Hyperlipidemias: Hegele RA

Hegele RA, Pollex RL. · No affiliation provided · Arterioscler Thromb Vasc Biol. · Pubmed #17522394 links to  free full text

This publication has no abstract.

Lanktree M, Hegele RA. · Vascular Biology Group, Robarts Research Institute, and Departments of Medicine & Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ont., Canada. · Cytogenet Genome Res. · Pubmed #19287152 No free full text.

Abstract: Despite successes in identifying genetic contributors to common metabolic phenotypes, only part of the heritable component of these traits has thus far been explained. Copy number variation (CNV) is likely to be responsible for some of the unexplained variation. As observed with single nucleotide changes, it is probable that both rare and common CNVs will contribute to susceptibility to metabolic disease. For instance, CNVs in the LDLR gene underlie a substantial portion of disease in patients with heterozygous familial hypercholesterolemia. As well, a common CNV in LPA encoding apolipoprotein(a) is the primary determinant of plasma lipoprotein(a) concentrations, a risk factor for atherosclerosis. Recent efforts to map CNVs in control populations have defined their size, frequency and distribution. Many of the identified CNVs overlap genes with important functions in metabolic pathways. The overlap of CNVs that were found in control datasets with functional candidate genes or genes with previous evidence of association with metabolic syndrome presents an important subset for future CNV association studies. Finally, we describe an approach to search for CNVs in a rare high-penetrance metabolic disorder, namely lipodystrophy. As methods to identify CNVs increase in precision and accuracy, the prospect of identifying their role in both rare Mendelian and common complex metabolic phenotypes will become a reality.

Hegele RA. · Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8. · Nat Rev Genet. · Pubmed #19139765 No free full text.

Abstract: Susceptibility to the growing global public health problem of cardiovascular disease is associated with levels of plasma lipids and lipoproteins. Several experimental strategies have helped us to clarify the genetic architecture of these complex traits, including classical studies of monogenic dyslipidaemias, resequencing, phenomic analysis and, more recently, genome-wide association studies and analysis of metabolic networks. The genetic basis of plasma lipoprotein levels can now be modelled as a mosaic of contributions from multiple DNA sequence variants, both rare and common, with varying effect sizes. In addition to filling gaps in our understanding of plasma lipoprotein metabolism, the recent genetic advances will improve our ability to classify, diagnose and treat dyslipidaemias.

Joy TR, Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, The Robarts Research Institute, in London, ON, Canada. · Nat Clin Pract Cardiovasc Med. · Pubmed #18506153 No free full text.

Abstract: This article sets out the clinical context of the research presented by Samaha et al. in an accompanying article in this issue. Hyperlipidemia is a common and important risk factor for cardiovascular disease. Current lipid-lowering therapies, particularly statins, lead to substantial decreases in cardiovascular disease morbidity and mortality, but use has been limited by safety or efficacy issues. The way has, therefore, been paved for the pharmaceutical development and clinical investigation of new lipid-lowering therapies. The clinical trial by Samaha et al. examines the safety and efficacy of microsomal triglyceride transfer protein inhibition for lowering lipids. Joy and Hegele explore the difficulties of translating microsomal triglyceride transfer protein inhibition into clinical practice because of the trade-off between efficacy and potential adverse effects. They also stress the need for outcome studies, rather than biochemical or surrogate studies, as the final arbiter for the clinical use of this new treatment.

Moride Y, Hegele RA, Langer A, McPherson R, Miller DB, Rinfret S. · Faculty of Pharmacy, Université de Montreal, Montréal, Quebec. · Can J Cardiol. · Pubmed #18401470 links to  free full text

Abstract: Peer-reviewed, evidence-based recommendations for statin use in primary prevention of cardiovascular events are limited. A narrative review of published randomized controlled trials and meta-analyses was conducted to critically appraise the benefits and risks of statins in primary prevention. Statins effectively reduce plasma concentrations of low-density lipoprotein cholesterol, and reduce the risk of cardiovascular events and death. The greatest benefits are observed in high-risk subjects, such as patients with diabetes or hypertension. Serious cardiovascular events should not be included among serious adverse events because they are efficacy outcomes and are dependent on the baseline risk of patients. Rates of specific serious adverse events, such as cancer and rhabdomyolysis, seem to be similar between the statin and control arms of the clinical trials examined. Thus, the benefits of statins in primary prevention outweigh the risks, particularly among high-risk patients. However, the benefit-risk ratio would likely be optimized through interventions designed to increase persistence and adherence in a real-life setting.

