Levels of Prebeta-1 High-Density Lipoprotein Are a Strong Independent Positive Risk Factor for Coronary Heart Disease and Myocardial Infarction: A Meta-Analysis.

Background We previously showed that levels of prebeta-1 high-density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from cells, including artery wall macrophages, are positively associated with coronary heart disease (CHD) and myocardial infarction (MI) risk. Methods and Results In a multiethnic follow-up cohort of 1249 individuals from University of California-San Francisco clinics, we determined the degree to which prebeta-1 HDL levels, both absolute and percentage of apolipoprotein AI, are associated with CHD and history of MI. Independent, strong, positive associations were found. Meta-analysis revealed for the absolute prebeta-1 HDL for the top tertile versus the lowest, unadjusted odds ratios of 1.90 (95% CI, 1.40-2.58) for CHD and 1.79 (95% CI, 1.35-2.36) for MI. For CHD, adjusting for established risk factors, the top versus bottom tertiles, quintiles, and deciles yielded sizable odds ratios of 2.37 (95% CI, 1.74-3.25, P<0.001), 3.20 (95% CI, 2.07-4.94, P<0.001), and 4.00 (95% CI, 2.11-7.58, P<0.001), respectively. Men and women were analyzed separately in a combined data set of 2507 individuals. The odds ratios for CHD and MI risk were similar. Higher levels of prebeta-1 HDL were associated with all 5 metabolic syndrome features. Addition of prebeta-1 HDL to these 5 features resulted in significant improvements in risk-prediction models. Conclusions Analysis of 2507 subjects showed conclusively that levels of prebeta-1 HDL are strongly associated with a history of CHD or MI, independently of traditional risk factors. Addition of prebeta-1 HDL can significantly improve clinical assessment of risk of CHD and MI.

Combatting professional burnout through creative writing.

Physician burnout is becoming an increasing problem. In fact, nearly half of all physicians feel completely depleted, to the point where one in seven has contemplated suicide. Causes for burnout development include: administrative overload, regulatory restrictions, loss of autonomy or control, workplace issues, decreased access to medicines for patients, and electronic medical records. On the opposite end of this spectrum is physician fulfillment. Creative writing can be a therapeutic method of self-fulfillment. This may provide not only focused relief from burnout but also another possible avenue for success for multitalented people such as physicians.

Neuroprotective profile of novel SRC kinase inhibitors in rodent models of cerebral ischemia.

Src kinase signaling has been implicated in multiple mechanisms of ischemic injury, including vascular endothelial growth factor (VEGF)-mediated vascular permeability that leads to vasogenic edema, a major clinical complication in stroke and brain trauma. Here we report the effects of two novel Src kinase inhibitors, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile (SKI-606) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methypiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927), on ischemia-induced brain infarction and short- and long-term neurological deficits. Two well established transient [transient middle cerebral artery occlusion (tMCAO)] and permanent [permanent middle cerebral artery occlusion (pMCAO)] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario. Brain penetration of Src inhibitors, their effect on blood-brain barrier integrity and VEGF signaling in human endothelial cells were also evaluated. Our results demonstrate that both agents potently block VEGF-mediated signaling in human endothelial cells, penetrate rat brain upon systemic administration, and inhibit postischemic Src activation and vascular leakage. Treatment with SKI-606 or SKS-927 (at the doses of 3-30 mg/kg i.v.) resulted in a dose-dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4- to 6-h after tMCAO. Src blockade after pMCAO resulted in accelerated improvement in recovery from motor, sensory, and reflex deficits during a long-term (3 weeks) testing period poststroke. These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke.

Src inhibition ameliorates polycystic kidney disease.

Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60(c-Src)) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation. With the use of the nonorthologous BPK murine model and the orthologous PCK rat model of ARPKD, greater Src activity was found to correlate with disease progression. Inhibition of Src activity with the pharmacologic inhibitor SKI-606 resulted in amelioration of renal cyst formation and biliary ductal abnormalities in both models. Furthermore, the effects of Src inhibition in PCK kidneys suggest that the ErbB2 and B-Raf/MEK/ERK pathways are involved in Src-mediated signaling in ARPKD and that this occurs without reducing elevated cAMP. These data suggest that Src inhibition may provide therapeutic benefit in PKD.

Globe-LFMC, a global plant water status database for vegetation ecophysiology and wildfire applications.

