Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p&lt;1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p&lt;5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.</p

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

No Risk of Arterial or Venous Thrombosis in Monoclonal Gammopathy of Undetermined Significance: Results from a Population-Based Study

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma (MM) and other lymphoproliferative disorders. Patients with MM have an increased risk of venous and arterial thrombosis. Results from previous studies have also shown an increased risk of thrombosis in MGUS. However, these studies have been performed on clinically established cohorts, and no previous study has examined the risk of thrombosis in light chain MGUS (LC-MGUS). Methods We performed a population-based study on the longitudinal cohort of the AGES-Reykjavik Study, consisting of 5,764 elderly Icelandic men and women. Through screening all participants with free light chain analysis and serum protein electrophoresis, MGUS and LC-MGUS were identified in 299 and 52 individuals, respectively. The outcome was first incidence/occurrence of venous or arterial thrombosis, as diagnosis or as cause of death. Information on outcomes was supplemented by health care records, available from nine years prior to study baseline and for a median follow-up time of 8.8 years. Through logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate history of arterial and venous thrombosis, respectively, at study baseline. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% CIs for the risk of first incidence of thrombosis during follow-up. Results A history of any thrombosis during the nine years prior to diagnosis was present in 30 (10.0%) of individuals with MGUS, 13 (25.0%) of individuals with LC-MGUS, and 643 (12.0%) of individuals without MGUS. In a model adjusting for age, sex, smoking, serum cholesterol levels, diabetes, hypertension, and family history of thrombosis, the odds of having had a thrombosis was not significantly different for neither MGUS (OR = 0.75, 95% CI 0.50-1.12) nor LC-MGUS (OR = 1.81, 0.92-3.58), compared to those without MGUS. During a median follow-up time of 8.8 years, 80 (26.8%) of individuals with MGUS, 14 (26.9%) of individuals with LC-MGUS, and 1,344 (25.0%) of individuals without MGUS were diagnosed with thrombosis. Individuals with MGUS and with LC-MGUS had no increased risk of arterial thrombosis, when adjusted for age, sex, cholesterol, diabetes, hypertension, smoking, and family history of thrombosis (HR 1.04, 0.82-1.32). Similarly, no increased risk was found in MGUS or LC-MGUS for venous thrombosis, in a model adjusted for age, sex, body mass index, and previous or current cancer (HR 0.89, 0.41-1.89). Excluding individuals with a diagnosis of thrombosis occurring before baseline, or adjusting for a personal history of thrombosis, did not affect the results. Summary and conclusions In this large, population-based, screening cohort study, we found no increased risk of arterial or venous thrombosis in MGUS. A history of thrombosis was more common in individuals with LC-MGUS, which might be an effect of higher age in LC-MGUS individuals. To our knowledge, this is the first study to investigate risk of thrombosis in LC-MGUS. The results from our screened study contradict previous findings from clinically established cohorts. Future work is needed to better understand observed differences between studies and across populations. For example, potential underlying factors may include aggregation of underlying comorbidities in clinically diagnosed MGUS patients, and biological variations (shared germline genetic susceptibility) by ethnic groups. Table. Risk of thrombosis in individuals with MGUS and LC-MGUS, compared to individuals without MGUS. MGUS LC-MGUS No MGUS No. HR (95% CI) No. HR (95% CI) No. HR (95% CI) Any thrombosis* 80 (26.76%) 1.01 (0.80-1.26) 14 (26.92%) 1.13 (0.80-1.26) 1,344 (25.02%) 1.00 (Reference) Arterial thrombosis† 76 (25.42%) 1.04 (0.82-1.32) 14 (26.92%) 1.16 (0.67-2.01) 1,240 (23.08%) 1.00 (Reference) Venous thrombosis†† 7 (2.34%) 0.89 (0.41-1.89) 0 (0.0%) - 151 (2.81%) 1.00 (Reference) *Results adjusted for age and sex. † Results adjusted for age, sex, smoking, hypertension, cholesterol, diabetes, and family history of arterial thrombosis. †† Results adjusted for age, sex, body mass index, and previous or current cancer. MGUS: monoclonal gammopathy of undetermined significance, LC-MGUS: light-chain monoclonal gammopathy of undetermined significance. HR: hazard ratio, CI: confidence interval. Disclosures Landgren: Celgene: Consultancy; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Consultancy; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; BMJ Publishing: Honoraria; Onyx: Consultancy; Medscape: Consultancy