Joy T, Cao H, Black G, Malik R, Charlton-Menys V, Hegele RA, Durrington PN. · Department of Vascular Biology and Medicine, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. · Orphanet J Rare Dis. · Pubmed #18154657 links to  free full text

Abstract: BACKGROUND: Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described. CASE PRESENTATION: We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene - H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case. CONCLUSION: Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.

Rahalkar AR, Hegele RA. · Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ont., Canada. · Mol Genet Metab. · Pubmed #18023224 No free full text.

Abstract: Monogenic disorders that cause abnormal levels of plasma cholesterol and triglycerides have received much attention due to their role in metabolic dysfunction and cardiovascular disease. While these disorders often present clinically during adulthood, some present most commonly in the pediatric population and can have serious consequences if misdiagnosed or untreated. This review provides an overview of monogenic lipid disorders that present with unusually high or low levels of plasma cholesterol and/or triglycerides during infancy, childhood and adolescence. Biochemical and genetic findings, clinical presentation and treatment options are discussed with an emphasis upon recent advances in our understanding and management of these monogenic disorders.

Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, 406-100 Perth Drive, London, ON N6A 5K8, Canada. · Genome. · Pubmed #17426749 No free full text.

Abstract: Much of the recent progress in treating patients with heart disease due to narrowed coronary arteries has resulted from studying disease evolution in patients with rare monogenic forms of disease. For instance, autosomal dominant familial hypercholesterolemia (FH, MIM (Mendelian Inheritance in Man) 143890) typically results from heterozygous mutations in LDLR encoding the low-density lipoprotein (LDL) receptor. Deficient LDLR activity results in elevated circulating LDL cholesterol, which accumulates within blood vessel walls, forming arterial plaques that can grow and eventually occlude the arterial lumen. Heterozygous LDLR mutations are usually detected using exon-by-exon sequence analysis (EBESA) of genomic DNA, a technology that has identified approximately 50 mutations in heterozygous FH (HeFH) subjects in Ontario. However, approximately 35% of Ontario HeFH patients had no EBESA-identified LDLR mutation. The diagnostic gap relates both to the genetic heterogeneity of FH and also to inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR. By means of a dedicated method to detect copy number variations (CNVs), additional heterozygous mutations in LDLR ranging from approximately 500 to >15 000 bases were uncovered, accounting for most of the remainder of Ontario HeFH patients. The appreciation of the key role of genomic CNVs in disease coincides with recent genome-wide mapping studies demonstrating that CNVs are common in apparently healthy people. CNVs thus represent a new level of genomic variation that is both an important mechanism of monogenic disease and a contributor to genomic variation in the general population; as well, it may have implications for evolution, biology, and possibly susceptibility to common complex diseases.

Yuan G, Al-Shali KZ, Hegele RA. · Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ont. · CMAJ. · Pubmed #17420495 links to  free full text

Abstract: Elevated plasma triglyceride concentration is a common biochemical finding, but the evidence for the benefit of treating this lipid disturbance remains less robust than that for treating elevated low-density lipoprotein-cholesterol. Part of the difficulty in the provision of specific recommendations has been the frequent coexistence of elevated triglycerides with other conditions that affect cardiovascular disease risk, such as depressed high-density lipoprotein-cholesterol, obesity, metabolic syndrome, proinflammatory and prothrombotic biomarkers, and type 2 diabetes. Recent investigations of outcomes of cardiovascular disease when medications are used to reduce triglyceride levels suggest that, although a net benefit probably exists, both relative and absolute risk reductions seem underwhelming when compared with the benefit of reducing low-density lipoprotein-cholesterol levels with treatment. However, the totality of evidence suggests that elevated triglyceride levels likely contribute independently to increased risk of cardiovascular disease, although there is no consensus about appropriate target levels. Furthermore, severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis, irrespective of its effect on risk of cardiovascular disease. We review the causes and classification of elevated triglyceride levels, the clinical manifestations of primary hypertriglyceridemia and the management of patients with elevated triglyceride levels.

