Impact of Lipoprotein(a)-Cholesterol on Accurate Classification of Familial Hypercholesterolemia (original) (raw)
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Journal of Clinical Lipidology, 2019
BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality and morbidity. Increased low-density lipoprotein cholesterol (LDL-C) level is its major risk factor. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated LDL-C since birth and subsequent premature CVD. There is a heterogeneity in the CVD onset in patients with FH. This is potentially due to the presence of other independent risk factors. Lipoprotein(a) [Lp(a)] is an LDL-like particle and represents a strong risk factor for CVD. OBJECTIVE: Our objective was to understand the contribution of Lp(a) in the susceptibility to CVD in individuals with genetic diagnosis of FH. METHODS: We measured Lp(a) levels in 2 independent and well-characterized genetic-FH cohorts: the FH-Gothenburg cohort (n 5 190) and the FH-CEGP Milan cohort (n 5 160). The genetic diagnosis
Atherosclerosis, 2011
Objective: Familial hypercholesterolemia (FH) is caused by defects in genes coding for proteins involved in low density lipoprotein (LDL) metabolism, and is associated with increased risk of premature coronary heart disease (CHD). The clinical phenotype of FH exhibits marked variability due to additional metabolic and environmental factors, and further biomarkers are required for appropriate risk assessment. The aim of the present study was to search for risk markers among FH patients. Methods and results: Clinical and biochemical parameters of FH subjects with early CHD events (CHDsusceptible) and FH subjects with late or no CHD events (CHD-resistant) were compared. Our data show that CHD-susceptible FH patients had significantly higher Lipoprotein (Lp) (a) levels compared to CHDresistant FH patients. When subdividing by gender, the main findings were that (i) CHD-susceptible women had significantly higher levels of both Lp(a), low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B as compared to CHD-resistant women, and (ii) CHD-resistant women had significantly lower Lp(a) levels and higher high density lipoprotein (HDL) cholesterol and apoA-I levels compared to CHD-resistant men. Conclusions: The data suggest that Lp(a) may be an important coronary risk marker in FH patients, in particular in combination with elevated LDL cholesterol levels among female subjects. Thus, measurement of Lp(a) levels may help identifying high-risk individuals who could benefit from an aggressive therapy, including statins to reduce LDL-cholesterol to guideline-recommended levels.
Lipids in Health and Disease
Background Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and increased cardiovascular disease (CVD) risk. FH patients often have increased lipoprotein(a) [Lp(a)] levels, which further increase CVD risk. Novel methods for accurately calculating LDL-C have been proposed. Methods Patients with FH were recruited by a network of Greek sites participating in the HELLAS-FH registry. LDL-C levels were calculated using the Friedewald (LDL-CF) and the Martin/Hopkins (LDL-CM/H) equations as well as after correcting LDL-CM/H for Lp(a) levels [LDL-CLp(a)corM/H]. The objective was to compare LDL-C levels and target achievement as estimated by different methods in FH patients. Results This analysis included 1620 patients (1423 adults and 197 children). In adults at diagnosis, LDL-CF and LDL-CM/H levels were similar [235 ± 70 mg/dL (6.1 ± 1.8 mmol/L) vs 235 ± 69 mg/dL (6.1 ± 1.8 mmol/L), respectively; P = NS], while LDL-CLp(a)corM...
The Lancet, 2013
Background Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify aff ected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-eff ect LDL-C-raising alleles. Methods In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UKbased sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identifi ed by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confi rmed mutation, those with an identifi ed mutation, and controls from WHII. Findings We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0•90 [SD 0•23]) was strongly associated with LDL-C concentration (p=1•4 × 10 − ⁷⁷; R²=0•11). Mutation-negative UK patients had a signifi cantly higher mean weighted LDL-C score (1•0 [SD 0•21]) than did WHII controls (p=4•5 × 10 − ¹⁶), as did the mutation-negative Belgian patients (0•99 [0•19]; p=5•2 × 10 − ²⁰). The score was also higher in UK (0•95 [0•20]; p=1•6 × 10 − ⁵) and Belgian (0•92 [0•20]; p=0•04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. Interpretation In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the effi ciency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease.
