WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels.

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.

Identification of a novel human cellular HDL biosynthesis defect.

AIMS: Severe high-density lipoprotein cholesterol (HDL-C) deficiency is attributed to mutations in several genes and may contribute to the genetic basis of coronary artery disease. To identify the cellular basis of a novel HDL-deficiency phenotype, we screened 54 subjects of French Canadian ancestry with severe HDL deficiency. METHODS AND RESULTS: We excluded individuals with mutations in genes currently associated with low HDL (ABCA1, LCAT, APOA-I, and SMPD1). We identified two patients in which cellular phospholipid efflux in the HDL biosynthesis process is impaired, whereas cholesterol efflux is normal. Two-dimensional gel electrophoresis analysis further showed that the two patients with impaired phospholipid efflux were defective primarily in the larger alpha-HDL subpopulations. In fibroblasts from affected subjects, oxysterol stimulation resulted in increased ABCA1 protein expression and normalized their defective phospholipid efflux defect. CONCLUSION: Our results indicate for the first time in humans that phospholipid and cholesterol efflux are two separate and distinct processes in cellular HDL biosynthesis. They further show for the first time that normal cellular phospholipid efflux is necessary for the formation of larger alpha-HDL particles. The defect in phospholipid efflux is due to defective ABCA1 protein regulation and can be corrected by treatment with physiological oxysterols, a current therapeutic target of interest, that may, with further studies, be used to raise HDL levels in patients with severe HDL deficiencies.

The therapeutic potential of high-density lipoprotein mimetic agents in coronary artery disease.

Low levels of high-density lipoprotein cholesterol (HDL-C) represent a major cardiovascular risk factor that is only modestly influenced by currently available drugs. Consequently, there has been interest in developing new therapeutic agents specifically targeting HDL-C to reduce risk in patients with coronary artery disease. One strategy involves the administration of therapies that mimic HDL-C or its properties, including reconstituted HDL, apolipoprotein A-I (apoA-I), apoA-I Milano, and apoA-I mimetic peptides. The atheroprotective effects of reconstituted HDL, apoA-I, and apoA-I Milano have been well documented in animal studies, and two recent clinical trials also provided encouraging results. The most investigated apoA-I mimetic peptide, D-4F, was shown to significantly reduce atherosclerotic lesions in animal models but data in humans are scarce. HDL-C mimetic agents constitute a promising novel strategy to reduce coronary artery disease risk but require further study in larger clinical trials.

Sphingomyelin phosphodiesterase-1 (SMPD1) coding variants do not contribute to low levels of high-density lipoprotein cholesterol.

BACKGROUND: Niemann-Pick disease type A and B is caused by a deficiency of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. In Niemann-Pick patients, SMPD1 gene defects are reported to be associated with a severe reduction in plasma high-density lipoprotein (HDL) cholesterol. METHODS: Two common coding polymorphisms in the SMPD1 gene, the G1522A (G508R) and a hexanucleotide repeat sequence within the signal peptide region, were investigated in 118 unrelated subjects of French Canadian descent with low plasma levels of HDL-cholesterol (< 5th percentile for age and gender-matched subjects). Control subjects (n = 230) had an HDL-cholesterol level > the 25th percentile. RESULTS: For G1522A the frequency of the G and A alleles were 75.2% and 24.8% respectively in controls, compared to 78.6% and 21.4% in subjects with low HDL-cholesterol (p = 0.317). The frequency of 6 and 7 hexanucleotide repeats was 46.2% and 46.6% respectively in controls, compared to 45.6% and 49.1% in subjects with low HDL-cholesterol (p = 0.619). Ten different haplotypes were observed in cases and controls. Overall haplotype frequencies in cases and controls were not significantly different. CONCLUSION: These results suggest that the two common coding variants at the SMPD1 gene locus are not associated with low HDL-cholesterol levels in the French Canadian population.

Evidence for a gene influencing high-density lipoprotein cholesterol on chromosome 4q31.21.

