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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.
Spracklen, CN, Karaderi, T, Yaghootkar, H, Schurmann, C, Fine, RS, Kutalik, Z, Preuss, MH, Lu, Y, Wittemans, LBL, Adair, LS, et al
American journal of human genetics. 2019;(1):15-28
Abstract
Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.
Noordam, R, Bos, MM, Wang, H, Winkler, TW, Bentley, AR, Kilpeläinen, TO, de Vries, PS, Sung, YJ, Schwander, K, Cade, BE, et al
Nature communications. 2019;(1):5121
Abstract
Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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A genome-wide study of lipid response to fenofibrate in Caucasians: a combined analysis of the GOLDN and ACCORD studies.
Irvin, MR, Rotroff, DM, Aslibekyan, S, Zhi, D, Hidalgo, B, Motsinger-Reif, A, Marvel, S, Srinivasasainagendra, V, Claas, SA, Buse, JB, et al
Pharmacogenetics and genomics. 2016;(7):324-33
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Abstract
BACKGROUND Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients. METHODS We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans). RESULTS A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P<0.05). CONCLUSION Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.
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The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis.
Huang, R, Guo, X, Chen, X, Zheng, Z, Wei, Q, Cao, B, Zeng, Y, Shang, H
Amyotrophic lateral sclerosis & frontotemporal degeneration. 2015;(5-6):359-65
Abstract
Associations between the fasting levels of serum lipid and amyotrophic lateral sclerosis (ALS) in Chinese populations remain largely unknown. Our objective was to analyse data from a cohort of ALS patients to determine these associations. Four hundred and thirteen ALS patients and 400 age- and gender-matched healthy controls were included. Fasting serum lipid concentration of all subjects, including total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglyceride (TG), were measured at the time of first visit. The revised ALS Functional Rating Scale (ALSFRS-R) was used to assess the severity of ALS. Systems Analysis by Review Manager 5 was used to evaluate differences in dyslipidaemia between ALS patients and controls. Results showed that ALS patients with higher triglyceride levels had longer survival time compared to patients with lower triglyceride levels (p < 0.05). We found a median prolonged life expectancy of 5.8 months for patients with serum triglyceride levels above the median of 127.5 mg/dl. Cox regression analysis indicated that disease duration and age were positively correlated with death, and triglyceride was positively correlated with survival. A meta-analysis indicated that there were no significant differences in mean total cholesterol, TG, LDL or the LDL/HDL ratio between patients and controls. In conclusion, high serum TG might be a protective factor for the survival of patients with ALS.
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Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin.
Mangravite, LM, Medina, MW, Cui, J, Pressman, S, Smith, JD, Rieder, MJ, Guo, X, Nickerson, DA, Rotter, JI, Krauss, RM
Arteriosclerosis, thrombosis, and vascular biology. 2010;(7):1485-92
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Abstract
OBJECTIVE Although statins are efficacious for lowering low-density lipoprotein cholesterol, there is wide interindividual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability. METHODS AND RESULTS Haplotypes in the LDLR 3'-untranslated region (3-UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial (335 blacks and 609 whites). LDLR haplotype 5 (LDLR L5) was associated with smaller simvastatin-induced reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (P=0.0002 to 0.03) in blacks but not whites. The combined presence of LDLR L5 and previously described HMGCR haplotypes in blacks was associated with significantly attenuated apolipoprotein B reduction (-22.4+/-1.5%, N=89) compared with both noncarriers (-30.6+/-1.5%, N=78, P=0.0001) and carriers of either individual haplotype (-28.2+/-1.1%, N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of low-density lipoprotein receptor surface expression using lymphoblast cell lines (P=0.03). CONCLUSIONS We have identified a common LDLR 3-UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by the greater prevalence of these combined haplotypes in blacks.