👤 Ben P M Imholz

A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL). We set out to model which proportion of patients reach targets using conventional and novel therapies. We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2. We applied 100% adherence rates and literature-based adherence rates from 62% to 80%. We included 1,059 heFH patients with and 9,420 heFH patients without coronary heart disease (CHD). With maximal dose statin, 8.3% and 48.1% of patients with and without CHD would reach their recommended LDL-c targets, respectively. This increases to 54.3% and 93.2% when ezetimibe is added. Addition of CETPi increases these numbers to 95.7% and 99.7%, whereas adding PCSK9i would result in 99.8% and 100% goal attainment. Using literature-based adherence rates, these numbers decrease to 3.8% and 27.3% for maximal dose statin, 5.8% and 38.9% combined with ezetimibe, 31.4% and 81.2% when adding CETPi, and 40.3% and 87.1% for addition of PCSK9i. Less than 10% with and 50% of heFH patients without CHD would reach treatment targets with maximal dose statin, but this substantially increases on addition of ezetimibe, CETPi, or PCSK9i. However, considering recently published adherence data, this might be lower in real life, especially in heFH patients with CHD. Show less

Intakes of n-3 polyunsaturated fatty acids (PUFAs), especially EPA (C20:5n-3) and DHA (C22:6n-3), are known to prevent fatal coronary heart disease (CHD). The effects of n-6 PUFAs including arachidonic acid (C20:4n-6), however, remain unclear. δ-5 and δ-6 desaturases are rate-limiting enzymes for synthesizing long-chain n-3 and n-6 PUFAs. C20:4n-6 to C20:3n-6 and C18:3n-6 to C18:2n-6 ratios are markers of endogenous δ-5 and δ-6 desaturase activities, but have never been studied in relation to incident CHD. Therefore, the aim of this study was to investigate the relation between these ratios as well as genotypes of FADS1 rs174547 and CHD incidence. We applied a case-cohort design within the CAREMA cohort, a large prospective study among the general Dutch population followed up for a median of 12.1 years. Fatty acid profile in plasma cholesteryl esters and FADS1 genotype at baseline were measured in a random subcohort (n = 1323) and incident CHD cases (n = 537). Main outcome measures were hazard ratios (HRs) of incident CHD adjusted for major CHD risk factors. The AA genotype of rs174547 was associated with increased plasma levels of C204n-6, C20:5n-3 and C22:6n-3 and increased δ-5 and δ-6 desaturase activities, but not with CHD risk. In multivariable adjusted models, high baseline δ-5 desaturase activity was associated with reduced CHD risk (P for trend = 0.02), especially among those carrying the high desaturase activity genotype (AA): HR (95% CI) = 0.35 (0.15-0.81) for comparing the extreme quintiles. High plasma DHA levels were also associated with reduced CHD risk. In this prospective cohort study, we observed a reduced CHD risk with an increased C20:4n-6 to C20:3n-6 ratio, suggesting that δ-5 desaturase activity plays a role in CHD etiology. This should be investigated further in other independent studies. Show less

Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date. We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 ± 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 ± 1.11 mmol/L for those with 18 or more (P for trend<0.0001). The association with TC levels was slightly stronger when the weighted GRS that weighted the magnitude of allelic effects was used. A panel of common genetic variants in the genes pivotal in cholesterol metabolism could possibly help identify those people who are at risk of high cholesterol levels. Show less

The delta-5 and delta-6 desaturases, encoded by the FADS1 and FADS2 genes, are rate-limiting enzymes in polyunsaturated fatty acid (PUFA) biosynthesis. Single nucleotide polymorphisms in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent genome-wide association studies. We examined whether genetic variations in the FADS gene cluster region interact with dietary intakes of n-3 (omega-3) and n-6 (omega-6) PUFAs to affect plasma total, HDL-, and non-HDL-cholesterol concentrations. Dietary intakes of n-3 and n-6 PUFAs, plasma concentrations of total and HDL cholesterol, and rs174546, rs482548, and rs174570 in the FADS gene cluster region were measured in 3575 subjects in the second survey of the Doetinchem Cohort Study. Significant associations between rs174546 genotypes and total and non-HDL-cholesterol concentrations were observed in the group with a high intake of n-3 PUFAs (> or =0.51% of total energy; P = 0.006 and 0.047, respectively) but not in the low-intake group (P for interaction = 0.32 and 0.51, respectively). The C allele was associated with high total and non-HDL-cholesterol concentrations. Furthermore, the C allele was significantly associated with high HDL-cholesterol concentrations in the group with a high intake of n-6 PUFAs (> or =5.26% of total energy, P = 0.004) but not in the group with a low intake (P for interaction = 0.02). Genetic variation in the FADS1 gene potentially interacts with dietary PUFA intakes to affect plasma cholesterol concentrations, which should be investigated further in other studies. Show less

The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further. Show less