Risk of Progression in Monoclonal Gammopathy of Undetermined Significance (MGUS): Results from a Population-Based Screening Study

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma and other lymphoproliferative disorders. In individuals with MGUS, the average risk of progression to a lymphoproliferative disorder has been estimated to be 1% per year, however, most previous studies have been performed on clinically established cohorts and very few have been population-based. A high monoclonal (M)-protein concentration, non-isotype IgG, and skewed free light chain (FLC) ratio are routinely taken into account when assessing risk for progression. Other risk factors have also been identified, such as low serum albumin. Methods The cohort under study consisted of 299 individuals, 158 men and 141 women, with MGUS, identified through screening the participants of the population-based, longitudinal AGES-Reykjavik Study using serum protein electrophoresis and FLC assessment. The median age was 78 years (range 67-93 years). The outcome was first incidence of lymphoproliferative disorder, denoting multiple myeloma, lymphoma, amyloidosis, lymphocytic leukemia, plasmacytoma, and Waldenström's macroglubulinemia. Information on outcomes was supplemented by cross-linkage to national registries, and median follow-up time was 8.8 years. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of lymphoproliferative disorders. Results were adjusted for serum albumin in categories (below 35 g/L, 35-40 g/L, or above 40 g/L), M-protein concentration (above or below 15 g/L), FLC ratio, levels of free light chains, use of statins, smoking status, renal function in categories, and M-protein isotype. The multivariate model was reduced in a step-wise manner to a final model with only significant covariates. Results During follow-up, 26 of 299 individuals with MGUS proceeded to develop a lymphoproliferative disorder, representing a cumulative risk of 8.7% and an annual risk of 1.0%. MM occurred in 17 of 218 individuals with non-IgM MGUS, representing a cumulative risk of 7.8% and an annual risk of 0.9%. In multivariate analysis, the final model contained serum albumin, M-protein concentration, and isotype A versus all other isotypes. Low serum albumin (HR = 6.3, 95% CI 1.0-40.6 for <35 g/L, and HR = 3.9, 95% CI 1.1-14.2 for 35-40 g/L), high M-protein concentration (HR = 4.1, 95% CI 1.2-14.0), and isotype A (HR = 5.8, 95% CI 1.6-21.0) were significantly associated with risk of progression. In a similar model for progression to multiple myeloma only, low serum albumin, high M-protein concentration, and isotype A were also significantly associated with risk of progression, although the impact of low serum albumin was greater (HR = 33.1, 95% CI 2.4-462.2 for <35 g/L, HR = 10.97, 95% CI 1.4-88.3 for 35-40). When assigning a risk score for progression where 1 point each was assigned for isotype IgA, serum albumin 15 g/L, the HRs for individuals with 1 point was 3.9 (95% CI 1.6-9.9), and for 2 points 10.02 (95% CI 2.3-43.3). No individual had 3 points. For Kaplan-Meier estimates from risk scores, see Figure. Summary and conclusions In this large, population-based screening study, we found an annual risk of progression from MGUS to lymphoproliferative disease of 1%. Low serum albumin, high M-protein concentration, and M-protein isotype A were all independent risk factors for progression. Our results are in line with results from previous studies where a low serum albumin at MGUS diagnosis also has been associated with shorter survival and/or malignant transformation. Results from our study contradict previous studies that have pointed to skewed FLC ratio as an important risk factor for progression; in our study, a skewed FLC ratio was not significantly associated with risk of progression when adjusted for other covariates. The findings in our study suggest that serum albumin is important to take into account when assessing the risk of progression for individuals with MGUS. Figure 1 Kaplan-Meier estimates for risk of progression, by risk score. Figure 1. Kaplan-Meier estimates for risk of progression, by risk score. Disclosures Korde: Medscape: Honoraria. Landgren:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; BMS: Honoraria; Celgene: Honoraria, Research Funding

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity

BackgroundAn international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.MethodsFourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.ResultsThe agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P &lt; .001), and physiological variability (49.2%, P &lt; .001).ConclusionsThe HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

BackgroundIn addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.Methods and resultsWe performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p&lt;1×10-4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p&lt;5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.ConclusionsBased on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response