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Efficacy of statins in familial hypercholesterolaemia: a long term cohort study

Objective To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. Design Cohort study with a mean follow-up of 8.5 years. Setting 27 outpatient lipid clinics. Subjects 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. Main outcome measures Risk of coronary heart disease in treated and “untreated” (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. Results In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). Conclusion Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population.

Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis.

BACKGROUND Tendon xanthomas are characteristic of familial hypercholesterolemia (FH). It is not clear whether FH patients with xanthomas have higher risk of cardiovascular disease (CVD) than those without xanthomas. The clinical diagnosis of FH in patients without xanthomas, namely requires the presence of CVD in the patient or in a first-degree relative. This may have masked the association between xanthomas and CVD in a number of studies. A diagnosis of FH based on the presence of a mutation in the low-density lipoprotein receptor (LDLR) gene is free from this selection on CVD. In this systematic review and meta-analysis, we therefore compared the risk of CVD between patients heterozygous for LDLR mutation with and without xanthomas. METHODS AND RESULTS We conducted a literature search with PubMed and the Web of Science up to January 14, 2009. We selected all articles examining more than 25 human heterozygous FH patients, that provided information about xanthomas. Articles had to be written in a Western European language. A total of 22 articles suited for analyses. A genetic confirmation of FH was compulsory to correctly assess the risk of CVD with presence of xanthomas. Age, male gender, LDL-cholesterol and triglyceride level were associated with the presence of xanthomas (p<0.05 for all). In patients with genetically confirmed FH, xanthomas were associated with a 3.20-fold higher risk of CVD (95% CI 2.12-4.82, p<0.01). CONCLUSIONS Xanthomas are associated with a 3 times higher risk of CVD among FH patients, suggesting that xanthomas and CVD may share etiology.

Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia.

AIMS Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD. METHODS AND RESULTS We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001). CONCLUSION We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD.

The risk of tendon xanthomas in familial hypercholesterolaemia is influenced by variation in genes of the reverse cholesterol transport pathway and the low-density lipoprotein oxidation pathway

AIMS The presence of tendon xanthomas is a marker of high risk of cardiovascular disease (CVD) among patients with familial hypercholesterolaemia (FH). Therefore, xanthomas and atherosclerosis may result from the same pathophysiological mechanisms. Reverse cholesterol transport (RCT) and low-density lipoprotein (LDL) oxidation are pathophysiological pathways of atherosclerosis, and it is well established that genetic variation in these pathways influences CVD risk. We therefore determined whether genetic variation in these pathways is also associated with the occurrence of tendon xanthomas in FH patients. METHODS AND RESULTS Four genetic variants in each pathway were genotyped in 1208 FH patients. We constructed a gene-load score for both pathways. The odds of xanthomas increased with the number of the risk alleles in the RCT pathway (OR 1.21, 95% CI 1.08-1.36, P(trend) = 0.0014). Similarly, higher numbers of risk alleles in the LDL oxidation pathway were associated with the presence of xanthomas (OR 1.24, 95% CI 1.08-1.41, P(trend) = 0.0015). CONCLUSION The presence of tendon xanthomas in FH patients is associated with genetic variation in the RCT and LDL oxidation pathways. These results support the hypothesis that xanthomas and atherosclerosis share pathophysiological mechanisms.

Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality

OBJECTIVE Fetal exposure to maternal hypercholesterolemia increases the extent of fatty-streak formation in fetal aortas as well as the rate of progression, and may therefore increase coronary heart disease (CHD) risk later in life. We hypothesized that the risk of CHD in untreated individuals with familial hypercholesterolemia (FH) is more extreme when the disease is transmitted maternally. METHODS In a large Dutch pedigree carrying the V408M mutation in the low-density lipoprotein (LDL) receptor gene, 161 individuals over seven generations were identified for which FH status and parent of origin of FH were known. We calculated standardized mortality ratios (SMR) and compared the consequences of maternal and paternal inheritance of FH by Poisson regression analysis. RESULTS Maternally inherited FH was associated with significantly higher excess mortality than FH transmitted by fathers (relative risk 2.2; p = 0.048): the SMR of maternal inheritance was 2.49 (95% confidence interval (CI) 1.45-3.99; p = 0.001), whereas it was not significantly increased in paternally inherited FH (SMR 1.30, 95% CI 0.65-2.32; p = 0.234). CONCLUSION Mortality rates are more increased when FH is inherited through the mother, supporting the fetal origin of adulthood disease hypothesis with all cause death, the most indisputable outcome measure. Future research should explore safe options for cholesterol-lowering therapy of pregnant women with FH in order to prevent unfavourable (epigenetic) consequences leading to atherosclerosis in their children.

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia

OBJECTIVES To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH). BACKGROUND The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH. METHODS In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking. RESULTS HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17-1.89, p=0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20-2.76, p=0.005). HapA was not associated with CHD. CONCLUSION We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.

