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We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.

Background The platelet P2Y12 receptor plays a key role in platelet activation. The H2 haplotype of the P2Y12 receptor gene (P2RY12) has been found to be associated with maximal aggregation response to adenosine diphosphate (ADP) and with increased risk for peripheral arterial disease. No data are available on its association with coronary artery disease (CAD). Methods The H2 haplotype of the P2RY12 was determined in 1378 unrelated patients of both sexes selected according to the presence of significant coronary artery disease (CAD group) or having normal coronary angiogram at cardiac catheterization (CAD-free group). Significant coronary artery disease was angiographically determined, and was defined as a greater than 50% visually estimated luminal diameter stenosis in at least one major epicardial coronary artery. Results In the studied population 71.9% had CAD (n = 991) and 28.1% had normal coronary angiogram (n = 387). H2 haplotype carriers were more frequent in the CAD group (p = 0.03, OR = 1.36, 95%CI = 1.02–1.82). The H2 haplotype was significantly associated with CAD in non-smokers (p = 0.007, OR = 1.83 95%CI = 1.17–2.87), but not in smokers. The association remained significant after adjustment for other covariates (age, triglycerides, HDL, hypertension, diabetes) by multivariate logistic regression (p = 0.004, OR = 2.32 95%CI = 1.30–4.15). Conclusion Gene sequence variations of the P2Y12 receptor gene are associated with the presence of significant CAD, particularly in non-smoking individuals.

The suppression of Ph1-positive hemopoiesis is a major goal in the treatment of CML; in this context the CML patients in blast crisis obtaining a complete clinical remission represent a useful model to investigate the behavior of the Ph1-positive and negative clones during bone marrow repopulation after ablative therapy.Seven CML patients in blast crisis (four lymphoid and three myeloid) who obtained a complete clinical remission after an intensive polychemotherapy treatment were evaluated by cytogenetic and molecular analysis both in blast and remission phases. Standard cytogenetic and Southern techniques were employed; in addition, minimal residual disease status (MRD) was ascertained by amplification (PCR) of the specific bcr-abl chimeric transcripts.After a single cycle of induction, all lymphoid cases displayed a complete restoration of Ph1-negative hemopoiesis; by contrast, one myeloid blast crisis showed a partial suppression of Ph1-positive hemopoiesis only after two cycles of chemotherapy, and in the remaining two cases the hematological remission was indeed a reversion to the chronic phase.Ph1-positive chronic clones present in lymphoid blast crisis showed a higher degree of sensitivity to intensive chemotherapy than those present in the myeloid cases. This observation further suggests that the growth properties of the Ph1-positive clones are highly variable from case to case and probably tend to progress during the time-course of the disease.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis. The initial experiments were supported by the DFG (Wi 2036/1-1). This work was supported by the Sonnenfeld-Stiftung, Berlin, Germany (to H.W.), the US National Institutes of Health (NIH) (grant DK058088 to M.S.-T.), INSERM (Institut National de la Santé et de la Recherche Médicale) and the Programme Hospitalier de Recherche Clinique (grant PHRC R 08-04 to C.F.)