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Objective: Individual propensity to chronic, low-grade inflammation -a determinant of atherosclerosis -is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10 cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2,547 relative pairs). Methods and results:In a variance component analysis, heritability of CRP values was significant (h 2 =0.39, p<0.0001). This effect was independent of BMI and was present in both diabetic (h 2 =0.42, p=0.003) and non-diabetic (h 2 =0.34, p=0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD=3.41, genome-wide p=0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD=1.35) and 17p11 (LOD=1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD=2.17) was evident at 3p21. Conclusions:A major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.

This study assessed the influence of short-term changes in smoking habit on blood levels of inflammatory markers, which have been associated with increased cardiovascular risk. Five inflammatory markers were measured before and 6 weeks after attempting smoking cessation in 138 healthy women. In the 48 participants who stopped smoking, white blood cell count (-0.7±1. 1-4 Inflammatory marker levels remain higher in ex-smokers compared with nonsmokers for years after quitting smoking, suggesting that smoking may have long-term effects on inflammatory diseases such as periodontitis, pulmonary disease, and atherosclerosis. Epidemiologic studies, however, provide limited information on how short-term changes in smoking habit influence blood levels of inflammatory markers in individuals. The aim of this study was to assess reversible pro-inflammatory effects of cigarette smoking on 5 inflammatory markers associated with increased cardiovascular risk (WBC, fibrinogen, CRP, intercellular adhesion molecule 1 [ICAM-1], and CD40 ligand [CD40L]) before and 6 weeks after smoking cessation in otherwise healthy women. METHODS Study DesignSubjects were female smokers who participated in a 2 × 2 factorial randomized trial designed to determine whether an exercise program or health education, with or without nicotine patches, was more successful for smoking cessation. Smoking cessation rates and changes in blood levels of inflammatory markers were similar for subjects randomized to exercise training and health education and have been reported elsewhere.5 This report describes changes in blood levels of inflammatory markers before and after smoking cessation in subjects who stopped smoking for 6 weeks from the prespecified quit day. ParticipantsFemale smokers were recruited by newspaper advertisement and were eligible for inclusion if they were 18 to 65 years of age, had smoked at least 5 cigarettes per day for the past 2 years, were motivated to stop smoking, and were generally in good health. Exclusion criteria were pregnancy, inability to undertake an exercise training program,

Background The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. Methods Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. Results Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. Conclusions The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

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