Biomedical subjects

Nathalie Laflamme

Publications and source records attributed to Nathalie Laflamme.

6 recordsLinked to original sources

PubMed2026

Predictors of aortic stenosis in homozygous familial hypercholesterolemia: A study from the Canadian HoFH registry.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. This disease is associated with a major risk of both atherosclerotic cardiovascular disease and aortic stenosis (AS). The predictors of AS in this population are not well established. OBJECTIVE: To investigate the univariable and multivariable predictors of AS in patients from the Canadian HoFH registry. METHODS: Individuals from the Canadian HoFH registry were included in this retrospective longitudinal study. Clinical data were obtained from the treating physicians using a standardized questionnaire. Cox proportional hazards models were used to investigate the predictors of AS. The observed lifetime risk of AS was calculated using Kaplan-Meier estimates. RESULTS: Among the 67 patients with HoFH, 25 (37%) developed AS. The mean age at baseline was 22 ± 17 years and women represented 57% of the cohort. The independent predictors of AS were the baseline LDL-C (hazard ratio [HR] 1.22 [1.09-1.35], P = .0003) as well as the presence of at least 1 null genetic variant (HR 3.73 [1.41-9.86], P = .008). Having a baseline LDL-C value above 13 mmol/L was associated with an observed lifelong risk of developing AS approaching 100% within this cohort, whereas having a value below this threshold was associated with a risk of 27% (P = .0002). CONCLUSION: This is the first systematic evaluation within a national HoFH registry to report the univariable and multivariable predictors of AS in patients with HoFH. An external validation of our results in an international cohort of HoFH is warranted.

Aortic stenosis↗

PubMed2006

Effects of job strain on blood pressure: a prospective study of male and female white-collar workers.

OBJECTIVES: We evaluated whether cumulative exposure to job strain increases blood pressure. METHODS: A prospective study of 8395 white-collar workers was initiated during 1991 to 1993. At follow-up, 7.5 years later, 84% of the participants were reassessed to estimate cumulative exposure to job strain. RESULTS: Compared with men who had never been exposed, men with cumulative exposure and those who became exposed during follow-up showed significant systolic blood pressure increments of 1.8 mm Hg (95% confidence interval [CI]=0.1, 3.5) and 1.5 mm Hg (95% CI=0.2, 2.8), respectively, and relative risks of blood pressure increases in the highest quintile group of 1.33 (95% CI = 1.01, 1.76) and 1.40 (95% CI = 1.14, 1.73). Effect magnitudes were smaller among women. Effects tended to be more pronounced among men and women with low levels of social support at work. CONCLUSIONS: Among these white-collar workers, exposure to cumulative job strain had a modest but significant effect on systolic blood pressure among men. The risk was of comparable magnitude to that observed for age and sedentary behavior. Men and women with low levels of social support at work appeared to be at higher risk for increases in blood pressure.

Adolescent↗

PubMed2005

A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French-Canadian premenopausal women.

UNLABELLED: Genes are important BMD determinants. We studied the association of an ESRRA gene functional variant with BMD in 1335 premenopausal women. The ESRRA genotype was an independent predictor of L2-L4 BMD, with an effect similar to smoking and equivalent to a 10-kg difference in weight. INTRODUCTION: Several genetic polymorphisms have been associated with osteoporosis or osteoporosis fractures, but no functional effect has been shown for most of these gene variants. Because functional studies have implicated estrogen-related receptor alpha (ESRRA) in bone metabolism, we evaluated whether a recently described regulatory variant of the ESRRA gene is associated with lumbar and hip BMD as measured by DXA and with heel bone parameters as measured by quantitative ultrasound (QUS). MATERIALS AND METHODS: Heel bone parameters were measured by right calcaneal QUS in 1335 healthy French-Canadian premenopausal women, and one-half of these women also had their BMD evaluated at two sites: femoral neck and lumbar spine (L2-L4) by DXA. All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance. The significance of the ESRRA contribution to the model was also assessed by two different permutation tests. RESULTS: A statistically significant association between ESRRA genotype and lumbar spine BMD was observed: women carrying the long ESRRA genotype had a 3.9% (0.045 g/cm2) higher lumbar spine BMD than those carrying the short ESRRA genotype (p = 0.004), independently of other risk factors measured. This effect of ESRRA genotype is similar to the effect of smoking and equivalent to a 10-kg difference in weight. This association was confirmed by permutation tests (p = 0.004). The same trend was observed for femoral neck BMD (2.6%, p = 0.07). However, no association was observed between ESRRA and QUS heel bone measures. CONCLUSION: These results support the genetic influence of this ESRRA regulatory variant on BMD.