OBJECTIVE: A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary atherosclerosis. To identify novel genes regulating plasma HDL-C levels, we investigated 13 multigenerational French Canadian families with an average of 12 affected individuals per family for genome-wide signals, which we subsequently fine mapped. METHODS AND RESULTS: We genotyped a total of 362 individuals, including 151 affected subjects for 485 autosomal microsatellite markers. In parametric 2-point linkage analyses, the highest 2-point logarithm of odds (lod) score of 4.6 was observed with marker D4S424 on chromosome 4q31.21 (at approximately 142 Mb). The multipoint analysis of this region resulted in a lod score of 3.8 and a lod -1 region of 12.2 cM, containing 40 known genes. The results were obtained by allowing for genetic heterogeneity among these extended pedigrees, and approximately 50% of families were linked to this region with the highest single-pedigree lod score being 3.6. We further restricted the linked region from 12.2 to 2.9 cM (2.37 Mb) by genotyping 15 additional markers in the 3 families with the highest lod scores. We sequenced 4 genes with a likely role in lipid metabolism as well as 2 genes residing directly under the linkage peak but found no evidence for a causative variant. None of the genes residing in the significantly restricted 2.37-Mb region has been associated previously with HDL-C metabolism. CONCLUSIONS: This study provides significant evidence for a gene influencing HDL-C on chromosome 4q31.21.

Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia.

OBJECTIVE: A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASP-responsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects. METHODS AND RESULTS: DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G968-->T) in 1 subject, resulting in Ser323-->Ile substitution in the carboxyl terminal region. This variant was not detected in 2176 additional chromosomes by restriction fragment length polymorphism or fluorescence polarization genotyping. Eight family members of the proband were identified with one altered (+/-)C5L2 allele. Nine other family members had the wild-type (+/+)C5L2 sequence. The abnormal allele was associated with increased plasma triglyceride, plasma cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP. Of 23 subjects tested in cell-based ASP bioactivity assays, those with C5L2(+/-) variant (n = 2) had a 50% reduction in ASP-stimulated triglyceride synthesis, glucose transport and marked reduction in maximal binding (B(max)). By contrast, a C5L2(+/+) family member responded normally, as did hyperapolipoprotein B normal ASP subjects compared with C5L2(+/+) controls (n = 6). CONCLUSIONS: The S323I variant may alter C5L2 function and might be one molecular basis contributing to familial combined hyperlipidemia.

Surgical strategies for severe calcification of the aorta (porcelain aorta) in two patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HzFH) is a rare genetic defect caused predominantly by mutations at the low-density lipoprotein receptor. Until recent advances in the management of this complex disorder, patients affected by HzFH rarely survived beyond 30 years of age. Two patients with HzFH who survived to adulthood and developed cardiovascular complications requiring surgery are reported. In these patients, a porcelain aorta complicated surgical management. Lipid profile, mutational analysis and pathological assessment of the aorta were performed in two patients referred for cardiac surgery. The first patient was a 46-year-old man with a history of coronary artery bypass grafting (CABG) and recurrent severe angina who, because of a heavily calcified ascending aorta, required a complex repeat CABG. The second patient was a 42-year-old woman who underwent CAGB at 28 years of age and presented 13 years later with aortic stenosis. The extensive calcifications of the whole aortic root required performance of a modified Cabrol procedure. A porcelain aorta appears to be a feature of HzFH. This has an important impact on surgical planning and management and on possible pathophysiological processes related to the cardiovascular complications of HzFH.

Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency.

Mutations in the ABCA1 gene cause defective cellular lipid efflux and severe familial HDL deficiency. We examined the prevalence of mutations at the ABCA1 gene in 58 unrelated probands of French-Canadian descent with HDL deficiency (HDL-C<5th percentile). A defective cellular cholesterol or phospholipid efflux (<75% and <70% of normal controls, respectively) was identified in 14/58 (24%) of subjects. Using direct sequencing of the ABCA1 gene, we found mutations in 12/58 ( approximately 20%) of subjects. Four probands were previously identified with diverse ABCA1 gene defects. However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Three probands had the S1731C mutation, while two others had the R1851X and K776N documented mutations, respectively. Taken together, these data suggest that approximately 20% of French-Canadian patients with severe HDL deficiency are associated with a defective ABCA1. Interestingly, in two families studied, mutations in the ABCA1 gene did not segregate with the lipid efflux defect, suggesting that other proteins are involved in the ABCA1-mediated cellular lipid efflux.

A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians.

