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Articles by J. Genest
Total Records ( 3 ) for J. Genest
  I Iatan , Z Dastani , R Do , D Weissglas Volkov , I Ruel , J. C Lee , A Huertas Vazquez , M. R Taskinen , A Prat , N. G Seidah , P Pajukanta , J. C Engert and J. Genest

Background— A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. HDL particles are modulated by a variety of lipases, including endothelial lipase, a phospholipase present on vascular endothelial cells. The proprotein convertase subtilisin/kexin type 5 (PCSK5) gene product is known to directly inactivate endothelial lipase and indirectly cleave and activate angiopoetin-like protein 3, a natural inhibitor of endothelial lipase. We therefore investigated the effect of human PCSK5 genetic variants on plasma HDL-C levels.

Methods and Results— Haplotypes at the PCSK5 locus were examined in 9 multigenerational families that included 60 individuals with HDL-C <10th percentile. Segregation with low HDL-C in 1 family was found. Sequencing of the PCSK5 gene in 12 probands with HDL-C <5th percentile identified 7 novel variants. Using a 2-stage design, we first genotyped these single-nucleotide polymorphisms (SNPs) along with 163 tagSNPs and 12 additional SNPs (n=182 total) in 457 individuals with documented coronary artery disease. We identified 9 SNPs associated with HDL-C (P<0.05), with the strongest results for rs11144782 and rs11144766 (P=0.002 and P=0.005, respectively). The SNP rs11144782 was also associated with very low-density lipoprotein (P=0.039), triglycerides (P=0.049), and total apolipoprotein levels (P=0.022). In stage 2, we replicated the association of rs11144766 with HDL-C (P=0.014) in an independent sample of Finnish low HDL-C families. In a combined analysis of both stages (n=883), region-wide significance of rs11144766 and low HDL-C was observed (unadjusted P=1.86x10–4 and Bonferroni-adjusted P=0.031).

Conclusions— We conclude that variability at the PCSK5 locus influences HDL-C levels, possibly through the inactivation of endothelial lipase activity, and, consequently, atherosclerotic cardiovascular disease risk.

  Z Awan , K Alwaili , A AlShahrani , L Langsetmo , D Goltzman and J. Genest

Familial hypercholesterolemia (FH) due to mutations in the low-density lipoprotein receptor (LDLR) gene exhibit severe, premature aortic calcification in a gene-dosage, age-dependent fashion. We sought to determine potential associations with mineral and skeletal indices.


We obtained computed tomography (CT) scan aortic calcium scores (AoCSs) in 19 (age 49 [SD 14] years) FH patients heterozygous for the 15-kb deletion at the LDLR gene and examined associations with various indices of mineral and skeletal homeostasis.


We found that mean bone mineral density (BMD) at the femoral neck in these patients did not differ from age-, sex-, and province-matched mean BMD, and we observed no association of AoCS with any marker of bone resorption. However, there were negative correlations between AoCS and serum concentrations of osteocalcin, a marker of bone formation (r = –0.64, P = 0.0034), urinary calcium (r = –0.59, P = 0.0085), and estimated glomerular filtration rate (r = –0.67, P = 0.0019).


We found that LDLR-deficient FH was not associated with obvious bone loss or a major disturbance in calcium homeostasis. The lack of LDLR, however, may modify osteoblast function or extracellular calcium distribution, manifesting as lower bone formation, and reduced calcium excretion, resulting in increased deposition in calcifying vascular tissue.

  M. S Kramer , R Evans , R. W Platt , L Goulet , L Seguin , C Dassa , J Lydon , H McNamara , M Dahhou and J. Genest

Background Mothers who give birth to preterm infants are at increased risk of mortality from coronary heart disease and stroke, but the biological pathways underlying these associations have not been explored.

Methods We carried out a case–control study nested in a large (n = 5337) prospective, multicentre cohort. All cohort women had an interview, examination and venipuncture at 24–26 weeks. Frozen plasma samples in spontaneous preterm births (n = 207) and 444 term controls were analysed for plasma homocysteine, folate, cholesterol (total, low-density lipoprotein and high-density lipoprotein) and thrombin–antithrombin (TAT) complexes. DNA was extracted and analysed for seven gene polymorphisms involved in thrombophilia or folate or homocysteine metabolism. Fresh placentas were fixed, stained and blindly assessed for histologic evidence of infarction and decidual vasculopathy.

Results High (above the median) plasma homocysteine and HDL cholesterol were significantly and independently associated with the risk of spontaneous preterm birth [adjusted odds ratios (OR)s = 1.9 (95% 1.1–3.3) and 0.5 (0.3–0.9), respectively]. A higher proportion of women with high homocysteine concentrations had decidual vasculopathy [(13.0 vs 6.8%; OR = 1.9 (1.1–3.5)], although the positive association between decidual vasculopathy and preterm birth did not achieve statistical significance [OR = 1.5 (0.9–2.7)]. No significant associations were observed with the DNA polymorphisms or with plasma TAT or folate levels.

Conclusions Similar vasculopathic risk factors may underlie preterm birth and adult coronary heart disease and stroke.

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