Absorptiometry, Photon↗

PubMed2005

Effect of the APOC3 Sst I SNP on fasting triglyceride levels in men heterozygous for the LPL P207L deficiency.

Lipoprotein lipase (LPL) plays a major role in triglyceride (TG)-rich lipoprotein catabolism. A mutation at codon 207 (P207L) in the exon 5 of the LPL gene has been associated with 50% reduction in postheparin plasma LPL activity and significant increase in plasma TG levels in heterozygous individuals with low HDL. However, heterogeneity in fasting TG concentrations among these carriers suggests that other factors may be involved in the expression of this hypertriglyceridemic state. Indeed, previous studies have shown that the rare S2 allele of the APOC3 Sst I polymorphism was associated with higher concentrations of TG levels in noncarriers of LPL defect. Therefore, we investigated the association of the APOC3 Sst I variant on fasting lipoprotein-lipid levels in a sample of 35 heterozygous men bearing the LPL P207L mutation. Genetic association analyses were performed using the two-genotype groups S1/S1 and S1/S2. The genotype S1/S2 group was characterized by greater plasma cholesterol (plasma-C, P=0.02), plasma-TG (P=0.04), very low-density lipoproteins (VLDL)-C (P=0.004), VLDL-TG (P=0.01), VLDL-apolipoprotein B (apoB) (P=0.001) levels and cholesterol/HDL-C ratio (P=0.008), as well as lower VLDL-TG/VLDL-apoB ratio compared to the S1/S1 genotype group. These results support an exacerbating effect of the APOC3 Sst I single-nucleotide polymorphism on fasting TG levels since a large number of smaller VLDL particles are observed in LPL-deficient men bearing the APOC3 S2 allele.

Adult↗

PubMed2003

Cooperation between toll-like receptor 2 and 4 in the brain of mice challenged with cell wall components derived from gram-negative and gram-positive bacteria.

In this study we investigated whether induction of toll-like receptor 2 (TLR2) amplifies the effect of a cell wall component derived from gram-positive bacteria, namely peptidoglycan (PGN). Mice received a first systemic lipopolysaccharide (LPS) injection to pre-induce TLR2 in various regions of the brain, and 6 h later, a second administration of either LPS or PGN. The data show a robust transcriptional activation of TLR2, TNF-alpha and monocyte chemotactic protein-1 (MCP-1) in microglial cells of mice challenged twice with LPS, whereas PGN essentially abolished this response. TLR4 plays a critical role in this process, because C3H/HeJ mice no longer responded to LPS but exhibited a normal reaction to PGN. Conversely, a robust signal for genes encoding innate immune proteins was found in the brain of TLR2-deficient mice challenged with LPS. However, the second LPS bolus failed to trigger TNF-alpha and IL-12 in TLR2-deficient mice, while the same treatment caused a strong induction of these genes in the cerebral tissue of wild-type littermates. The present data provide evidence that cooperation exists between TLR4 and TLR2. While TLR4 is absolutely necessary to engage the innate immune response in the brain, TLR2 participates in the regulation of genes encoding TNF-alpha and IL-12 during severe endotoxemia. Such collaboration between TLR4 and TLR2 may be determinant for the transfer from the innate to the adaptive immunity within the CNS of infected animals.

Adaptation, Physiological↗

PubMed2003

[Human molecular genetics: from monogenic to polygenic or complex disorders].

Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.

Genetic Predisposition to Disease↗