Globe-LFMC is an extensive global database of live fuel moisture content (LFMC) measured from 1,383 sampling sites in 11 countries: Argentina, Australia, China, France, Italy, Senegal, Spain, South Africa, Tunisia, United Kingdom and the United States of America. The database contains 161,717 individual records based on in situ destructive samples used to measure LFMC, representing the amount of water in plant leaves per unit of dry matter. The primary goal of the database is to calibrate and validate remote sensing algorithms used to predict LFMC. However, this database is also relevant for the calibration and validation of dynamic global vegetation models, eco-physiological models of plant water stress as well as understanding the physiological drivers of spatiotemporal variation in LFMC at local, regional and global scales. Globe-LFMC should be useful for studying LFMC trends in response to environmental change and LFMC influence on wildfire occurrence, wildfire behavior, and overall vegetation health.

Author Correction: Globe-LFMC, a global plant water status database for vegetation ecophysiology and wildfire applications.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Levels of prebeta-1 high-density lipoprotein are elevated in 3 phenotypes of dyslipidemia.

BACKGROUND: Prebeta-1 high-density lipoprotein (HDL) is a small subspecies of HDL that functions as the HDL quantum particle and is the principal acceptor of cholesterol effluxed from macrophages through the ATP-binding cassette transporter, ABCA1. High levels of prebeta-1 HDL are associated with increased risk of structural coronary artery disease and myocardial infarction. OBJECTIVE: We aimed to compare prebeta-1 HDL levels in normal subjects and in 3 phenotypes of dyslipidemia. METHODS: We studied 2435 individuals (1388 women; 1047 men). Of these, 2018 were not taking lipid-lowering medication when enrolled: 392 were normolipidemic controls; 713 had elevated levels of low-density lipoprotein cholesterol; 623 had combined hyperlipidemia; and 290 had hypertriglyceridemia. RESULTS: Relative to controls, prebeta-1 HDL levels were increased in all 3 dyslipidemic phenotypes, particularly the combined and hypertriglyceridemia groups. This increase possibly reflects increased acceptor capacity of apolipoprotein B-100 containing lipoproteins for entropically driven transfer of cholesteryl esters from HDL via cholesteryl ester transfer protein. Multiple regression analysis revealed that the main predictor variables significantly associated with prebeta-1 HDL levels were apolipoprotein A-I (apoA-1) (ß = 0.500), triglyceride (ß = 0.285), HDL-C (ß = -0.237), and age (ß = -0.169). There was an interaction between apoA-1 and sex (female vs male; ß = -0.110). Among postmenopausal women, estrogenized subjects had a similar level of prebeta-1 HDL compared to those not receiving estrogens. CONCLUSIONS: Prebeta-1 HDL levels are elevated in the 3 most common types of hyperlipidemia and are most strongly influenced by the levels of apoA-1, triglyceride, and HDL-C.

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease.

AIM: To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD). METHODS: We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis. RESULTS: This study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity. CONCLUSION: The data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice.

Constitutive tyrosine kinase activity of Bcr-Abl promotes proliferation and survival of chronic myelogenous leukemia (CML) cells. Inhibition of Bcr-Abl tyrosine kinase activity or signaling proteins activated by Bcr-Abl in CML cells blocks proliferation and causes apoptotic cell death. The selective Abl kinase inhibitor, STI-571 (marketed as Gleevec), is toxic to CML cells in culture, causes regression of CML tumors in nude mice, and is currently used to treat CML patients. Here we describe a p.o. active, dual Src/Abl kinase inhibitor with potent antiproliferative activity against CML cells in culture. This 4-anilino-3-quinolinecarbonitrile (SKI-606) ablates tyrosine phosphorylation of Bcr-Abl in CML cells and of v-Abl expressed in fibroblasts. SKI-606 inhibits phosphorylation of cellular proteins, including STAT5, at concentrations that inhibit proliferation in CML cells. Phosphorylation of the autoactivation site of the Src family kinases Lyn and/or Hck is also reduced by treatment with SKI-606. Once daily oral administration of this compound at 100 mg/kg for 5 days causes complete regression of large K562 xenografts in nude mice.

Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors.

HM74 (GPR109B) and the highly homologous gene, HM74A (GPR109A) code for Gi-G protein-coupled orphan receptors that recently have been discovered to be involved in the metabolic effects of niacin. The B vitamin niacin is an important agent used in the treatment of dyslipidemias, but its use is limited by side effects. The novel role of the adjacent HM74 and HM74A genes in the metabolism of niacin may provide new targets for drug development. Human genetic variations in HM74 and HM74A have been reported but have not been studied in detail. These variations may play a role in the response to agents targeting receptors coded by these genes. Here we show that many of the nonsynonymous SNPs listed in public databases for HM74 and HM74A are artifacts resulting from extensive homology between these two genes. This may be representative of a neglected phenomenon in reporting sequences of highly homologous genes. We provide primer sequences that permit selective amplification of the complete coding regions of HM74 and HM74A. Using these primers, we show that subsequent sequencing of HM74 and HM74A reveals a novel and unique variation in the HM74A gene. Haplotype analysis suggests four SNPs can define the five major haplotypes that lie within a single haplotype block encompassing these two genes.

PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors.

Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.

Antibody-targeted chemotherapy with the calicheamicin conjugate hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide targets Lewisy and eliminates Lewisy-positive human carcinoma cells and xenografts.

PURPOSE: Linking a cytotoxic anticancer drug to an antibody that recognizes a tumor-associated antigen can improve the therapeutic index of the drug. We asked whether a conjugate of the cytotoxic antibiotic N-acetyl gamma calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewis(y) (Le(y)) antigen could eliminate carcinomas that express Le(y). Because Le(y) is highly expressed on carcinomas of colon, breast, lung, ovary, and prostate, a CalichDMH conjugate targeting Le(y) could provide a treatment option for various cancers. EXPERIMENTAL DESIGN: The humanized anti-Le(y) antibody hu3S193 was conjugated to CalichDMH via the bifunctional AcBut linker. Selectivity and avidity of the conjugate (hu3S193-CalichDMH) for Le(y)-BSA or Le(y+) cells was tested by BIAcore or flow cytometry. Cytotoxicity of hu3S193-CalichDMH was compared with toxicity of a control conjugate on monolayers of Le(y+) and Le(y-) carcinoma cells. Inhibition of tumor growth by hu3S193-CalichDMH was assessed on three types of s.c. xenografts. RESULTS: Hu3S193-CalichDMH had similar selectivity as hu3S193. The conjugate had lower affinity for Le(y)-BSA but not for Le(y+) cells. When tested on monolayers of human Le(y+) carcinoma cells, hu3S193-CalichDMH was more cytotoxic than a control conjugate. This difference in efficacy was not noted on Le(y-) cells. Efficacy of hu3S193-CalichDMH depended on the expression of Le(y) and on the sensitivity of the cells to CalichDMH. In vivo, hu3S193-CalichDMH inhibited growth of xenografted human gastric (N87), colon (LOVO), and prostate carcinomas (LNCaP). When used against N87 xenografts, hu3S193-CalichDMH arrested tumor growth for at least 100 days. CONCLUSION: Hu3S193-CalichDMH can specifically eliminate Le(y+) tumors. These results support development of this conjugate for treatment of carcinomas.

Antibody-targeted chemotherapy with immunoconjugates of calicheamicin.

Targeted delivery of cytotoxic agents to tumours is believed to improve both their anti-tumour efficacy and their safety. Antibodies specific for tumour-associated antigens have been used to deliver cytotoxic agents to tumour cells. Calicheamicin is a potent cytotoxic agent that causes double-strand DNA breaks, resulting in cell death. When conjugated to monoclonal antibodies specific for tumour-associated antigens, calicheamicin exerts strong antigen-specific anti-tumour effects against human tumour xenografts in preclinical models. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin, exemplified by gemtuzumab ozogamicin (Mylotarg), is a clinically validated therapeutic strategy for the treatment of human cancer.

Identification and metabolic profiling of patients with lysosomal acid lipase deficiency.

BACKGROUND: Lysosomal acid lipase (LAL), encoded by the LIPA gene, catalyzes the intracellular hydrolysis of cholesteryl esters and triglycerides in hepatocytes and macrophages. LIPA defects cause accumulation of these lipids in lysosomes. LAL deficiency (LAL D) presents and progresses as a continuum with dyslipidemia, hepatomegaly, and liver fibrosis. OBJECTIVE: To improve the understanding of the genetic basis of LAL D, an underappreciated cause of dyslipidemia and cirrhosis, we studied DNA samples from patients with various phenotypes of dyslipidemia. METHODS: Participants (N = 1357) were identified by lipid profiles and screened for the common disease causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232). RESULTS: Six patients were heterozygous for this variant. Complete LIPA sequencing revealed a patient, subsequently confirmed to have LAL D, with a heterozygous frameshift mutation involving deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and phenotype. Genetic, clinical, and lipoprotein profiles of these sisters plus 6 additional family members are reported. Profiles of 2 other LAL D patients monitored for 2 decades are presented. Cholesterol homeostasis was studied to investigate rates of cholesterol synthesis and absorption in 4 LAL D patients. High-density lipoprotein (HDL) subspecies were also analyzed. CONCLUSIONS: We used this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to identify additional mutations) as a means to further elucidate the genetic basis of LAL D among individuals with a suggestive clinical phenotype.

