Citations

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P <1×10 −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

Background We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Methods and Results Subjects aged <50 years (mean age, 37; range, 22–49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal or abnormal coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 normal and 13 abnormal subjects passed rigorous quality control and were used for microarray assessment of gene expression. Of 9 genes differentially expressed at false discovery rate <0.1%, we here focus upon abnormal subjects having elevated expression of HMGB1 (high mobility group box 1) which we unexpectedly found to be linked to low LAMC1 (laminin gamma 1) expression. This linkage was corroborated by 3 of our past studies and confirmed bio‐functionally. Compared with normal BOEC, abnormal BOEC released 13±3‐fold more HMGB1 in response to lipopolysaccharide; and they deposited one tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow‐up data are provided for 4 normal subjects (followed 13.4±0.1 year) and for 12 abnormal subjects (followed 9.1±4.5 years). Conclusions The known pathogenic effects of high‐ HMGB1 and low‐ LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype.

Background and objectives It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality. Design, setting, participants, & measurements The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g). Results Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales. Conclusions Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering.

AbstractBackgroundBlood involvement by mycosis fungoides (MF)/Sézary syndrome (SS) influences prognosis and therapeutic decisions. MF/SS blood stage is currently determined by absolute CD4 + CD26− or CD4 + CD7‐cell counts, which quantification method may overestimate MF/SS by including CD26− or CD7− normal CD4+ T‐cells, or underestimate disease burden when MF/SS cells show incomplete loss of CD26 and/or CD7. Recently, through the standardization effort led by the International Clinical Cytometry Society (ICCS), recommendation was made to quantify MF/SS by enumerating immunophenotypically aberrant CD4+ T‐cells, rather than CD26− or CD7− in isolation.MethodsWe compared these two quantitation methods in 309 MF/SS patients who had blood samples analyzed by flow cytometry immunophenotyping (FCI) over a 1‐year period.ResultsUsing the European Organization of Research and Treatment of Cancer (EORTC)/International Society for Cutaneous Lymphomas (ISCL) criteria, 221 (71.5%) patients had a blood stage corresponding to B0, 57 (18.4%) to B1, and 31 (10%) to B2. By FCI analysis, a total of 62 patients (20.0%) were found positive for MF/SS. Among EORTC B0 patients, 11/221 (5%) were positive by FCI (false negatives), and among EORTC Stage B1 patients, 35/57 (61%) were negative by FCI (false positives). Regarding patients positive for MF/SS cells by FCI, there was an overall excellent correlation (r = .999, p < .001) between the EORTC/ISCL method and FCI method; however, four (6.5%) patients would have an altered B stage between B0 and B1.ConclusionThe MF/SS cell quantification method using immunophenotypic aberrancies, as recommended by the ICCS, allows to distinguish MF/SS cells from background benign T‐cells and enables for more accurate staging, especially among patients currently being considered to have B0 and B1 stage diseases.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Abstract Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values &lt; 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. Significance: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

Abstract Purpose: T-cell immunoglobulin and ITIM domain (TIGIT), a member of the immune checkpoint family, is important in normal T-cell biology. However, the phenotypical profile and clinical relevance of TIGIT in follicular lymphoma is largely unknown. Experimental Design: Biopsy specimens from a cohort of 82 patients with follicular lymphoma were analyzed using mass cytometry to explore the phenotype and biological and clinical significance of TIGIT+ T cells. Results: TIGIT is highly expressed on intratumoral T cells and its expression alters T-cell phenotype in follicular lymphoma. TIGIT is abundantly expressed on Treg cells, resulting in an enhanced suppressive property. TIGIT expression on non-Treg/TFH T cells defines a population that exhibits an exhausted phenotype. Clinically, increased numbers of TIGIT+ T cells are associated with inferior patient outcomes and poor survival. We observe that anti–PD-1 therapy with pembrolizumab alters the phenotype of TIGIT+ T subsets and identifies a role for CD28 expression on TIGIT+ T cells in treatment response. Conclusions: The current study provides a comprehensive analysis of the phenotypic profile of intratumoral TIGIT+ T subsets and their prognostic relevance in follicular lymphoma. Inhibition of TIGIT signaling may be an additional mechanism to prevent T-cell suppression and exhaustion in B-cell lymphoma.