Sofía Pérez-Calahorra

Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship

Background— Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL protein receptor adaptor 1 ( LDLRAP1 ). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results— Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB , 5 for LDLRAP1 , and 41 for LDLR ), 45 compound heterozygous for LDLR , 3 double heterozygous for LDLR and PSCK9 , and 2 double heterozygous for LDLR and APOB . No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions— HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.Background—Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL protein receptor adaptor 1 (LDLRAP1). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results—Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB, 5 for LDLRAP1, and 41 for LDLR), 45 compound heterozygous for LDLR, 3 double heterozygous for LDLR and PSCK9, and 2 double heterozygous for LDLR and APOB. No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions—HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.

Serum Lipid Responses to Weight Loss Differ between Overweight Adults with Familial Hypercholesterolemia and Those with Familial Combined Hyperlipidemia

The effect of weight loss on lipids differs among individuals, although whether it can modify the management of hereditary hyperlipidemias has not yet been explored. The objective of this study was to examine the effect of weight loss on cholesterol metabolism, assessed by circulating noncholesterol sterols, in overweight adults with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). We conducted a 6-mo weight loss intervention in untreated individuals (FH: n = 28; FCHL: n = 50) with a body mass index of >25 kg/m(2) and mean age of 46.9 ± 11.3 y, of whom 53.8% were men. A hypocaloric diet was implemented and serum lipid analyses, including noncholesterol sterols, were assessed. Global significant mean weight losses of 5.7 kg (-6.6%) and 6.6 kg (-7.6%) were achieved after 3 and 6 mo, respectively. Mean non-HDL cholesterol and triglyceride (TG) changes at 3 and 6 mo compared with baseline were -5.8% (P = 0.004) and -7.1% (P = 0.014), and -30.1% (P < 0.001) and -31.4% (P < 0.001), respectively. Among participants who lost ≥5% body weight, only significant changes in TGs and non-HDL cholesterol were observed in FCHL participants. Sterol precursors of cholesterol synthesis decreased significantly by 10.4% at 6 mo in FCHL participants, mostly because of a 23.9% lathosterol reduction. Baseline synthesis precursors were associated with TG reduction in FCHL participants (P = 0.039; R(2) = 0.20), and intestinally derived sterols were inversely associated with non-HDL cholesterol changes in FH participants (P = 0.036; R(2) = 0.21). Thus, FCHL participants had a better lipid-lowering response to weight loss than did FH participants. This response was positively associated with baseline cholesterol synthesis, which was reduced by weight loss. Our results confirm the cholesterol overproduction mechanism of FCHL and its interaction with fat mass, while also supporting the differential management of familial hyperlipidemias if obesity coexists. This trial was registered at clinicaltrials.gov as NCT01995149.

Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia

Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486–0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex.

Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE

BACKGROUND A substantial proportion of individuals clinically diagnosed as familial hypercholesterolemia (FH) do not carry pathogenic mutations in candidate genes. Whether in them the high cholesterol trait is transmitted monogenically has not been studied. OBJECTIVES We assessed the inheritance pattern, penetrance, and expression of high low-density lipoprotein (LDL)-cholesterol (LDLc) in families with genetic hypercholesterolemia (GH) without known causative mutations (non-FH-GH). METHODS The study included probands with a clinical diagnosis of FH and their families attending 2 lipid clinics in Spain. Inclusion criteria for probands were LDLc >95th percentile, triglycerides <90th percentile, at least 1 first-degree family member with LDLc >90th percentile, >5 points in the Dutch Lipid Clinic Network criteria score, and absence of mutations in LDLR, APOB, PCSK9 or APOE. Eleven FH families with a LDLR mutation were also examined for comparison. RESULTS We analyzed 49 non-FH-GH probands and 277 first-and second-degree relatives. LDLc was >90th percentile in 37.8% of blood relatives, at concentrations similar to those of probands. LDLc had a normal distribution in non-FH-GH families, in contrast with a bimodal distribution in FH families. When a dominant model was tested, family-based association tests gave much lower heritability values for total cholesterol and LDLc in non-FH-GH (0.39 and 0.32, respectively) than in FH (0.78 and 0.61, respectively). CONCLUSIONS Non-FH-GH families have a milder lipid phenotype than genetically defined FH. The heritage pattern of LDLc in non-FH-GH does not fit with a monogenic disorder. Our findings support the concept that most non-FH-GHs are polygenic hypercholesterolemias.