Identification and validation of novel androgen-regulated genes in prostate cancer.

Androgen-regulated genes (ARGs) are essential for the development of the prostate. Ironically, ARGs are also responsible for the pathogenesis of prostate cancer. We used oligonucleotide array technology to study the expression profiles of ARGs in LNCaP prostate cancer cells and identified 692 dihydrotestosterone-regulated genes. Representative clusters containing genes with similar expression patterns to prostate-specific antigen and other known ARGs are discussed. Based on functional information, we categorized several candidate targets for prostate cancer therapy and diagnosis. Although many of these candidate targets are known to play an important role in cancer development, several are novel genes to the field of prostate cancer. A cross-comparison study of our results with those that have been previously published from three other array experiments using a similar LNCaP model validated 13 of these candidate targets as androgen-regulated. FKBP51 (FK506-binding immunophilin 51) was found in the same cluster as prostate-specific antigen and its protein expression was increased in LNCaP cells treated with either dihydrotestosterone or synthetic androgen R1881. Results from mining the Gene Logic BioExpress database showed that FKBP51 expression is significantly higher in the prostate cancer group than in the normal and normal adjacent group. Additionally, the androgen-independent prostate tumor xenograft, CWR22R, had higher FKBP51 protein levels than that of the androgen-dependent prostate tumor xenograft, CWR22. A tissue microarray study further revealed that FKBP51 protein expression was higher in prostate cancer specimens than in benign prostate tumor samples. These results suggest the potential value of FKBP51 as a novel diagnostic marker or target for prostate cancer therapy.

Targeting vascular and avascular compartments of tumors with C. novyi-NT and anti-microtubule agents.

Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that C. novyi-NT in combination with anti-microtubule agents can cause the destruction of both the vascular and avascular compartments of tumors. The two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with C. novyi-NT. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by C. novyi-NT. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which C. novyi-NT spores could germinate. A single intravenous injection of C. novyi-NT plus selected anti-microtubule agents was able to cause regressions of several human tumor xenografts in nude mice in the absence of excessive toxicity.

Reduced expression of EphrinA1 (EFNA1) inhibits three-dimensional growth of HT29 colon carcinoma cells.

Ephrin A1 (EFNA1) is a GPI-anchored ligand that preferentially binds to the receptor tyrosine kinase, EphA2. EphA2 is over-expressed in malignant melanocytes and in prostate carcinoma cells. Whether activation of EphA2 by EFNA1 is involved in aberrant growth or differentiation of cancer cells is currently not known. We studied the effect of reducing EFNA1 on the growth of a colon carcinoma cell line (HT29). HT29 cells were transfected with EFNA1 antisense yielding clones that expressed less than 25% of EFNA1 found in vector controls. EFNA1-antisense transfectants grew slower than controls when cultured as three-dimensional spheroids. When grown as monolayers, the transfectants had a similar doubling time of the vector controls. These results indicated that autocrine stimulation of EphA2 by EFNA1 could trigger an indirect growth signal by overcoming 'contact inhibition'. Following addition of EFNA1-Fc to HT29 cells, tyrosine hyperphosphorylation of EphA2, E-cadherin, and beta-catenin were observed. Because the function of E-cadherin is associated with contact inhibition of HT29 cells, phosphorylation of E-cadherin and beta-catenin by activation of EphA1 is one possible mechanism by which HT29 cells alleviate contact inhibition.

Flooding patterns of the Okavango Wetland in Botswana between 1972 and 2000.

The inundated area of the Okavango Delta changes annually and interannually. The variability relates to regional precipitation over the catchment area in the Angolan highlands, and to local rainfall. The patterns of the wetland were captured using more than 3000 satellite images for the period 1972 to 2000, near daily NOAA AVHRR data for 1985-2000, and less frequent images of the Landsat sensors from 1972 onwards. One AVHRR image for every 10-day period was classified into land and water using an unsupervised classification method. Evaluation against Landsat TM and ERS2-ATSR data indicate an agreement of 89% for the size of estimated inundation area. Results show that the wetland area has varied between approximately 2450 km2 and 11400 km2 during the last 30 years.

Evidence that an HMGA1 gene variant associates with type 2 diabetes, body mass index, and high-density lipoprotein cholesterol in a Hispanic-American population.

BACKGROUND: High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans. METHODS: This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI). RESULTS: In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09-1.90, P=0.011). The variant was also associated with BMI (positively, P=0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P=0.047). CONCLUSIONS: As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency.

Relation of increased prebeta-1 high-density lipoprotein levels to risk of coronary heart disease.

Preß-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preß-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preß-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preß-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preß-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preß-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preß-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preß-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preß-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preß-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.