Factor relationships of metabolic syndrome and echocardiographic phenotypes in the HyperGEN study

BACKGROUND: Metabolic syndrome and its risk factors are predictors of cardiovascular events. Metabolic syndrome is also directly associated with echocardiographic phenotypes. METHODS: The current study is the first to investigate the factors associated with both metabolic syndrome risk factors and echocardiographic phenotypes and assess their heritability. Multivariate factor analysis was performed on 15 traits in 1393 African-Americans and 1133 whites, as well as stratified by type 2 diabetes mellitus status. RESULTS: Factor analysis with varimax rotation established four to five latent factors across ethnicities and diabetes mellitus stratifications. Among metabolic syndrome risk factors, blood pressure was the most highly correlated with cardiac traits. The factor domains, in the order of the proportion of variance explained, were 'left ventricle wall thickness', 'left ventricle geometry', 'blood pressure', 'BMI-insulin', and 'lipid-insulin'. Factor analysis without any rotation identified special (cross domain) metabolic syndrome-echocardiographic factors, 'blood pressure-left ventricle geometry' and 'blood pressure-left ventricle dimension-wall thickness' in whites. Fifty to 57% of the total original risk factor variance was explained by the latent factors. Heritability was highest for BMI-insulin (37-53%), lowest for 'blood pressure' factors (15-27%), and intermediate for metabolic syndrome-echocardiographic factors. CONCLUSION: These latent factors identified can be utilized as summary phenotypes in epidemiological, linkage, and association studies.     

The degree of fetal metformin exposure does not influence fetal outcome in gestational diabetes mellitus

The purpose of the study was to examine in vivo placental transfer of metformin, its association with neonatal outcome in metformin-treated gestational diabetes (GDM) patients, and influence of metformin exposure on maternal glycemic control and weight gain. Two hundred and seventeen GDM patients were randomized to metformin or insulin in Turku University Hospital, Finland. Metformin concentrations were determined by mass spectrometry in maternal serum at 36 gestational weeks (gw) and at birth, and in umbilical cord blood. Main outcome measures were birth weight, gw at birth, umbilical artery pH and neonatal hypoglycemia, maternal weight gain, HbA1c and fructosamine concentration. Median umbilical cord/maternal serum metformin concentration ratio was 0.73. There were no differences in birth weight measured in grams or SD units (p = 0.49), or gw at birth (p always ≥0.49) between insulin- and metformin-treated patients stratified by trough metformin concentration tertiles measured at 36 gw. Rate of neonatal hypoglycemia (p = 0.92) and umbilical artery pH value (p = 0.78) was similar in insulin- and metformin-treated patients stratified by cord metformin concentration tertiles. Maternal glycemic control was similar in metformin concentration tertiles at 36 gw. Maternal weight gain was 223 g greater per week (p = 0.038) in the lowest metformin tertile compared to other tertiles combined. Maternal and fetal exposure to metformin is similar. Maternal or fetal metformin concentrations do not predict maternal glycemic control or neonatal outcome, but low maternal exposure may lead to greater maternal weight gain.     

Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10⁻⁸; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10⁻¹⁴). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.