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1.  Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity 
Diabetes  2014;63(12):4378-4387.
We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance and secretion, and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs-per-allele [95%CI]:−0.03[−0.04,−0.01];p=0.004). This score was associated with lower BMI (−0.01[−0.01,−0.0;p=0.02) and gluteofemoral fat-mass (−0.03[−0.05,−0.02;p=1.4×10−6), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (0.02[0.01,0.03];p=0.001). While the secretion score had a stronger association with T2D in leaner individuals (pinteraction=0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI- or waist-strata(pinteraction>0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
PMCID: PMC4241116  PMID: 24947364
Genetics; type 2 diabetes; insulin resistance; insulin secretion; adipose expandability
2.  Pregnancy complications in acquired thrombotic thrombocytopenic purpura: a case–control study 
Pregnant women with a history of acquired thrombotic thrombocytopenic purpura (TTP) are considered at risk for disease recurrence and might be at risk for miscarriage, similar to other autoimmune disorders. However, the exact entity of these risks and their causes are unknown. The aim of this study was to evaluate risk factors associated with adverse pregnancy outcome, in terms of both gravidic TTP and miscarriage, in women affected by previous acquired TTP.
We conducted a nested case–control study in women with a history of acquired TTP enrolled in the Milan TTP registry from 1994 to October 2012, with strict inclusion criteria to reduce referral and selection bias.
Fifteen out of 254 women with acquired TTP were included, namely four cases with gravidic TTP, five with miscarriage, and six controls with uncomplicated pregnancy. In the cases, ADAMTS13 activity levels in the first trimester were moderately-to-severely reduced (median levels <3% in gravidic TTP and median levels 20% [range 14-40%] in the women with miscarriage) and anti-ADAMTS13 antibodies were invariably present, while in the control group ADAMTS13 activity levels were normal (median 90%, range 40-129%), with absence of detectable anti-ADAMTS13 antibodies. Reduced levels of ADAMTS13 activity (<25%) in the first trimester were associated with an over 2.9-fold increased risk for gravidic TTP and with an over 1.2-fold increased risk for miscarriage (lower boundary of the confidence interval of the odds ratio). In addition, the presence of anti-ADAMTS13 antibodies during pregnancy was associated with an over 6.6-fold increased risk for gravidic TTP and with an over 4.1-fold increased risk for miscarriage.
ADAMTS13 activity evaluation and detection of anti-ADAMTS13 antibody could help to predict the risk of complications in pregnant women with a history of acquired TTP.
PMCID: PMC4279798  PMID: 25431165
ADAMTS13; Anti-ADAMTS13 antibodies; Miscarriage; Pregnancy; Thrombotic thrombocytopenic purpura
3.  Preoperative Hematocrit Concentration and the Risk of Stroke in Patients Undergoing Isolated Coronary-Artery Bypass Grafting 
Anemia  2013;2013:206829.
Background. Identification and management of risk factors for stroke following isolated coronary artery bypass grafting (CABG) could potentially lower the risk of such serious morbidity. Methods. We retrieved data for 30-day stroke incidence and perioperative variables for patients undergoing isolated CABG and used multivariate logistic regression to assess the adjusted effect of preoperative hematocrit concentration on stroke incidence. Results. In 2,313 patients (mean age 65.9 years, 73.6% men), 43 (1.9%, 95% CI: 1.4–2.5) developed stroke within 30 days following CABG (74.4% within 6 days). After adjustment for a priori defined potential confounders, each 1% drop in preoperative hematocrit concentration was associated with 1.07 (95% CI: 1.01–1.13) increased odds for stroke (men, OR: 1.08, 95% CI: 1.01–1.16; women, OR: 1.02, 95% CI: 0.91–1.16). The predicted probability of stroke for descending preoperative hematocrit concentration exceeded 2% for values <37% (<37% for men (adjusted OR: 2.39, 95% CI: 1.08–5.26) and <38% for women (adjusted OR: 2.52, 95% CI: 0.53–11.98), with a steeper probability increase noted in men). The association between lower preoperative hematocrit concentration and stroke was evident irrespective of intraoperative transfusion use. Conclusion. Screening and management of patients with low preoperative hematocrit concentration may alter postoperative stroke risk in patients undergoing isolated CABG.
PMCID: PMC3657438  PMID: 23738059
4.  Prevalence of Disease and Relationships between Laboratory Phenotype and Bleeding Severity in Platelet Primary Secretion Defects 
PLoS ONE  2013;8(4):e60396.