Cascade screening of familial hypercholesterolemia must go on

PURPOSE This study assesses the success of the recently terminated Dutch nationwide cascade screening by examining whether children with familial hypercholesterolemia (FH) were identified through family screening or due to cardiovascular (CVD) events in the FH parent. METHODS We collected clinical information of all children (0-18 years) with FH with a pathogenic variant at our outpatient lipid clinic between 1992 and 2014 and their FH parents and FH grandparents. RESULTS We analysed 292 FH children from 205 parents with FH. A history of premature CVD was present in 20% of the parents (29% of the fathers, 9% of the mothers) and 49% of the FH grandparents. CONCLUSION The fact that CVD is still a presenting event of FH in especially fathers shows that nationwide screening might have been terminated too early. Therefore we recommend to proceed the cascade screening.

A frequent variant in the ABCA1 gene is associated with increased coronary heart disease risk and a better response to statin treatment in familial hypercholesterolemia patients

AIMS Statins are essential for the reduction of risk of coronary heart disease (CHD) in familial hypercholesterolemia (FH). One of many genes influenced by statin treatment is the ATP-binding cassette transporter A1 (ABCA1) gene, which plays an important role in metabolism of high-density lipoprotein (HDL). The present aim was to test if the ABCA1 C69T polymorphism influences CHD risk and response to statin treatment. METHODS AND RESULTS In a large cohort of 1686 FH patients without a history of CHD before 1 January 1990, we analysed statin-ABCA1 C69T polymorphism interaction by comparing treated and untreated patients. We used a Cox proportional hazard model adjusted for sex, birth year, and smoking. In analyses restricted to untreated patients, the TT genotype was associated with 1.7 times higher CHD risk than the CC genotype (hazard ratio (HR) =1.65, 95% confidence interval (95% CI): 1.08-2.53; P = 0.02). Conversely, in statin-treated FH patients, CHD risk in TT individuals was not increased (HR: 0.65, 95% CI: 0.35-1.24; P = 0.2). Formal testing confirmed this interaction (P = 0.03). HDL-cholesterol levels were significantly more raised in statin-treated patients with the TT than with the CC genotype (two-way ANOVA, P = 0.045). CONCLUSION In untreated FH patients, the TT genotype of the ABCA1 C69T polymorphism was associated with increased CHD risk. However, in statin-treated patients, CHD risk was no longer significantly different between genotypes, at least partially explained by a higher rise in HDL-cholesterol levels during statin treatment in TT individuals.

Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

Background— In humans, the E4 allele of the apolipoprotein E gene is associated with increased coronary heart disease risk. Surprisingly, in rodents, apolipoprotein E4 only accelerates the atherosclerotic process when transgenic for the human low-density lipoprotein receptor (LDLR) protein. We therefore investigated whether the LDLR locus interacted with the apolipoprotein E gene genotype on coronary heart disease risk in patients clinically diagnosed with familial hypercholesterolemia with and without LDLR mutation. We investigated whether the presence of an LDLR mutation diminishing LDLR function was protective in E4/E4 carriers. Methods and Results— In a cohort of 2400 patients clinically diagnosed with familial hypercholesterolemia, we found an LDLR gene mutation in 1383 patients, whereas in 1013 patients, such mutation was not present. In 92 patients homozygous for the apolipoprotein E4, the presence of an LDLR mutation conferred lower coronary heart disease risk (hazard ratio, 0.16; 95% CI, 0.05–0.58; P=0.005). Mirroring these results, the apolipoprotein E4/E4 genotype was also associated with lower coronary heart disease risk in patients with familial hypercholesterolemia with an LDLR mutation (hazard ratio, 0.26; hazard ratio, 0.08–0.80; P=0.02). Conclusions— LDLR function is key to the detrimental effects of apolipoprotein E4 in humans. Kinetic studies in humans are now required to study the consequences of our observation for prevention of both coronary heart disease and Alzheimer disease.

5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia

BACKGROUND Tendon xanthomas are characteristic for familial hypercholesterolemia (FH), and are associated with a higher risk of coronary heart disease (CHD). They often present with local inflammation. Inflammation may therefore be involved in their pathogenesis, as it is in the pathogenesis of CHD. A key role in the inflammatory pathway is played by the 5-lipoxygenase activating protein (ALOX5AP), which is known to influence the risk of CHD in FH. To test our hypothesis that ALOX5AP contributes to the development of xanthomas, we studied whether variants in the ALOX5AP gene influence the risk of xanthomas. METHODS We examined 945 patients with genetically confirmed heterozygous FH to determine whether they had tendon xanthomas. We genotyped seven polymorphisms in the ALOX5AP gene and constructed haplotypes of these polymorphisms. RESULTS The A allele of the rs9551963 polymorphism was associated with an increased risk of xanthomas (OR 1.52, 95% CI 1.11-2.07, p=0.01), while the A allele of rs17222842 was protective (OR 0.62, 95% CI 0.43-0.90, p=0.01). These two polymorphisms fully explained the risk estimates of all haplotypes. Individual haplotypes, however, were not significantly associated with xanthomas. CONCLUSION Variants in the ALOX5AP gene are associated with the presence of xanthomas in FH patients. This result supports our hypothesis that inflammation is a pathogenetic factor of xanthomas.