Immunochip analysis identifies novel susceptibility loci in the human leukocyte antigen region for acquired thrombotic thrombocytopenic purpura.

Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case-control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02-3.27, P = 1.64 × 10-14 ). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 × 10-5 to 7.60 × 10-5 ). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 × 10-19 ). Imputation of classic HLA genes followed by stepwise conditional analysis revealed that the combination of rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in acquired TTP. Our results refined the association of the HLA class II locus with acquired TTP, confirming its importance in the etiology of this autoimmune disease.

Correlation between ankle-arm blood pressure index (AAI) and atherosclerotic vascular involvement in coronary arteries.

Several reports indicated that presence of peripheral arterial disease (PAD) and low ankle-arm index (AAI) are independently associated with a substantial increase in cardiovascular mortality, particularly from coronary heart disease (CHD). The goal of the study was to evaluate whether the AAI correlates with extension and severity of the atherosclerotic vascular involvement in coronary arteries. One-hundred and sixty-one male inpatients who consecutively underwent coronary angiography were referred to our Vascular Laboratory for ultrasonographic examination of lower extremity arteries. Coronary artery disease (CAD) was classified by its extent (number of major coronary vessels affected by at least one stenosis of 50% or more) and severity (sum of the maximum percentages of stenosis in each of the major coronary vessels). Differences in AAI and other covariates in relation to extent and severity of CAD were evaluated using univariate and multiple regression analysis. Total cholesterol (p < 0.05) and, inversely, AAI (p < 0.005) were correlated with extent of CAD. Total cholesterol (p < 0.005), LDL-cholesterol (p < 0.05), triglycerides (p < 0.05), diabetes (p < 0.05) and, inversely, AAI (p < 0.005) were correlated with the severity score. After multiple regression analysis including these covariates, AAI was independently and inversely correlated with the extent and severity (for both: p < 0.005) of coronary artery atherosclerotic involvement. The AAI is strongly, independently and inversely correlated with the extent and severity of coronary artery atherosclerosis. We suggest that the determination of the AAI can be of help for identifying patients who are likely to have wide and severe coronary atherosclerosis.

[In-hospital mortality of elderly patients with myocardial infarct. Difference between the sexes]. / Mortalità intraospedaliera in pazienti anziani con infarto miocardico. Differenze tra i due sessi.

The number of women who become ill and die from acute myocardial infarction (AMI) increases steadily with age. It is not yet clearly defined whether and why women suffer from a higher in-hospital mortality rate after AMI. In this study we evaluated the importance of the female sex as a risk factor for in-hospital mortality in elderly patients suffering from AMI. A retrospective study was performed in 724 patients (429 males, 295 females) aged > or = 65 years (mean age 74.9 +/- 6.3 years) consecutively admitted to San Giovanni Battista Hospital in Turin during the period 1988-1991 with validated primary discharge diagnosis of AMI. In-hospital mortality was significantly higher in females (34.6%) compared to males (25.6%, p > 0.01). After multivariate analysis female sex was not independent predictive for in-hospital death. Multivariate analysis was therefore repeated in the various sections of the history of AMI (anamnestic variables, including age and sex: physical signs on admission, ECG findings, laboratory tests, clinical progress, including complications and treatment) in order to identify the factors responsible for the higher mortality rate in women. These were found to be low hemoglobin values (< 12 g/dl) on admission, development of cardiac failure disorders and rhythm disturbances during hospitalization, and differences in therapeutic procedures. In spite of the absence of an independent unfavourable effect of female sex, elderly women with AMI have a higher in-hospital mortality rate. A more precarious state of health on admission, a peculiar susceptibility to severe complications during hospital-stay and differences in therapeutic procedures appear to be the factors responsible for this increased mortality rate in women.

[Associations between arterial hypertension and other cardiovascular risk factors in subjects over 65 years of age]. / Associazione tra ipertensione arteriosa ed altri fattori di rischio cardiovascolare in soggetti ultrasessantacinquenni.

The goal of this study was to evaluate whether in subjects aged 65 or over hypertensive patients have a greater prevalence of risk factors than normotensives. 1369 subjects, aged 65 or over, have been retrospectively investigated. The following risk factors were considered: cigarette smoking, left ventricular hypertrophy, diabetes mellitus and atrial fibrillation (analyzed as dichotomous variables), B.M.I., blood concentration of total, -LDL-HDL cholesterol, triglycerides and total/HDL cholesterol ratio (analyzed as continuous variables). The mean number of risk factors was calculated in hypertensive and normotensive subjects; the association between hypertension and risk factors was evaluated using univariate and multiple logistic regression analysis. 451 subjects (32.9%) were found to be hypertensives. The average number of risk factors was significantly greater in hypertensive than in normotensive subjects (1.85 +/- 1.27 vs 1.39 +/- 1.15, p < 0.001), and, in both groups, in men than in women. Left ventricular hypertrophy (p < 0.001), total cholesterol (p < 0.001), diabetes mellitus (p < 0.001) and atrial fibrillation (p < 0.01) were found to be independently associated with the presence of hypertension. We concluded that among the elderly there is a greater prevalence of risk factors in hypertensive than in normotensive subjects and that some risk factors--left ventricular hypertrophy, atrial fibrillation, diabetes mellitus, and blood levels of atherogenic lipids--are independently associated with the presence of hypertension.