The prevalence of platelet primary secretion defects (PSD) among patients with bleeding diathesis is unknown. Moreover, there is paucity of data on the determinants of bleeding severity in PSD patients.
To determine the prevalence of PSD in patients with clinical bleeding and to study the relationships between the type of platelet defect and bleeding severity.
Data on patients referred for bleeding to the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan (Italy) in the years between 2008 and 2012 were retrieved to study the prevalence of PSD. Demographic, clinical and laboratory information on 32 patients with a diagnosis of PSD was used to compare patients with or without associated medical conditions and to investigate whether or not the type and extension of platelet defects were associated with the bleeding severity score (crude and age-normalized) or with the age at first bleeding requiring medical attention.
The estimated prevalence of PSD among 207 patients with bleeding diathesis and bleeding severity score above 4 was 18.8% (95% confidence interval [CI]: 14.1–24.7%). Patients without associated medical conditions had earlier age of first bleeding (18 vs 45 years; difference: -27 years; 95% CI: -46 to -9 years) and different platelet functional defect patterns (Fisher's exact test of the distribution of patterns, P = 0.007) than patients with accompanying medical conditions. The type and extension of platelet defect was not associated with the severity of bleeding.
PSD is found in approximately one fifth of patients with clinical bleeding. In patients with PSD, the type and extension of laboratory defect was not associated with bleeding severity.
PMCID: PMC3614926  PMID: 23565241
5.  Identification of genetic risk variants for deep vein thrombosis by multiplexed next-generation sequencing of 186 hemostatic/pro-inflammatory genes 
Next-generation DNA sequencing is opening new avenues for genetic association studies in common diseases that, like deep vein thrombosis (DVT), have a strong genetic predisposition still largely unexplained by currently identified risk variants. In order to develop sequencing and analytical pipelines for the application of next-generation sequencing to complex diseases, we conducted a pilot study sequencing the coding area of 186 hemostatic/proinflammatory genes in 10 Italian cases of idiopathic DVT and 12 healthy controls.
A molecular-barcoding strategy was used to multiplex DNA target capture and sequencing, while retaining individual sequence information. Genomic libraries with barcode sequence-tags were pooled (in pools of 8 or 16 samples) and enriched for target DNA sequences. Sequencing was performed on ABI SOLiD-4 platforms. We produced > 12 gigabases of raw sequence data to sequence at high coverage (average: 42X) the 700-kilobase target area in 22 individuals. A total of 1876 high-quality genetic variants were identified (1778 single nucleotide substitutions and 98 insertions/deletions). Annotation on databases of genetic variation and human disease mutations revealed several novel, potentially deleterious mutations. We tested 576 common variants in a case-control association analysis, carrying the top-5 associations over to replication in up to 719 DVT cases and 719 controls. We also conducted an analysis of the burden of nonsynonymous variants in coagulation factor and anticoagulant genes. We found an excess of rare missense mutations in anticoagulant genes in DVT cases compared to controls and an association for a missense polymorphism of FGA (rs6050; p = 1.9 × 10-5, OR 1.45; 95% CI, 1.22-1.72; after replication in > 1400 individuals).
We implemented a barcode-based strategy to efficiently multiplex sequencing of hundreds of candidate genes in several individuals. In the relatively small dataset of our pilot study we were able to identify bona fide associations with DVT. Our study illustrates the potential of next-generation sequencing for the discovery of genetic variation predisposing to complex diseases.
PMCID: PMC3305575  PMID: 22353194
Deep vein thrombosis; venous thromboembolism; next-generation sequencing; target capture; multiplexing; FGA; rs6025; heamostateome; DVT; VTE
6.  Genome-Wide Association Studies in Myocardial Infarction and Coronary Artery Disease 
Myocardial infarction (MI) and its major determinant, coronary artery disease (CAD), are complex diseases arising from the interaction between several genetic and environmental factors. Until recently, the genetic basis of these diseases was poorly understood. Genome-wide genetic association studies have afforded a comprehensive insight into the association between genetic variants and diseases. To date, seven genome-wide association studies have been conducted in CAD/MI, identifying thirteen genomic regions at which common genetic variants influence the predisposition to these diseases. This review article summarizes the progress achieved in the genetic basis of MI and CAD by means of genome-wide association studies and the potential clinical applications of these findings.
PMCID: PMC3466835  PMID: 23074578
Genome-wide association study; Myocardial infarction; Coronary artery disease

Results 1-6 (6)