The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency was examined in a group of 54 unrelated French Canadian subjects. The lecithin:cholesterol acyl transferase (LCAT) and apolipoprotein (apo) A-I gene were analyzed in all probands by direct DNA sequencing. While no LCAT mutation was detected, a novel nonsense apoA-I mutation (E136X) was found in 3/54 probands. Genetic analysis of two kindreds showed a strong co-segregation of the apoA-I locus with the low HDL-C trait. The E136X mutation was detected in families by MaeI restriction digestion. E136X carriers (n=17) had marked HDL-C deficiency; among the nine carriers > or = 35 years old, five men had developed premature coronary artery disease (CAD). A peptide of apparent molecular weight of 14 kDa was identified in fresh plasma, the HDL fractions and lipoprotein deficient plasma from the three probands but not in normal controls (n=3), suggesting that the mutant apoA-I peptide is secreted and binds lipids. The mutation was not observed in an additional 210 chromosomes from unrelated subjects of French Canadian descent, < 60 years of age, with CAD and low HDL-C levels. We conclude that apoA-I (E136X) is a cause of HDL-C deficiency in the French Canadian population and is associated with premature CAD.

Effect of fenofibrate on plasma lipoprotein composition and kinetics in patients with complete hepatic lipase deficiency.

OBJECTIVE: The goal of this study was to characterize the effect of microcoated fenofibrate (160 mg/day for 6 months) on plasma lipoprotein composition and kinetics in 2 patients with complete hepatic lipase (HL) deficiency. METHODS AND RESULTS: Fenofibrate treatment normalized the plasma lipoprotein profile of patients with complete HL deficiency, as evidenced by significant reductions in the plasma concentration of cholesterol (-49%) and triglycerides (-82%) and a significant increase in low-density lipoprotein (LDL) size (251.5+/-1.8 versus 263.5+/-0.7 A). The in vivo kinetics of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL apolipoprotein (apo)B-100 and plasma apoA-I and apoA-II were studied using a primed-constant infusion of L-[5,5,5-D3]-leucine for 12 hours in the fasted state. Fenofibrate treatment in complete HL-deficient patients substantially decreased plasma concentrations of VLDL, IDL, and LDL apoB-100 attributable to important increases in VLDL (+325%), IDL (+129%), and LDL (+218%) apoB-100 fractional catabolic rates (FCR). IDL apoB-100 FCR nevertheless remained 60% lower after treatment compared with values obtained in controls (n=5). The kinetics of plasma apoA-I and apoA-II as well as the capacity of total plasma and of high-density lipoprotein particles to efflux cellular cholesterol from normal human skin fibroblasts was not altered by fenofibrate. CONCLUSIONS: Fenofibrate therapy exerts a pronounced antiatherogenic effect on triglyceride-rich lipoproteins even in the complete absence of HL.

Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency.

BACKGROUND: Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C). METHODS AND RESULTS: We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C <5th percentile) in 64 subjects (12 women and 52 men). Apolipoprotein AI-mediated cellular cholesterol and phospholipid efflux were measured in fibroblasts from HypoA subjects, 9 controls, 2 patients with Tangier disease, and 5 patients with hyperalphalipoproteinemia. A phospholipid efflux defect was defined as <70% of controls. Mean HDL-C was 0.49+/-0.21 mmol/L. Cholesterol and phospholipid efflux correlated strongly (r=0.72, P<0.001). Phospholipid efflux and HDL-C (r=0.64, P<0.001) correlated in HypoA subjects. However, phospholipid or cholesterol efflux was no longer a determinant of HDL-C levels at higher levels (> approximately 1.0 mmol/L) of HDL-C. In HypoA subjects, 4 cases of Tangier disease and 6 of familial HDL deficiency (heterozygous Tangier disease) were identified (10 of 64; 16%). In the remaining 54 subjects, mean lipid efflux was not significantly different from controls and subjects with hyperalphalipoproteinemia. A phospholipid efflux defect was identified in 7 additional HypoA subjects, and a cholesterol efflux defect was detected in 11 subjects. In 2 of these subjects, the ABCA1 gene was ruled out as the cause of the efflux defect, while in 3, the low HDL-C trait segregated with the ABCA1 gene locus. CONCLUSIONS: Lipidation of lipid-poor apolipoprotein AI may not be a major determinant of cholesterol accumulation within more mature HDL particles and increasing cholesterol or phospholipid efflux beyond normal levels may not lead to increase in plasma HDL-C levels. ABCA1 is essential in the initial steps of HDL formation but other plasma events are major modulators of HDL-C levels.

