The impact of positive clinical signs (xanthoma and/or family history) and positive familial hypercholesterolaemia (FH) mutation status on risk of coronary artery disease (CAD) over and above that predicted by low-density lipoprotein (LDL) cholesterol level alone has not been fully determined. We assessed whether positive clinical signs and genetic FH diagnosis affected CAD risk among subjects with significantly elevated LDL cholesterol levels (≥180 mg/dL, or ≥140 mg/dL in subjects <15 years of age).Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 636 patients with severe hypercholesterolaemia (mean age, 45 years; 300 males [47%], CAD diagnosis, 185 [29%]), and the presence of clinical FH signs (xanthoma and/or family history) were assessed. CAD prevalence was compared between four subject groups categorized based on these parameters. Compared with the reference group without FH mutations or clinical signs of FH, subjects with clinical signs of FH or FH mutations had three- to four-fold higher odds of developing CAD (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.5-14.5; P = 0.0011 and OR, 3.4; 95% CI, 1.0-10.9; P = 0.0047, respectively), whereas those with clinical signs of FH and FH mutation(s) had >11-fold higher odds of developing CAD (OR, 11.6; 95% CI, 4.4-30.2; P = 1.1 × 10-5) after adjusting for known risk factors including LDL cholesterol.Our findings revealed an additive effect of positive clinical signs of FH and positive FH mutation status to CAD risk among patients with significantly elevated LDL cholesterol.
Background: Whole exome sequencing (WES) has shown ~30% success in the diagnosis of Mendelian disorders. Few data exists regarding clinical application of WES for the molecular diagnosis of familial hypobetalipoproteinemia (FHBL), which is characterized as extremely low LDL cholesterol level. Methods: WES was performed on 36 individuals including 32 patients exhibiting low LDL-C (less than 70 mg/dl) primarily, and 4 unaffected family members from 23 families. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the autosomal codominant pattern; 4) C-score < 10 calculated using in silico prediction software named Combined Annotation Dependent Depletion. Results: Among 181,404 variants found in those individuals, we found 48,786 nonsense, missense, or splice site variants, of which 14,415 were rare (MAF ≤ 1% or not reported). Filtering assuming autosomal codominant pattern of inheritance combined with the use of C-score, we identified heterozygous mutations in 7 families, and homozygous or compound heterozygous mutations in 4 families within the coding region of APOB gene, eight of which were novel (c.394A>T/p.Lys132*, c.1902_1903delTC/p.Ser634fs, c.2702T>G/p.Met901Arg, c.2946delC/p.Ser982fs, c.4437G>C/p.Leu1479Phe, c.4439_4440delTT/p.Phe1480fs, c.11283C>A/p.Cys3761*, c.11433dupT/p.Glu3812fs). Moreover, we identified compound heterozygous mutations in 1 family within the coding region of PCSK9 gene, one of which was novel (c.1301G>A/p.Arg434Gln). Conclusion: WES combined with integrated variant annotation prediction successfully identified causative mutations in patients with FHBL either with APOB gene mutation(s) or PCSK9 gene mutation(s) in 12 among 23 families (52%). Although such comprehensive approach is useful to determine true causative mutations, other strategies are needed to identify novel causative genes, which could potentially lead to the development of novel pharmacological target for dyslipidemia.
The genetic background of familial combined hyperlipidemia (FCHL) has not been fully clarified. Because several nuclear receptors play pivotal roles in lipid metabolism, we tested the hypothesis that genetic variants of nuclear receptors contribute to FCHL.We screened all the coding regions of the PPARalpha, PPARgamma2, PPARdelta, FXR, LXRalpha, and RXRgamma genes in 180 hyperlipidemic patients including 60 FCHL probands. Clinical characteristics of the identified variants were evaluated in other 175 patients suspected of coronary disease. We identified PPARalpha Asp140Asn and Gly395Glu, PPARgamma2 Pro12Ala, RXRgamma Gly14Ser, and FXR -1g->t variants. Only RXRgamma Ser14 was more frequent in FCHL (15%, P<0.05) than in other primary hyperlipidemia (4%) and in controls (5%). Among patients suspected of coronary disease, we identified 9 RXRgamma Ser14 carriers, who showed increased triglycerides (1.62+/-0.82 versus 1.91+/-0.42 [mean+/-SD] mmol/L, P<0.05), decreased HDL-cholesterol (1.32+/-0.41 versus 1.04+/-0.26, P<0.05), and decreased post-heparin plasma lipoprotein lipase protein levels (222+/-85 versus 149+/-38 ng/mL, P<0.01). In vitro, RXRgamma Ser14 showed significantly stronger repression of the lipoprotein lipase promoter than RXRgamma Gly14.These findings suggest that RXRgamma contributes to the genetic background of FCHL.
Background: Mutations in multiple genes were implicated in lone atrial fibrillation (AF) in which abnormally-functioning mutants may cause ectopic activity or action potential duration shortening. However, few data exist regarding functional characterization of these mutations to identify a causal relationship between a gene variant and occurrence of AF. Objective: We sought to determine the frequency of potassium and sodium channel gene mutations in patients with lone AF and characterized the electrophysiological properties of the detected mutations. Methods: We studied 82 patients with lone AF whose onset was 47±11 years old (60 men, mean age 56 years). There were 22 (27%) with familial AF and 51 (62%) with paroxysmal AF. In these patients, we screened for variants in all exons of KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2 KCNA5, SCN5A, SCN1B, SCN2B, SCN3B, and SCN4B. The potassium and sodium currents were analyzed using whole-cell patch clamp technique. Results: We identified 2 mutations in KCNH2 (T436M and T89...
Aim: Postprandial hypertriglyceridemia is recognized as an independent risk factor for cardiovascular disease. The aim of this study was to identify differences between fasting and postprandial TG levels, focusing on the influence of waist circumference. Methods: Subjects included 1,505 men and 798 women aged 3865 years who were not taking medications for diabetes or dyslipidemia. Fasting TG levels were measured after an overnight fast, and postprandial TG levels were measured 2 hours after a standardized rice-based lunch (total 740 kcal, 20 g fat, 30 g protein, and 110 g carbohydrates) in the afternoon on the same day. Results: Fasting and postprandial TG levels were highly correlated in both men (r=0.86, p<0.001) and women (r=0.84, p<0.001). Waist circumference was positively correlated with fasting TG (r=0.38 in men and r=0.36 in women) and postprandial TG (r=0.42 in men and r=0.45 in women), respectively. On multiple regression analyses, the association of waist circumference with postprandial TG was still significant (standardized β=0.10 in men and standardized β=0.15 in women, p<0.001) after the inclusion of HbA1c, age, high-density-lipoprotein (HDL)-cholesterol, alcohol consumption, and fasting TG in the regression model.Conclusion: Postprandial TG has a better relation with waist circumference than fasting TG.
Background: Sitosterolemia is a rare recessive form of inherited disease characterized by increased levels of plant sterols such as sitosterol, the cause of which is ATP-binding cassette (ABC) sub-family G member 5 (ABCG5) or ABCG8 gene mutations. However, few data exist regarding the clinical features and significance of heterozygous sitosterolemic carrier due to the rarity of this disease. The aim of our study was to determine the clinical impact of heterozygous mutation carriers of ABCG5 or ABCG8 gene. Methods and Results: We performed genetic analyses of ABCG5 and ABCG8 genes for the 15 family members of patients with homozygous sitosterolemia from different 3 families, and investigated their serum sitosterol levels as well as their lipid levels. We identified 12 heterozygous carriers (male=6, mean age=40) which exhibit single mutation in ABCG5 gene among these families (c.130C>T, c.1306G>A, c.1813_1817delCTTTT) as well as 3 normal family members (male=1, mean age=48). Although there were no significant differences in TC, TG, HDL-C, and LDL-C levels between heterozygous carriers and normal family members, serum sitosterol level of heterozygous carriers was significantly higher than that of normal family members (10.8±4.3 vs 2.7±0.5 μg/ml, p<0.05). Interestingly, heterozygous carriers showed neither xanthomas nor any coronary artery diseases. Conclusions: These results demonstrate that heterozygous ABCG5 gene mutation carriers which are somewhat difficult to be identified by the conventional methods may exist among the common normolipidemic patients without significant clinical manifestations. We suggest that the functional analysis of ABCG5 or ABCG8 may facilitate identifying hyper sitosterolemic carriers.