Registro Nacional de Dislipemias de la Sociedad Española de Arteriosclerosis: situación actual

INTRODUCTION Clinical registries are a very effective tool to verify the usual clinical practice, to compare clinical strategies and to improve the knowledge of diagnostic and therapeutic new procedures. METHODS The National Registry of Dyslipemias of the Spanish Society of Arteriosclerosis (SEA) is an on-line, retrospective and prospective database where the different Spanish lipid units accredited by the SEA introduce data from patients with disorders of lipid metabolism. RESULTS The registry was created in 2013, and since then clinical, analytical, genetic and evolutionary data of 4,449 patients have been introduced until June 2017. In the last year the registry has given rise to a considerable number of international publications and there are several more in progress. An ambitious incentive plan for inclusion of patients has been initiated to get the SEA registry as a global reference that helps to improve the knowledge and clinical management of these patients. CONCLUSIONS From the coordinating group of the registry we encourage all SEA partners to collaborate in the multiple forms that the registry allows, and to make it an international scientific reference.

Single Nucleotide Variants Associated With Polygenic Hypercholesterolemia in Families Diagnosed Clinically With Familial Hypercholesterolemia

INTRODUCTION AND OBJECTIVES Approximately 20% to 40% of clinically defined familial hypercholesterolemia cases do not show a causative mutation in candidate genes, and some of them may have a polygenic origin. A cholesterol gene risk score for the diagnosis of polygenic hypercholesterolemia has been demonstrated to be valuable to differentiate polygenic and monogenic hypercholesterolemia. The aim of this study was to determine the contribution to low-density lipoprotein cholesterol (LDL-C) of the single nucleotide variants associated with polygenic hypercholesterolemia in probands with genetic hypercholesterolemia without mutations in candidate genes (nonfamilial hypercholesterolemia genetic hypercholesterolemia) and the genetic score in cascade screening in their family members. METHODS We recruited 49 nonfamilial hypercholesterolemia genetic hypercholesterolemia families (294 participants) and calculated cholesterol gene scores, derived from single nucleotide variants in SORT1, APOB, ABCG8, APOE and LDLR and lipoprotein(a) plasma concentration. RESULTS Risk alleles in SORT1, ABCG8, APOE, and LDLR showed a statistically significantly higher frequency in blood relatives than in the 1000 Genomes Project. However, there were no differences between affected and nonaffected members. The contribution of the cholesterol gene score to LDL-C was significantly higher in affected than in nonaffected participants (P = .048). The percentage of the LDL-C variation explained by the score was 3.1%, and this percentage increased to 6.9% in those families with the highest genetic score in the proband. CONCLUSIONS Nonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C. Their contribution varies greatly among families, indicating the complexity and heterogeneity of these forms of hypercholesterolemias. The gene score explains a small percentage of LDL-C, which limits its use in diagnosis.

Rapid resolution of xanthelasmas after treatment with alirocumab

Xanthelasmas are superficial fat deposits around the eyelids commonly present in different hyperlipidemias and associated with increased cardiovascular risk. Statins or other lipid-lowering treatments do not usually modify them. We present the case of a middle-age man with severe high levels of LDL cholesterol from youth due to a genetically defined heterozygous familiar hypercholesterolemia (HeFH). He presented large xanthelasmas of both inner eyelids in spite of long term treatment with statins and ezetimibe that disappeared after treatment with alirocumab75 mg every 2 weeks for 26 months. His LDL cholesterol went from 164 mg/dL to 47 mg/dL with alirocumab. Xanthelasma regression was not previously reported with lipid-lowering drugs in HeFH. This case demonstrates that regression of skin lipid lesions can be achieved with very low LDL cholesterol concentrations.

