Comparison of body mass index and waist circumference as predictors of cardiometabolic health in a population of young Canadian adults

<p>Abstract</p> <p>Background</p> <p>This study aimed to investigate whether waist circumference (WC) or body mass index (BMI) is a better predictor of blood lipid concentrations among young men and women from different ethnocultural groups.</p> <p>Methods</p> <p>Participants were 1181 healthy men (n = 358) and women (n = 823) aged 20-29 years taken from the cross-sectional Toronto Nutrigenomics and Health Study. Analyses were conducted separately for men and women, and for Caucasian and East Asian ethnocultural groups. Serum triglycerides (TG) and total to HDL cholesterol ratio (TC:HDL cholesterol) were used as outcomes. Associations between the adiposity and blood lipid measures were examined using partial correlations and odds ratios derived from logistic regression models.</p> <p>Results</p> <p>WC had a stronger association with serum lipid concentrations than BMI. WC was significantly related to TG and TC:HDL cholesterol after adjusting for BMI and covariates among men and women (P ≤ 0.01). However, after adjusting for WC and covariates, BMI was not significantly associated with the two serum lipid measures. WC was a better predictor of TG and TC:HDL among all sex and ethnocultural subgroups except among East Asian women where little difference between the two measures was observed.</p> <p>Conclusions</p> <p>WC is a stronger predictor of cardiometabolic health when compared with BMI among young adults, especially among men.</p

Evaluations of land cover risk factors for canine leptospirosis: 94 cases (2002–2009)

Associations of land cover/land use variables and the presence of dogs in urban vs. rural address locations were evaluated retrospectively as potential risk factors for canine leptospirosis in Kansas and Nebraska using Geographic Information Systems (GIS). The sample included 94 dogs positive for leptospirosis predominantly based on a positive polymerase chain reaction test for leptospires in urine, isolation of leptospires on urine culture, a single reciprocal serum titer of 12,800 or greater, or a four-fold rise in reciprocal serum titers over a 2–4 weeks period; and 185 dogs negative for leptospirosis based on a negative polymerase chain reaction test and reciprocal serum titers less than 400. Land cover features from 2001 National Land Cover Dataset and 2001 Kansas Gap Analysis Program datasets around geocoded addresses of case/control locations were extracted using 2500 m buffers, and the presence of dogs’ address locations within urban vs. rural areas were estimated in GIS. Multivariate logistic models were used to determine the risk of different land cover variables and address locations to dogs. Medium intensity urban areas (OR = 1.805, 95% C.I. = 1.396, 2.334), urban areas in general (OR = 2.021, 95% C.I. = 1.360, 3.003), and having urban address locations (OR = 3.732, 95% C.I. = 1.935, 7.196 entire study region), were significant risk factors for canine leptospirosis. Dogs regardless of age, sex and breed that live in urban areas are at higher risk of leptospirosis and vaccination should be considered

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase–mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.publishedVersio

Genome-Wide Association Analysis Identifies a Mutation in the Thiamine Transporter 2 (SLC19A3) Gene Associated with Alaskan Husky Encephalopathy

Alaskan Husky Encephalopathy (AHE) has been previously proposed as a mitochondrial encephalopathy based on neuropathological similarities with human Leigh Syndrome (LS). We studied 11 Alaskan Husky dogs with AHE, but found no abnormalities in respiratory chain enzyme activities in muscle and liver, or mutations in mitochondrial or nuclear genes that cause LS in people. A genome wide association study was performed using eight of the affected dogs and 20 related but unaffected control AHs using the Illumina canine HD array. SLC19A3 was identified as a positional candidate gene. This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. Dogs have two copies of this gene located within the candidate interval (SLC19A3.2 – 43.36–43.38 Mb and SLC19A3.1 – 43.411–43.419 Mb) on chromosome 25. Expression analysis in a normal dog revealed that one of the paralogs, SLC19A3.1, was expressed in the brain and spinal cord while the other was not. Subsequent exon sequencing of SLC19A3.1 revealed a 4bp insertion and SNP in the second exon that is predicted to result in a functional protein truncation of 279 amino acids (c.624 insTTGC, c.625 C>A). All dogs with AHE were homozygous for this mutation, 15/41 healthy AH control dogs were heterozygous carriers while 26/41 normal healthy AH dogs were wild type. Furthermore, this mutation was not detected in another 187 dogs of different breeds. These results suggest that this mutation in SLC19A3.1, encoding a thiamine transporter protein, plays a critical role in the pathogenesis of AHE.University of California, Davis. School of Veterinary Medicine. Center for Companion Animal Healt

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

BACKGROUND: When rates of uptake of other drugs differ between treatment arms in long-term trials, the true benefit or harm of the treatment may be underestimated. Methods to allow for such contamination have often been limited by failing to preserve the randomization comparisons. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, patients were randomized to fenofibrate or placebo, but during the trial many started additional drugs, particularly statins, more so in the placebo group. The effects of fenofibrate estimated by intention-to-treat were likely to have been attenuated. We aimed to quantify this effect and to develop a method for use in other long-term trials. METHODOLOGY/PRINCIPAL FINDINGS: We applied efficacies of statins and other cardiovascular drugs from meta-analyses of randomized trials to adjust the effect of fenofibrate in a penalized Cox model. We assumed that future cardiovascular disease events were reduced by an average of 24% by statins, and 20% by a first other major cardiovascular drug. We applied these estimates to each patient who took these drugs for the period they were on them. We also adjusted the analysis by the rate of discontinuing fenofibrate. Among 4,900 placebo patients, average statin use was 16% over five years. Among 4,895 assigned fenofibrate, statin use was 8% and nonuse of fenofibrate was 10%. In placebo patients, use of cardiovascular drugs was 1% to 3% higher. Before adjustment, fenofibrate was associated with an 11% reduction in coronary events (coronary heart disease death or myocardial infarction) (P = 0.16) and an 11% reduction in cardiovascular disease events (P = 0.04). After adjustment, the effects of fenofibrate on coronary events and cardiovascular disease events were 16% (P = 0.06) and 15% (P = 0.008), respectively. CONCLUSIONS/SIGNIFICANCE: This novel application of a penalized Cox model for adjustment of a trial estimate of treatment efficacy incorporates evidence-based estimates for other therapies, preserves comparisons between the randomized groups, and is applicable to other long-term trials. In the FIELD study example, the effects of fenofibrate on the risks of coronary heart disease and cardiovascular disease events were underestimated by up to one-third in the original analysis. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64783481