Pollex RL, Hegele RA. · Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. · Curr Opin Lipidol. · Pubmed #17353666 No free full text.

Abstract: PURPOSE OF REVIEW: This review examines the role of copy number variation in the human genome as a newly recognized determinant of lipoprotein and metabolic phenotypes. RECENT FINDINGS: Much of the recent progress defining the molecular basis of lipoprotein disorders has been the result of studying genomic DNA at the single nucleotide level, for instance with nucleotide sequence analysis or genotyping to detect single nucleotide polymorphisms. Focus on single nucleotides, however, fails to capture the complete spectrum of potential genetic variability. Recent genome-wide mapping studies have demonstrated the surprising ubiquity of large-scale copy number variations in apparently healthy people, adding to the complexity of the 'normal' genome, but also emphasizing this form of genetic variation as a potential disease mechanism. The application of this understanding to the genetics of lipoprotein disorders has been rapid. For instance, the use of novel techniques to detect copy number variations, such as multiplex ligation-dependent probe amplification, has revealed many additional causative mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia. SUMMARY: Copy number variations thus represent a new level of genomic variation that is both an important mechanism of monogenic lipoprotein disorders and a potential contributor to common complex lipoprotein and metabolic phenotypes in the general population.

Yuan G, Wang J, Hegele RA. · Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ont. · CMAJ. · Pubmed #16606962 links to  free full text

Abstract: Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.

Al-Shali KZ, Hegele RA. · Robarts Research Institute and University of Western Ontario, London, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #15205220 links to  free full text

Abstract: Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and Hutchinson-Gilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases FPLD2 and HGPS are more likely to provide clues about new pathways for the general process of atherosclerosis. Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome are laminopathies caused by mutation in LMNA that feature atherosclerosis, which is related to proatherogenic metabolic disturbances and to the generalized process of accelerated aging, respectively. These monogenic diseases may provide clues about new pathways for atherogenesis.

Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, John P. Robarts Research Institute, University of Western Ontario, 406-100 Perth Drive, London, ON, Canada N6A 5K8. · Atheroscler Suppl. · Pubmed #11923122 No free full text.

Abstract: In familial hypercholesterolemia (FH), early coronary heart disease (CHD) is a complex trait that results from a large monogenic component of susceptibility due to elevated LDL cholesterol. This was demonstrated by observation of the high risk of early CHD in FH subjects compared with the general population. However, not all subjects with a LDLR gene mutation suffer with early CHD. Furthermore, studies in extended multigenerational families showed that even for this strong monogenic effect the environment could substantially modulate the age at death from CHD. Anecdotal examples of apparent modulation of atherosclerosis severity by lifestyle changes were also seen in other monogenic metabolic problems, such as hepatic lipase deficiency and Dunnigan-type familial partial lipodystrophy. Thus, even within apparently clear-cut rare monogenic metabolic diseases, such as FH, among carriers there can be a variability in the expression of important quantitative end points, such as early CHD. In some cases, the environment, including lifestyle factors, appears to play a key role in modulating the disease severity. This complexity could have implications for diagnosis and treatment.

Hegele RA. · John P. Robarts Research Institute, London, Ontario, Canada. · Am J Hum Genet. · Pubmed #11704922 links to  free full text

This publication has no abstract.

Hegele RA. · Robarts Research Institute, Ontario, London, Canada. · Mol Genet Metab. · Pubmed #11136544 No free full text.

