are involved in a variety of cellular processes, including transcription, RNA processing, protein trafficking, receptor signaling, and control of the cytoskeleton (32,33,68). WW domain-mediated interactions have been implicated in cancer (4, 75), in hereditary disorders, such as Liddle's syndrome (66) and Rett's syndrome (8), as well as in Alzheimer's (46, ...
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