Our previous genomewide linkage scan of 428 nuclear families (GeneQuest) identified a significant genetic susceptibility locus for premature myocardial infarction (MI) on chromosome 1p34-36. We analyzed candidate genes in the locus with a population-based association study involving probands with premature coronary artery disease (CAD) and/or MI from the GeneQuest families (381 cases) and 560 controls without stenosis detectable by coronary angiography. A nonconservative substitution, R952Q, in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. Three additional white populations were used for follow-up replication studies: another independent cohort of CAD- and/or MI-affected families (GeneQuest II: 441 individuals from 22 pedigrees), an Italian cohort with familial MI (248 cases) and 308 Italian controls, and a separate Cleveland GeneBank cohort with sporadic MI (1,231 cases) and 560 controls. The association was significantly replicated in two independent populations with a family history of CAD and/or MI, the GeneQuest II family-based replication cohort and the Italian cohort, but not in the population with sporadic disease. The R952Q variant of LRP8 increased activation of p38 mitogen-activated protein kinase by oxidized low-density lipoprotein. This extensive study, involving multiple independent populations, provides the first evidence that genetic variants in LRP8 may contribute to the development of premature and familial CAD and MI.

The lymphocyte-monocyte ratio (LMR) is a systemic inflammatory marker for prediction of disease development, progress, and survival. Recently, a genome-wide association study identified genetic variations in ITGA4 and HLA-DRB1 that affect the LMR levels and were widely believed to be susceptibility genes for autoimmune diseases, including rheumatoid arthritis (RA). However, the role of LMR in RA patients remains unclear. The LMR level and other laboratory data of 66 RA patients, 163 osteoarthritis (OA) patients, and 131 healthy controls (HC) were compared using binary logistic regression. The correlations between LMR and disease activity and other inflammatory markers were measured using the Spearman rank test. ROC curve analyses assessed the diagnostic accuracy of LMR in RA. The LMR and lymphocyte count were significantly lower in RA patients, whereas the monocyte count was significantly higher relative to the HC group/OA patients (p < 0.01). A decreased LMR has been associated with increased disease activity (p = 0.012). In addition, the DAS28 and traditional inflammatory markers, including ESR, CRP, RDW, PLR, and NLR, and immune-related factors, such as C4, IgA, and IgM, were inversely correlated with LMR, while hemoglobin and albumin were positively correlated with LMR. The ROC curve showed that the area under the curve of LMR was 0.705 (95%CI = 0.630-0.781). The corresponding specificity and sensitivity were 82.82 and 45.45%, respectively. The present study shows that the LMR is an important inflammatory marker which could be used to identify disease activity in RA patients and to distinguish RA from OA patients.

These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.

AGGF1 is an angiogenic factor, and its deregulation is associated with a vascular malformation consistent with KlippelTrenaunay syndrome (KTS). This study defines the molecular mechanism for transcriptional regulation of AGGF1 expression. Transcription of AGGF1 starts at two nearby sites, ؊367 and ؊364 bp upstream of the translation start site. Analyses of 5-and 3-serial promoter deletions defined the core promoter/regulatory elements, including two repressor sites (from ؊1971 to ؊3990 and from ؊7521 to ؊8391, respectively) and two activator sites (a GATA1 consensus binding site from ؊295 to ؊300 and a second activator site from ؊129 to ؊159). Both the GATA1 site and the second activator site are essential for AGGF1 expression. A similar expression profile was found for GATA1 and AGGF1 in cells (including various endothelial cells) and tissues. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrated that GATA1 was able to bind to the AGGF1 DNA in vitro and in vivo. Overexpression of GATA1 increased expression of AGGF1. We identified one rare polymorphism ؊294C>T in a sporadic KTS patient, which is located in the GATA1 site, disrupts binding of GATA1 to DNA, and abolishes the GATA1 stimulatory effect on transcription of AGGF1. Knockdown of GATA1 expression by siRNA reduced expression of AGGF1, and resulted in endothelial cell apoptosis and inhibition of endothelial capillary vessel formation and cell migration, which was rescued by purified recombinant human AGGF1 protein. These results demonstrate that GATA1 regulates expression of AGGF1 and reveal a novel role for GATA1 in endothelial cell biology and angiogenesis.The AGGF1 gene, previously known as VG5Q, encodes an angiogenic factor with 714 amino acid residues (1). AGGF1 was identified through genetic analysis of Klippel-Trenaunay syndrome (KTS, MIM #149000), 2 which is a congenital vascular disorder composed of capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues (2-5). KTS is a congenital disorder, but most cases are sporadic. The genetic basis of KTS is complex and may involve multiple genes, environmental factors, and their interactions (6). To date, identification of susceptibility genes associated with KTS has relied upon gross cytogenetic defects reported in KTS patients. Three chromosomal abnormalities have been identified in three separate KTS patients: two balanced translocations t(5.11)(q13.3;p15.1) and t(8,14)(q22.3;q13), and an extra supernumerary ring chromosome 18 (7-9). Chromosomal breakpoints involved in KTS translocation t(5;11)(q13.3; p15.1) have been fully characterized. No gene has been identified within a 100-kb region flanking the chromosome 11p15.1 translocation breakpoint. In contrast, the chromosome 5p13.3 breakpoint is located in the promoter/regulatory region of the AGGF1 gene and leads to increased transcriptional activation of AGGF1 by 3-fold (1). The results suggest that deregulation of AGGF1 is associated with KTS. However, the molecular mech...