Abstract: Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) is a rare monogenic form of insulin resistance characterized by loss of subcutaneous fat from the extremities, trunk, and gluteal region. FPLD recapitulates the main metabolic attributes of the insulin resistance syndrome, including central obesity, hyperinsulinemia, glucose intolerance and diabetes, dyslipidemia, and hypertension. Through the use of focused DNA sequencing of positional candidate genes on chromosome 1q21, we discovered that FPLD results from mutations in LMNA (R482Q; OMIM 150330.0010), which is the gene that encodes nuclear lamins A and C. By stratifying members of extended FPLD pedigrees according to LMNA genotype, we found that hyperinsulinemia is present early in the course of the disease and that dyslipidemia (characterized by high triglycerides and depressed HDL cholesterol) precedes the development of glucose abnormalities. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. The findings in FPLD indicate that defective structure of the nuclear envelope produces a phenotype of insulin resistance. The findings may have relevance for common insulin resistance and for drug-associated lipodystrophies, whose molecular basis is unknown at present.

Marcovina SM, Hegele RA, Koschinsky ML. · Department of Medicine, University of Washington, 2121 North 35th Street, Seattle, WA 98103-9103, USA. · Curr Cardiol Rep. · Pubmed #10980828 No free full text.

Abstract: Although retrospective case-control studies continue to indicate that plasma lipoprotein(a) concentrations are associated with coronary heart disease (CHD), several large population-based prospective studies have failed to confirm that Lp(a) is an independent risk factor. However, evidence exists from several studies to suggest that elevated plasma Lp(a) increases the CHD risk associated with more traditional risk factors. Although identification of the functional role of Lp(a) in atherogenesis has been thwarted by the physical, chemical, and genetic complexity of Lp(a), the structural similarity of Lp(a) to both the fibrinolytic proenzyme plasminogen and low-density lipoprotein (LDL) has suggested a prothrombotic or atherogenic role (or both) for this lipoprotein. Because the clinical determination and application of plasma Lp(a) concentration poses several challenges, we cannot recommend its routine measurement at this time. Rather, plasma Lp(a) determinations should be limited to either patients at high risk for the development of CHD or patients at borderline risk for the development of CHD in whom uncertainty may exist about how aggressively to treat modifiable risk factors such as elevated LDL cholesterol.

Wang J, Ban MR, Kennedy BA, Anand S, Yusuf S, Huff MW, Pollex RL, Hegele RA. · Vascular Biology Research Group, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5K8, Canada. · Nat Clin Pract Cardiovasc Med. · Pubmed #18779834 No free full text.

Abstract: BACKGROUND: Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify other useful variants, we evaluated the association of two common APOA5 single-nucleotide polymorphisms across the range of classic hyperlipoproteinemia phenotypes. METHODS: We assessed plasma lipoprotein profiles and APOA5 S19W and -1131T>C genotypes in 678 adults from a single tertiary referral lipid clinic and in 373 normolipidemic controls matched for age and sex, all of European ancestry. RESULTS: We observed significant stepwise relationships between APOA5 minor allele carrier frequencies and plasma triglyceride quartiles. The odds ratios for hyperlipoproteinemia types 2B, 3, 4 and 5 in APOA5 S19W carriers were 3.11 (95% CI 1.63-5.95), 4.76 (2.25-10.1), 2.89 (1.17-7.18) and 6.16 (3.66-10.3), respectively. For APOA5 -1131T>C carriers, the odds ratios for these hyperlipoproteinemia subtypes were 2.23 (95% CI 1.21-4.08), 3.18 (1.55-6.52), 3.95 (1.85-8.45) and 4.24 (2.64-6.81), respectively. The overall odds ratio for the presence of either allele in lipid clinic patients was 2.58 (95% CI 1.89-3.52). CONCLUSIONS: A high proportion of patients with four classic hyperlipoproteinemia phenotypes are carriers of either the APOA5 S19W or -1131T>C variant or both. These two variants are robust genetic biomarkers of a range of clinical hyperlipoproteinemia phenotypes linked by hypertriglyceridemia.

Wang J, Ban MR, Zou GY, Cao H, Lin T, Kennedy BA, Anand S, Yusuf S, Huff MW, Pollex RL, Hegele RA. · Vascular Biology Research Group 2 Clinical Trials Group, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. · Hum Mol Genet. · Pubmed #18596051 No free full text.

Abstract: Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.