Effect of different fat-enriched meats on non-cholesterol sterols and oxysterols as markers of cholesterol metabolism: Results of a randomized and cross-over clinical trial

BACKGROUND AND AIM Different kinds of fatty acids can affect the synthesis, absorption, and elimination of cholesterol. This study was carried out to assess the associations of cholesterol metabolism with the intake of two meats with different fatty acid composition in healthy volunteers. METHODS AND RESULTS The study group was composed of 20 subjects (12 males and eight females; age, 34.4 ± 11.6 years; body mass index (BMI), 23.5 ± 2.3 kg/m(2); low-density lipoprotein (LDL) cholesterol, 2.97 ± 0.55 mmol/l; high-density lipoprotein (HDL) cholesterol, 1.61 ± 0.31 mmol/l; triglycerides (TG), 1.06 ± 0.41 mmol/l) who completed a 30-day randomized and cross-over study to compare the cholesterol metabolism effect of 250 g of low-fat lamb versus 250 g of high-fat lamb per day in their usual diet. Cholesterol absorption, synthesis, and elimination were estimated from the serum non-cholesterol sterol and oxysterol concentrations analyzed by a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). No changes in weight, plasma lipids, or physical activity were observed across the study. Cholesterol intestinal absorption was decreased with both diets. Cholesterol synthesis and elimination decreased during the low-fat lamb dietary intervention (ρ = 0.048 and ρ = 0.005, respectively). CONCLUSION Acute changes in the diet fat content modify the synthesis, absorption, and biliary elimination of cholesterol. These changes were observed even in the absence of total and LDL cholesterol changes in plasma. REGISTRATION NUMBER FOR CLINICAL TRIALS ClinicalTrials.gov PRS, NCT02259153.

Cholesterol oversynthesis markers define familial combined hyperlipidemia versus other genetic hypercholesterolemias independently of body weight

Primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH), and familial combined hyperlipidemia (FCHL) are polygenic genetic diseases that occur with hypercholesterolemia, and both share a very high cardiovascular risk. In order to better characterize the metabolic abnormalities associated with these primary hypercholesterolemias, we used noncholesterol sterols, as markers of cholesterol metabolism, to determine their potential differences. Hepatic cholesterol synthesis markers (desmosterol and lanosterol) and intestinal cholesterol absorption markers (sitosterol and campesterol) were determined in non-FH GH (n=200), FCHL (n=100) and genetically defined heterozygous familial hypercholesterolemia subjects (FH) (n=100) and in normolipidemic controls (n=100). FCHL subjects had lower cholesterol absorption and higher cholesterol synthesis than non-FH GH, FH and controls (P<.001). When noncholesterol sterols were adjusted by body mass index (BMI), FCHL subjects had higher cholesterol synthesis than non-FG GH, FH and controls (P<.001). An increase in BMI was accompanied by increased cholesterol synthesis and decreased cholesterol absorption in non-FH GH, FH and controls. However, this association between BMI and cholesterol synthesis was not observed in FCHL. Non-high-density-lipoprotein cholesterol showed a positive correlation with cholesterol synthesis markers similar to that of BMI in non-FH GH, FH and normolipemic controls, but there was no correlation in FCHL. These results suggest that FCHL and non-FH GH have different mechanisms of production. Cholesterol synthesis and absorption are dependent of BMI in non-FH GH, but cholesterol synthesis is increased as a pathogenic mechanism in FCHL independently of age, gender, APOE and BMI.

Homozygous Familial Hypercholesterolemia in SpainCLINICAL PERSPECTIVE

Background— Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL protein receptor adaptor 1 ( LDLRAP1 ). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results— Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB , 5 for LDLRAP1 , and 41 for LDLR ), 45 compound heterozygous for LDLR , 3 double heterozygous for LDLR and PSCK9 , and 2 double heterozygous for LDLR and APOB . No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions— HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.Background—Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL protein receptor adaptor 1 (LDLRAP1). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results—Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB, 5 for LDLRAP1, and 41 for LDLR), 45 compound heterozygous for LDLR, 3 double heterozygous for LDLR and PSCK9, and 2 double heterozygous for LDLR and APOB. No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions—HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.