Is the decreased high-density lipoprotein cholesterol in the metabolic syndrome due to cellular lipid efflux defect?

The metabolic syndrome (MS) is associated with cardiovascular disease. The low high-density lipoprotein cholesterol (HDL-C) seen in the MS is associated with increased hepatic secretion of apolipoprotein B-containing lipoproteins. Patients with low HDL-C and abnormal cellular lipid efflux due to ABCA1 gene defects (Tangier disease) also have elevated plasma triglycerides. In the present study, we examined the cellular cholesterol and phospholipid efflux in patients with low HDL-C and features of the MS. Forty-four patients with a HDL-C below the fifth percentile for age and gender were selected. The MS was defined by a low HDL-C and at least two additional features: body mass index at least 30 kg/m(2), plasma triglycerides at least 150 mg/dl, fasting glucose at least 110 mg/dl, and blood pressure at least 130/85 mm Hg. Cellular lipid efflux was examined on fibroblasts obtained from study subjects, nine normal controls and six subjects with Tangier disease. In 22 patients identified with the MS, HDL-C was 21 +/- 7 mg/dl, triglyceride levels were 340 +/- 157 mg/dl, and cellular cholesterol and phospholipid efflux were 107 +/- 18% and 105 +/- 17% of controls, respectively. No patient with the MS and low HDL-C showed a cellular lipid efflux defect. We conclude that primary cellular lipid efflux defects do not contribute to the low HDL-C frequently encountered in the MS.

Effect of increasing metabolic syndrome score on atherosclerotic risk profile and coronary artery disease angiographic severity.

The metabolic syndrome (MS) is a frequent cause of coronary artery disease (CAD), and recently the National Cholesterol Education Program Adult Treatment Panel III suggested its diagnosis in the presence of 3 to 5 quantitatively defined markers. Because the consequences of the MS are likely related to the number and diversity of markers, we studied the relation between the number of markers-the MS score-and the degree of abdominal obesity, risk factor profile, and severity of CAD. One thousand one hundred eight subjects of a mostly white population with symptoms of CAD (793 men and 315 women; 58.1 +/- 9.8 years of age) were divided into 6 groups based on their MS scores. A low high-density lipoprotein cholesterol level was the most frequently observed marker, followed by increased blood pressure, triglycerides, waist circumference, and fasting glucose. As the MS score increased so did abdominal obesity, parameters of "nontraditional" dyslipidemia with surrogate markers of dense low-density lipoprotein and high-density lipoprotein particles, blood pressure, fasting glucose, insulin, and the homeostatic model assessment insulin resistance index. Similarly, an increasing MS score was significantly related to more severe coronary angiographic alterations and higher frequencies of unstable angina, myocardial infarction, percutaneous coronary intervention, and coronary artery bypass grafting. Therefore, the MS score provides a clinically useful index of MS severity and the associated atherosclerotic risk factor profile. It also correlates with the angiographic severity of CAD and its clinical complications.

Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease.

BACKGROUND AND OBJECTIVES: Several studies suggested that the insulin resistance-associated metabolic syndrome (MS) is a major risk factor for coronary artery disease (CAD), but the criteria to identify MS were only recently standardized by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III. METHODS: We evaluated the incidence of the newly defined MS in patients with documented CAD and compared the characteristics of patients with and without this syndrome. RESULTS: In a Canadian population with CAD (793 men and 315 women, age 58.1+/-9.8 years) 51% had MS. As compared to patients without the MS syndrome, these patients had significantly higher waist circumference, blood pressure levels and fasting glucose and triglyceride, but lower high-density lipoprotein (HDL)-cholesterol levels. Their homeostatic model assessment (HOMA) insulin resistance index was significantly higher, with indicators of highly atherogenic, small low-density lipoprotein (LDL) and HDL particles. Family history of diabetes and the use of hypoglycemic agents, beta-blockers and thiazides were more frequent, but physical exercise and alcohol consumption were less frequent in MS positive patients. Cumulative coronary stenosis score and the frequency of patients with >50% coronary artery narrowing were higher and there was a strong tendency for higher rates of previous myocardial infarction in MS positive patients. CONCLUSIONS: In a CAD population documented in 1991-1992, 51% of participants had MS and in several respects a more advanced coronary disease than those without the syndrome. These results support the view of NCEP ATP III, that in CAD prevention, beyond lowering LDL-cholesterol levels, interventions concerning the constituents of MS should be important.

