Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes". Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10-4) and GC rs4588 (p = 1 x 10-6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10-11) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16-1.41, p = 1.1 x 10-7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D

Circulating adiponectin levels are paradoxically associated with mortality rate. A systematic review and meta-analysis. Online supplemental material

<p>Online supplemental material of paper entitled: "Circulating adiponectin levels are paradoxically associated with mortality rate. A systematic review and meta-analysis. It contains 2 tables describing papers included in the meta-analysis and quality assessment of them along with figures of additional analyses: funnel plots, forest plots and subgroup analyses</p

Circulating Metabolites Associate With and Improve the Prediction of All-Cause Mortality in Type 2 Diabetes.

Death rate is increased in type 2 diabetes. Unraveling biomarkers of novel pathogenic pathways capable to identify high-risk patients is instrumental to tackle this burden. We investigated the association between serum metabolites and all-cause mortality in type 2 diabetes and then whether the associated metabolites mediate the effect of inflammation on mortality risk and improve ENFORCE (EstimatioN oF mORtality risk in type2 diabetic patiEnts) and RECODe (Risk Equation for Complications Of type 2 Diabetes), two well-established all-cause mortality prediction models in diabetes. Two cohorts comprising 856 individuals (279 all-cause deaths) were analyzed. Serum metabolites (n = 188) and pro- and anti-inflammatory cytokines (n = 7) were measured. In the pooled analysis, hexanoylcarnitine, kynurenine, and tryptophan were significantly and independently associated with mortality (hazard ratio [HR] 1.60 [95% CI 1.43-1.80]; 1.53 [1.37-1.71]; and 0.71 [0.62-0.80] per 1 SD). The kynurenine-to-tryptophan ratio (KTR), a proxy of indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine and contributes to a proinflammatory status, mediated 42% of the significant association between the antiatherogenic interleukin (IL) 13 and mortality. Adding the three metabolites improved discrimination and reclassification (all P &lt; 0.01) of both mortality prediction models. In type 2 diabetes, hexanoylcarnitine, tryptophan, and kynurenine are associated to and improve the prediction of all-cause mortality. Further studies are needed to investigate whether interventions aimed at reducing KTR also reduce the risk of death, especially in patients with low IL-13

The Synergic Association of hs-CRP and Serum Amyloid P Component in Predicting All-Cause Mortality in Patients With Type 2 Diabetes

Objective: Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes. Research design and methods: Four cohorts comprising 2,499 patients with diabetes (643 all-cause deaths) were analyzed. The improvement of mortality prediction was addressed using two well-established prediction models, namely, EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE) and Risk Equations for Complications of Type 2 Diabetes (RECODe). Results: Both hs-CRP and SAP were independently associated with all-cause mortality (hazard ratios [HRs] [95% CIs]: 1.46 [1.34-1.58] [P &lt; 0.001] and 0.82 [0.76-0.89] [P &lt; 0.001], respectively). Patients with SAP ≤33 mg/L were at increased risk of death versus those with SAP &gt;33 mg/L only if hs-CRP was relatively high (&gt;2 mg/L) (HR 1.96 [95% CI 1.52-2.54] [P &lt; 0.001] and 1.20 [0.91-1.57] [P = 0.20] in hs-CRP &gt;2 and ≤2 mg/L subgroups, respectively; hs-CRP-by-SAP strata interaction P &lt; 0.001). The addition of hs-CRP and SAP significantly (all P &lt; 0.05) improved several discrimination and reclassification measures of both ENFORCE and RECODe all-cause mortality prediction models. Conclusions: In type 2 diabetes, hs-CRP and SAP show opposite and synergic associations with all-cause mortality. The use of both markers, possibly in combination with others yet to be unraveled, might improve the ability to predict the risk of death in the real-life setting

The Genetic Sonogram Today: What is the Role of “Soft Markers” in the Prediction of Down Syndrome?

Background: The aim of this study is to evaluate the role of “soft markers” in the prediction of Down syndrome (DS). Methods: This study includes an unselected population of 1999 pregnant women who requested a fetal karyotype test using amniocentesis at gestational ages ranging from 15 to 20 weeks. Before performing the amniocentesis, an ultrasound examination was conducted to detect the presence of a series of fetal “soft markers.” Results: We identified 148 fetuses affected by DS and 1795 euploid fetuses (control group). The marker found to have the most significant likelihoodratio (LR) was increased nuchal fold. The marker found to have the greatest sensitivity was echogenic intracardiac focus. The other soft markers (as single markers) were not significant. Conclusions: An ultrasound scan cannot diagnose or rule out DS. However, it can be a useful method for modifying the baseline “a priori” probability of DS in any particular patient

Insights from Molecular Characterization of Adult Patients of Families with Multigenerational Diabetes Mellitus

Multigenerational diabetes of the adulthood is a mostly overlooked entity, simplistically comprised in the large basin of type 2 diabetes. The general aim we are pursuing in last years is to unravel the genetic causes of such form of diabetes. Identifying among families with multigenerational diabetes those carrying mutations in known monogenic diabetes genes is the first step to then concentrate on remaining pedigrees where to unravel new diabetogenes.Targeted Next Generation Sequencing of 27 monogenic diabetes-genes has been carried out in 55 family probands and identified mutations verified among their relatives by Sanger sequencing.Nine variants (in 8 probands) survived our filtering/prioritization strategy. After likelihood of causality assessment by established guidelines, 6 variants were classified as "pathogenetic/likely pathogenetic" and 2 as "of uncertain significance".Combining present with our previous data on the six genes causing the most common forms of maturity-onset diabetes of the young allows inferring that 23.6% families with multigenerational diabetes of the adulthood carry mutations in known monogenic diabetes-genes.Our findings indicate that the genetic background of hyperglycemia is unrecognized in the vast majority of families with multigenerational diabetes of the adulthood. These families now become the object of further research aimed at unraveling new diabetogenes