Metabolism, 1992
Familial Hypercholesterolemia (FH) is a condition characterized by markedly elevated blood cholesterol, low-density lipoproteins (LDL), and apolipoprotein B-100 (apo B). The molecular basis of this monogenie disease is the defective functioning of the cellular receptor for LDL that recognizes apo B. Lipoprotein(a) [Lp(a)] is a circulating lipoprotein that is structurally related to LDL, as it also contains apo B. To assess the impact of the LDL receptor deficiency on the plasma Lp(a) concentration, we measured Lp(a) in 28 FH patients and in 31 unaffected relatives. Because elevation of Lp(a) concentration in plasma of patients with coronary artery disease (CAD) appears to occur independently from plasma cholesterol levels, to avoid potentially confounding problems, members of the families chosen had no history for the disease. Whereas apo B clearly showed a bimodality of distribution by being significantly higher in the FH patients (188 2 38 mg/dL) than in the unaffected relatives (82 f 18 mg/dL), Lp(a) concentration did not differ in the two groups of patients (30 2 24 mg/dL in the FH patients Y 31 + 23 in the normolipidemic relatives). Similar results were obtained when only siblings were further considered. We conclude that although Lp(a) is closely related to LDL structurally, its level in plasma is not significantly affected by the LDL receptor activity.
Endocrine, 2022
Background: Lipoprotein(a) [Lp(a)] is a risk factor of coronary heart disease, however, its effects on stroke are less well-defined. Methods: We performed a single-center, retrospective case-control study in 1,953 and 196 ischemic stroke and hemorrhagic stroke in-hospital patients, respectively. Controls were healthy individuals that were matched for sex and age (±5 years) for the ischemic (1:1 ratio) and hemorrhagic (1:2 ratio) stroke. Lp(a) concentration was measured using the latex agglutination turbidimetric method. Logarithmic transformation and quartile categorization were applied to adjust for the skewed distribution of Lp(a). Conditional logistic regression models were used to assess the association between Lp(a) and stroke risk. Results: Median Lp(a) concentration was higher in stroke patients when compared with controls (12.2 vs. 8.60 mg/dL) and hemorrhagic strokes (14.40 vs. 13.40 mg/dL). The conditional multivariate analysis revealed a positive association between Lp(a) and ischemic stroke (OR =2.03, 2.36, and 2.03 for quartiles 2, 3 and 4, respectively, vs. quartile 1; P<0.001). In addition, elevated Lp(a) was also significantly associated with increased hemorrhagic stroke risk, after adjusted for potential covariates (OR =1.93, 3.24, and 2.19 for quartile 2, 3 and 4 respectively vs. quartile 1, P<0.05). The stratified analyses for ischemic and hemorrhagic stroke revealed significant association between elevated log-transformed Lp(a) and ischemic stroke in men. Furthermore, there was a trend towards a higher stroke risk for younger patients compared with older patients. Conclusions: Elevated serum Lp(a) is significantly positively correlated with ischemic and hemorrhagic stroke risk in the Chinese Han population, especially among men and younger patients.
European Journal of Human Genetics, 1998
for LDLR mutations and for apo(a) genotype. Three lines of evidence showed a significant effect of FH on Lp(a) levels: (1) Lp(a) values were significantly higher in FH individuals compared to non-FH relatives (p < 0.001), although the distribution of apo(a) alleles was not different in the two groups; (2) comparison of Lp(a) concentrations in 28 sib pairs, identical by descent (i.b.d.) at the apo(a) locus but non-identical for LDLR status, extracted from this large sample demonstrated significantly elevated Lp(a) concentrations in sibs with FH (p < 0.001); (3) single i.b.d. apo(a) alleles were associated with significantly higher Lp(a) concentrations (p < 0.0001) in FH than non-FH family members. Variability in associated Lp(a) levels also depended on FH status and was highest when i.b.d. alleles were present in FH subjects and lowest when present in non-FH individuals. The study demonstrates that sib pair analysis makes it possible to detect the effect of a minor gene in the presence of the effect of a major gene. Given the interactive effect of elevated LDL and high Lp(a) on CHD risk our data suggest that elevated Lp(a) may add to the CHD risk in FH subjects.