High-density lipoproteins: multifunctional vanguards of the cardiovascular system.

The plasma level of high-density lipoprotein (HDL)-cholesterol is inversely correlated with coronary artery disease, the leading cause of death worldwide. HDL particles are thought to mediate the uptake of peripheral cholesterol and, through exchange of core lipids with other lipoproteins or selective uptake by specific receptors, return this cholesterol to the liver for bile acid secretion or hormone synthesis in steroidogenic tissues. HDL particles also act on vascular processes by modulating vasomotor function, thrombosis, cell-adhesion molecule expression, platelet function, nitric oxide release, endothelial cell apoptosis and proliferation. Many of these effects involve signal transduction pathways and gene transcription. Several genetic disorders of HDLs have been characterized at the molecular level. The study of naturally occurring mutations has considerably enhanced understanding of the role of HDL particles. Some mutations causing HDL deficiency are associated with premature coronary artery disease, while others, paradoxically, may be associated with longevity. Modulation of HDL metabolism for therapeutic purposes must take into account, not only the cholesterol content of a particle but its lipid (especially phospholipid) composition, apolipoprotein content, size and charge. Current therapeutic strategies include the use of peroxisome proliferating activator receptor-alpha agonists (fibrates) that increase apolipoprotein AI production and increase lipoprotein lipase activity, statins that have a small effect on HDL-cholesterol but markedly reduce low-density lipoprotein-cholesterol, the cholesterol/HDL-cholesterol ratio and niacin that increases HDL-cholesterol. Potential therapeutic targets include inhibition of cholesteryl ester transfer protein, modulating the ATP-binding cassette A1 transporter, and decreasing HDL uptake by scavenger receptor-B1. Novel therapies include injection of purified apolipoprotien AI and short peptides taken orally, mimicking some of the biological effects of apolipoprotein AI.

Incidence, coronary risk profile and angiographic characteristics of prediabetic and diabetic patients in a population with ischemic heart disease.

BACKGROUND: Recently, the threshold of fasting blood glucose indicating diabetes mellitus was lowered to 7.00 mmol/L (126 mg/dL) and the term 'impaired fasting glucose' (IFG; fasting blood glucose ranging from 6.11 mmol/L to 6.99 mmol/L or from 110 mg/dL to 126 mg/dL) was introduced to define a prediabetic state. OBJECTIVE: To evaluate the incidence of the above states in a Canadian population with suspected coronary artery disease and to compare their risk profiles and angiographic status to normoglycemic subjects. PATIENTS AND METHODS: Revision of the database of 1108 consecutive patients (793 males and 315 females; mean age 58.1+/-9.8 years) undergoing clinical, biochemical and elective angiographic studies because of suspected coronary artery disease. RESULTS: One third of the patients had either IFG (8.5%), or were diabetics (24.2%). Unlike the 747 normoglycemic patients, both IFG (n=94) and diabetic (n=267) subjects showed an insulin resistance profile, with abdominal obesity, and dislipidemia characterized by high triglycerides in the presence of low high density lipoprotein-cholesterol and high normal or elevated blood pressure. Both prediabetics and diabetics had a significantly higher homeostatic model assessment insulin resistance index than normoglycemics (P<0.0001), the index also being higher for diabetics than for prediabetics (P<0.0001). Coronary atherosclerosis was documented in most patients of the three groups and was significantly more severe in diabetics than in IFG patients (P=0.0359) or normoglycemics (P=0.0069), with no differences between the former two groups. CONCLUSIONS: As expected, the new definitions identify more patients with impaired homeostasis than earlier criteria. IFG patients have similar coronary risk profile as diabetics, suggesting the need for similar coronary precautions.

Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.

Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.

Long-term rates of cardiovascular events in patients with the metabolic syndrome according to severity of coronary-angiographic alterations.

OBJECTIVES: To assess the long-term risk of mortality and cardiovascular events, related to metabolic syndrome (MetS), in patients with less, or more severe coronary artery disease (CAD). METHODS: One thousand and eighty patients were divided in four groups, according to severity of CAD (1=less than 50% or nonsignificant stenoses; 2=greater or significant stenoses), and according to MetS (A=no; B=yes). Risk was evaluated with the Cox regression analysis. RESULTS: About 18.9% of patients had less and 81.1% more advanced CAD. MetS was present in 45.1% of the first, and in 52.9% of the second group. At baseline, patients with MetS, or significant stenoses, had less favorable medical, biochemical, and angiographic characteristics. During a follow-up of 12.6+/-3.4 years, group 1B had higher incidence (16.3 vs. 7.1%) and hazard ratio [2.36 (1.001-5.57; P=0.0497)] of myocardial infarction than group 1A; group 2B had a higher incidence (19.0 vs. 11.7%) and hazard ratio [1.67 (1.18-2.37; P=0.0041)] of stroke than group 2A. Groups 2A and 2B, as compared with groups 1A and 1B, had a higher incidence of myocardial infarction (39.1 vs. 7.1; 41.8 vs. 16.3%); group 2B had higher incidence of stroke than group 1B (19.0 vs. 9.8%). After adjustment for common risk factors, group 2B retained an elevated risk of stroke. After additional adjustment for diabetes, no event was significantly related to MetS. CONCLUSION: At baseline, coronary patients with MetS, or significant angiographic alterations, had more cardiovascular risk factors. During follow-up, both MetS and significant CAD increased the risk of cardiovascular morbidity but not of mortality.

Intra-operative echographic localization for radioactive ophthalmic plaques in choroidal melanoma.

The objectives were to evaluate the beneficial effect of intra-operative echographic plaque site localization and to assess the rate of complications of postplaque insertion. This paper is a descriptive study of 48 patients with choroidal melanoma who underwent iodine-125 (I(125)) or ruthenium-106 (Ru(106)) plaque radiotherapy with intra-operative echographic confirmation of plaque placement with the aid of a nonradioactive plaque (dummy) at McGill University Health Centre from 1997 to 2003. Patients' mean age was 63.7 years; 52% (25/48) male, 48% (23/48) female. Twenty-seven percent (13/48) of the tumors were confined to the right eye and 73% (35/48) to the left eye. Forty-eight percent (23/48) of the tumors were located posterior to the equator, 14.6% (7/48) were anterior to the equator, 18.7% (9/48) in posterior pole, and 18.7% (9/48) at equator. Sixty-nine percent (33/48) received I(125) and 31% (15/48) had Ru(106) treatment. Ninety percent of the dummy plaques were initially positioned suboptimally and required repositioning under echographic guidance. At mean follow-up of 18.8 months, there was no tumor-related death or metastasis, but one patient required enucleation. The dummy plaque technique under echographic visualization resulted in reduction of radioactive exposure time during surgery of up to 50%. Intra-operative echographic utilization has the ability to localize precisely the tumor-plaque relationship, thereby optimizing the radiation delivered to the choroidal melanoma, while minimizing the surgeon's exposure time.

Iodine-125 radiotherapy for choroidal melanoma.

The objective was to evaluate the effect of the gender, size, and tumor location at the time of the diagnosis on the regression response of choroidal melanoma following plaque radiotherapy treatment. The paper is a longitudinal prospective study of 28 patients diagnosed with choroidal melanoma at McGill University Health Centre from 1997 to 2002. All patients were treated with episcleral iodine-125 (I(125)) plaque radiotherapy. Plaques were inserted at the tumor site under echographic visualization. All patients had medium-size tumors, except for three. Patients had periodic ophthalmic evaluation at 3 and 6 months post radiation treatment, followed by 6-month intervals thereafter. Patients' mean age was 62 +/- 15 years, 16 males and 12 females. Fifty percent of the tumors were located posterior to the equator with significant reduction in size at 12 months post plaque radiotherapy treatment. Significant regression was observed in all the tumor diameters at 5 years post treatment follow-up. Reduction in the depth diameter was significant (P < 0.01) in both male and female groups post treatment. There was a 25% (P < 0.001) reduction in the medium size of tumors at 5-year follow-up. Tumors located posterior to the equator responded best to I(125) plaque radiotherapy. Male patients responded better than females to treatment. Medium-size melanoma responded well to plaque radiotherapy.