Rahalkar AR, Wang J, Sirrs S, Dimmick J, Holmes D, Urquhart N, Hegele RA, Mattman A. · Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. · Clin Chem. · Pubmed #18310149 links to  free full text

This publication has no abstract.

Awan Z, Alrasadi K, Francis GA, Hegele RA, McPherson R, Frohlich J, Valenti D, de Varennes B, Marcil M, Gagne C, Genest J, Couture P. · McGill University Health Center/Royal Victoria Hospital, 687 Pine avenue West, Montréal, QC H3A 1A1, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #18239150 links to  free full text

Abstract: BACKGROUND: Patients with homozygous familial hypercholesterolemia (hmzFH) attributable to LDL receptor gene mutations have shown a remarkable increase in survival over the last 20 years. Early onset coronary heart disease (CHD) and calcific aortic valve stenosis are the major complications of this disorder. We now report extensive premature calcification of the aorta in patients with hmzFH. METHODS AND RESULTS: We examined 25 hmzFH patients from Canada; mean age was 32 years (range 5 to 54), and mean baseline cholesterol before treatment was 19+/-5 mmol/L (737+/-206 mg/dL). Aortic calcification was quantified using computed tomography (CT). An elevated mean calcium score was found in patients by age 20 and correlated with age (r(2)=0.53, P=0.001). One quarter (24%) of patients underwent aortic valve surgery. CONCLUSIONS: We document premature severe aortic calcifications in all adult hmzFH patients studied. These presented considerable surgical management challenges. Strategies to identify and monitor aortic calcification in hmzFH by noninvasive techniques are required, as are clinical trials to determine whether additional or more intensive therapies will prevent the progression of such calcifications. Whether vascular calcifications in hmzFH subjects are related to sustained increases in LDL-C levels or to other mechanisms, such as abnormal osteoblast activity, remains to be determined.

Cao H, Alston L, Ruschman J, Hegele RA. · Vascular Biology Group, Robarts Research Institute, London, Ontario, Canada. · Lipids Health Dis. · Pubmed #18237401 links to  free full text

Abstract: BACKGROUND: Mice with a deleted Cav1 gene encoding caveolin-1 develop adipocyte abnormalities and insulin resistance. From genomic DNA of patients with atypical lipodystrophy and hypertriglyceridemia who had no mutations in any known lipodystrophy gene, we used DNA sequence analysis to screen the coding regions of human CAV1 (MIM 601047). RESULTS: We found a heterozygous frameshift mutation in CAV1, designated I134fsdelA-X137, in a female patient who had atypical partial lipodystrophy, with subcutaneous fat loss affecting the upper part of her body and face, but sparing her legs, gluteal region and visceral fat stores. She had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis. In addition, she had some atypical features, including congenital cataracts and neurological findings. Her father was also heterozygous for this mutation, and had a similar pattern of fat redistribution, hypertriglyceridemia and congenital cataracts, with milder neurological involvement. An unrelated patient had a different heterozygous frameshift mutation in the CAV1 gene, designated -88delC. He also had a partial lipodystrophy phenotype, with subcutaneous fat loss affecting the arms, legs and gluteal region, but sparing his face, neck and visceral fat stores. He also had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis; however he had no clinically apparent neurological manifestations. The mutations were absent from the genomes of 1063 healthy individuals. CONCLUSION: Thus, very rare CAV1 frameshift mutations appear to be associated with atypical lipodystrophy and hypertriglyceridemia.

Wang J, Cao H, Ban MR, Kennedy BA, Zhu S, Anand S, Yusuf S, Pollex RL, Hegele RA. · Vascular Biology Research Group, Robarts Research Institute and Schulich School of Medicine and Dentistry, London, Ontario, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #17717288 links to  free full text

Abstract: OBJECTIVE: The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects. METHODS AND RESULTS: We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2-30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio [OR] 52, 95% confidence interval [CI] 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy. CONCLUSIONS: Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders.

Morel CF, Thomas MA, Cao H, O'Neil CH, Pickering JG, Foulkes WD, Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada. · J Clin Endocrinol Metab. · Pubmed #16636128 links to  free full text

Abstract: CONTEXT: To date, all cases of familial partial lipodystrophy type 2 (FPLD2; Mendelian Inheritance in Man 151660) result from missense mutations in LMNA, which encodes nuclear lamin A/C (Mendelian Inheritance in Man 150330). OBJECTIVE: The objective of the study was to carry out mutational analysis of LMNA in two sisters with a particularly severe FPLD2 phenotype. DESIGN: This was a descriptive case report with molecular studies. SETTING: The study was conducted at a referral center. PATIENTS: We report two sisters of South Asian origin. The first presented with acanthosis nigricans at age 5 yr, diabetes with insulin resistance, hypertension and hypertriglyceridemia at age 13 yr, and partial lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 yr. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES AND RESULTS: LMNA sequencing showed that the sisters were each heterozygous for a novel G>C mutation at the intron 8 consensus splice donor site, which was absent from the genomes of 300 healthy individuals. The retention of intron 8 in mRNA predicted a prematurely truncated lamin A isoform (516 instead of 664 amino acids) with 20 nonsense 3'-terminal residues. The mutant lamin A isoform failed to interact normally with emerin and failed to localize to the nuclear envelope. CONCLUSIONS: This is the first LMNA splicing mutation to be associated with FPLD2, and it causes a severe clinical and metabolic phenotype.

Pollex RL, Hanley AJ, Zinman B, Harris SB, Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute and University of Western Ontario, London, Ontario, Canada. · Int J Obes (Lond). · Pubmed #16276364 No free full text.

Abstract: OBJECTIVES: To determine the prevalence of 'hypertriglyceridemic waist' (HTGW) in Oji-Cree, to examine its interaction with hepatic nuclear factor-1alpha (HNF1A) in association with type 2 diabetes, and to characterize its putative genetic determinants. METHOD: The presence or absence of HTGW was determined in 522 Oji-Cree subjects (223 males, 299 females), >or=18 years of age, in whom physical measurements and fasting plasma analyte concentrations were gathered, and a 75-g oral glucose tolerance test was administered, as part of a cross-sectional study. Subjects were genotyped for HNF1A codon 319, angiotensinogen (AGT) codons 174 and 235, G-protein beta3-subunit (GNB3) nucleotide 825, fatty acid-binding protein (FABP2) codon 54, nucleotides -455 and -482 of the apolipoprotein (apo) C-III (APOC3) promoter, and a 5-bp insertion/deletion polymorphism within the 3'-untranslated region of protein phosphatase 1 regulatory subunit 3 (PPP1R3). RESULTS: The unadjusted prevalence of HTGW in Oji-Cree adults was 20.5%, with more males affected than females (27.8 vs 15.1%, P=0.0004). Logistic regression analysis, adjusted for age and gender, showed type 2 diabetes was associated with both HNF1A G319S (odds ratio (OR) 4.85, 95% CI 2.45, 9.58) and HTGW (OR 4.96, 95% CI 2.49, 9.88). When the HNF1A mutation and HTGW were present in combination, the OR for type 2 diabetes was markedly increased (OR 43.2, 95% CI 12.4, 150). In women only, both GNB3 825C>T and FABP2 A54T genotypes were significantly associated with HTGW (OR 2.02, 95% CI 1.01, 4.05 and OR 1.95, 95% CI 1.01, 3.74, respectively). CONCLUSIONS: HTGW is prevalent in Oji-Cree, especially in men. The ORs for type 2 diabetes were similar ( approximately 5-fold) for subjects with either the presence of HTGW or the private HNF1A G319S mutation. These two independent risk factors acted synergistically to confer an even greater increased risk of type 2 diabetes.

Hegele RA, Guy J, Ban MR, Wang J. · Vascular Biology Group, Robarts Research Institute, London, Ontario, Canada. · Lipids Health Dis. · Pubmed #16098225 links to  free full text

Abstract: BACKGROUND: NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations in NPC1L1 in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. RESULTS: In 101 dyslipidemic subjects, we found that NPC1L1 haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the common NPC1L1 haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol. CONCLUSION: These preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment.