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Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.

ABSTRACT: Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10^-5) and 53% lower triglyceride level ( P=2×10^-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10^-7), a 30% decrease in triglycerides ( P=5×10^-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.

SUBMITTER: Peloso GM

PROVIDER: S-EPMC7044908 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceEarly-onset Alzheimer disease (EOAD) is a rare form of Alzheimer disease (AD) with a large genetic basis that is only partially understood. In late-onset AD, elevated circulating cholesterol levels increase AD risk even after adjusting for the apolipoprotein E ε4 (APOE E4) allele, a major genetic factor for AD and elevated cholesterol levels; however, the role of circulating cholesterol levels in EOAD is unclear.ObjectivesTo investigate the association between circulating cholesterol levels and EOAD and to identify genetic variants underlying this possible association.Design, setting, and participantsIn this case series, plasma cholesterol levels were directly measured in 267 samples from the AD research centers (ADRCs) of Emory University and University of California, San Francisco, collected from January 21, 2009, through August 21, 2014. The association between cholesterol and EOAD was examined using multiple linear regression. To determine the underlying genetic variants, APOB, APP, PSEN1, and PSEN2 were sequenced in samples from 2125 EOAD cases and controls recruited from 29 ADRCs from January 1, 1984, through December 31, 2015. Data were analyzed from November 23, 2016, through April 10, 2018.ExposuresClinical diagnosis, age at clinical diagnosis, plasma cholesterol measures (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B), and genetic variants in APOE, APP, PSEN1, PSEN2, and APOB.Main outcomes and measuresThe primary outcome was the association between EOAD and plasma cholesterol measures. The secondary outcome was the association between EOAD and the burden of genetic variants in APOB.ResultsOf the 2125 samples that underwent genetic sequencing, 1276 were from women (60.0%) and 654 (30.8%) were from patients with EOAD (mean [SD] ages, 55.6 [4.3] years for cases and 72.0 [9.6] years for controls). APOE E4 explained 10.1% of the variance of EOAD. After controlling for APOE E4, EOAD cases had higher levels of total cholesterol (mean difference [SE], 21.9 [5.2] mg/dL; P = 2.9 × 10-5), LDL-C (mean difference [SE], 22.0 [4.5] mg/dL; P = 1.8 × 10-6), and ApoB (mean difference [SE], 12.0 [2.4] mg/dL; P = 2.0 × 10-6) than controls in 267 frozen samples. Approximately 3% of EOAD cases carried known AD-causing mutations. Gene-based rare variant burden testing in 2066 samples showed that rare APOB coding variants were significantly more abundant in EOAD cases after adjusting for sex, APOE E4, genetic principal components, ADRC center, and batch (effect size, 0.20; P = 4.20 × 10-4).Conclusions and relevanceElevated LDL-C levels were associated with higher probability of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which codes for the major protein of LDL-C. Collectively, these novel findings highlight the important role of LDL-C in EOAD pathogenesis and suggest a direct link of APOB variants to AD risk.

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Project description:Background Evidence on the relationship between the low−/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and carotid plaques remains limited. This study aimed to examine the association between LDL-C/HDL-C and carotid plaques in participants with coronary heart disease (CHD) and to further explore the extent to which a healthy lifestyle reduces the risk of LDL-C/HDL-C-related carotid plaques. Methods This large-scale and multi-centre retrospective study included 9426 CHD patients (aged 35–75 years) between January 1, 2014 and September 30, 2020. The LDL-C/HDL-C values were converted to the following tertiles: lowest (< 2.15), middle (2.15–3), and highest (> 3). Healthy lifestyle-related factors referred to whether or not the participant was a non-smoker and non-drinker. Participants were divided into an unfavourable group (those who did not adhere to healthy lifestyle factors), intermediate (only one unhealthy factor), and favourable (neither of the two unhealthy factors). Logistic regression was used for statistical analyses. Results Of the 9426 participants, 6989 (74.15%) CHD patients had carotid plaques. After adjustment for confounders, each unit increase in the LDL-C/HDL-C was significantly associated with carotid plaques (OR: 1.61; 95%CI: 1.43–1.84; P < 0.001). Multivariate logistic regression revealed that carotid plaques risk for the highest tertile (> 3) was 1.18 times that of the lowest quartile (< 2.15). Compared with an unfavourable lifestyle, an intermediate or a favourable lifestyle was associated with a significant 30% (OR: 0.70; 95%CI: 0.64–0.78; P < 0.001) or 67% (OR: 0.33; 95%CI: 0.29–0.37; P < 0.001) reduction in carotid plaques risk, respectively, among CHD patients with high LDL-C/HDL-C. There were significantly additive and multiplicative interactions between lifestyle and LDL-C/HDL-C with regards to carotid plaques. Conclusion A high LDL-C/HDL-C is associated with a risk of carotid plaques developing in CHD patients. Adhering to a healthy lifestyle has additive beneficial effects on reducing the risk of carotid plaques, especially in relation to the highest LDL-C/HDL-C. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12944-021-01575-w.

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Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.

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