Hyperlipidemias: Yusuf S

Yusuf S, Lonn E, Bosch J. · Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. · Lancet. · Pubmed #19345816 No free full text.

This publication has no abstract.

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.

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.

Gupta M, Doobay AV, Singh N, Anand SS, Raja F, Mawji F, Kho J, Karavetian A, Yi Q, Yusuf S. · William Osler Health Centre, Brampton, Ont. · CMAJ. · Pubmed #11944758 links to  free full text

Abstract: BACKGROUND: Coronary artery disease affects a significantly larger proportion of Canadians of South Asian origin than Canadians of other ethnic origins. We compared differences in presentation, risk factors and management of myocardial infarction (MI) between South Asian Canadians and matched control subjects. METHODS: We reviewed the charts of 553 South Asian patients and 553 non-South Asian matched control subjects presenting with acute MI (International Classification of Diseases code 410) to 2 hospitals in Canada from January 1994 to April 1999. We identified South Asian subjects by their surnames and first names, and by using self-reported ethnicity and country of birth when available. Patients of Southeast Asian and Middle Eastern origin were excluded. The remaining patients were classified as non-South Asian. Subjects were matched by age within 5 years, sex, discharge date within 6 months and hospital of admission. Presentation characteristics, risk factors and major complications were compared between the 2 groups. RESULTS: The median time from symptom onset to presentation with acute MI was significantly longer among the South Asian subjects than among the control subjects (3.92 v. 3.08 hours) (p = 0.04). The South Asians were more likely than the control subjects to have diabetes mellitus (43.4% v. 28.2%) (p < 0.001) despite having a significantly lower mean body mass index (25.7 v. 28.0) (p = 0.05) but were less likely to have hyperlipidemia (36.2% v. 42.7%, p = 0.05), to smoke (29.3% v. 67.8%) (p < 0.001) or to have pre-existing vascular disease (49.4% v. 55.0%, p = 0.04). Treatment of acute MI was similar between the South Asian and matched control groups. Also similar were the in-hospital outcomes, including mortality (9.6% and 7.8%, p = 0.27). INTERPRETATION: There are clear differences in the risk factor profile between Canadians of South Asian origin and those of non-South Asian origin who have acute MI. Despite the higher incidence of cardiovascular disease in the South Asian population, our results indicate that the in-hospital case-fatality rate for MI is the same for South Asian and non-South Asian Canadians.