ZAP-70 and CD38 expression are independent prognostic factors in patients with B-cell chronic lymphocytic leukaemia and combined analysis improves their predictive value.

Recently identified biological risk factors in B-cell chronic lymphocytic leukemia (B-CLL) include ZAP-70 and CD38 expression. The present study was conducted to clarify whether a combined analysis could improve predictive impact of these two parameters. We examined the expression of ZAP-70 and CD38 by flow cytometry method in 217 newly diagnosed, consecutive, unselected and well characterized B-CLL patients in relation to laboratory parameters and clinical outcome. We confirmed that both ZAP-70 as well as CD38 were independent of prognostic factors. There was a significant correlation between the percentage of leukemic cells positive for ZAP-70 and the percentage of CD38+CD19+ cells (R=0.629; p=0.000001). Combined analysis of ZAP-70 and CD38 showed concordant results in 158/217 patients (72.8%), while in 59 patients the results were discordant (27.2%). A mean treatment free survival (TFS) was the longest in ZAP-70-CD38-patients (45.6 months, comparing to 13.6 months in ZAP-70+CD38+ group). Also a mean overall survival was the longest in ZAP-70-CD38- patients (224.7 months compared to 77.9 months in ZAP-70+CD38+ patients)

ZAP-70 and CD38 expression are independent prognostic factors in patients with B-cell chronic lymphocytic leukaemia and combined analysis improves their predictive value.

Recently identified biological risk factors in B-cell chronic lymphocytic leukemia (B-CLL) include ZAP-70 and CD38 expression. The present study was conducted to clarify whether a combined analysis could improve predictive impact of these two parameters. We examined the expression of ZAP-70 and CD38 by flow cytometry method in 217 newly diagnosed, consecutive, unselected and well characterized B-CLL patients in relation to laboratory parameters and clinical outcome. We confirmed that both ZAP-70 as well as CD38 were independent of prognostic factors. There was a significant correlation between the percentage of leukemic cells positive for ZAP-70 and the percentage of CD38+CD19+ cells (R=0.629; p=0.000001). Combined analysis of ZAP-70 and CD38 showed concordant results in 158/217 patients (72.8%), while in 59 patients the results were discordant (27.2%). A mean treatment free survival (TFS) was the longest in ZAP-70-CD38-patients (45.6 months, comparing to 13.6 months in ZAP-70+CD38+ group). Also a mean overall survival was the longest in ZAP-70-CD38- patients (224.7 months compared to 77.9 months in ZAP-70+CD38+ patients)

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis