Validation of a genetic risk score for atrial fibrillation: A prospective multicenter cohort study.

BACKGROUND: Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF. METHODS AND FINDINGS: Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27-7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF. CONCLUSIONS: Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01970969.

A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer.

BACKGROUND: The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing. OBJECTIVES: To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy. METHODS: We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network-defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in BRCA1 and BRCA2 and the seven-gene test strategy for variants in BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, and PALB2. Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance. RESULTS: The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the BRCA1/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort. CONCLUSIONS: Testing seven breast cancer-associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.

Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history.

AIMS: Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD. METHODS AND RESULTS: The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmö Diet and Cancer study--a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48-1.94; Ptrend = 1.6 × 10(-15) and HR = 1.92 for GRS50; 95% CI: 1.67-2.20; Ptrend = 6.2 × 10(-22)]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P = 3 × 10(-6)). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45-1.89) or GRS50 (HR = 1.87; 95% CI: 1.63-2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P < 0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P < 0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85-3.12) than those with low GRS50. CONCLUSION: The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals.

Use of low density lipoprotein particle number levels as an aid in statin treatment decisions for intermediate risk patients: a cost-effectiveness analysis.

BACKGROUND: The 2013 ACC/AHA guideline recommended either no statin therapy or moderate-intensity statin therapy (MST) for intermediate risk patients-those with 5-7.5% 10-year risk and without cardiovascular disease (CVD), hypercholesterolemia or diabetes. The guideline further suggested that the therapy choice be based on patient-clinician discussions of risks and benefits. Since low-density lipoprotein particle (LDL-P) levels were reported to be associated with CVD independently of traditional risk factors in intermediate and low risk patients, we investigated the cost-effectiveness of using LDL-P levels to identify intermediate risk patients likely to benefit from initiating or intensifying statin therapy. METHODS: We evaluated 5 care strategies for intermediate risk patients. These included the strategies suggested by the guideline: no-statin therapy and MST. We compared each of these strategies to a related strategy that incorporated LDL-P testing. No-statin therapy was compared with the strategy of MST for those with high LDL-P levels and no statin therapy for all other patients (test-and-MST). MST was compared with the strategy of high-intensity statin therapy (HST) for those with high LDL-P levels and MST for all other patients (test-and-HST). We also evaluated the strategy of HST for all. Costs (payer perspective) and utilities were assessed over a 5-year time horizon in a Markov model of 100,000 hypothetical intermediate risk patients. RESULTS: HST dominated all other strategies, costing less and-despite causing 739 more cases of diabetes than did MST-resulting in more quality adjusted life-years (QALYs). For patient-clinician discussions that would otherwise lead to the MST strategy, we found the test-and-HST strategy reduced costs by $4.67 MM and resulted in 134 fewer CVD events and 115 additional QALYs. For patient-clinician discussions that would otherwise lead to no statin therapy, we found that the test-and-MST strategy reduced costs by $3.25 MM, resulted in 97 fewer CVD events and 44 additional QALYs. CONCLUSIONS: The HST strategy was cost saving and improved outcomes in intermediate risk patients. For patient and clinicians concerned about the adverse events associated with HST, using LDL-P levels to target intensified statin therapy could improve outcomes and reduce costs.

Genetic risk for atrial fibrillation could motivate patient adherence to warfarin therapy: a cost effectiveness analysis.

BACKGROUND: Atrial fibrillation (AF) increases risk of stroke, and although this stroke risk can be ameliorated by warfarin therapy, some patients decline to adhere to warfarin therapy. A prospective clinical study could be conducted to determine whether knowledge of genetic risk for AF could increase adherence to warfarin therapy for patients who initially declined therapy. As a prelude to a potential prospective clinical study, we investigated whether the use of genetic information to increase adherence could be cost effective. METHODS: Markov model assessed costs and utilities of two care strategies for AF patients who declined warfarin therapy. In the usual care strategy patients received aspirin. In the test strategy genetic risk for AF was assessed (genotype of the 4q25 locus) and some patients with a positive genetic test (≥1 risk allele) were assumed to adhere to warfarin therapy. The remaining patients received aspirin. The incremental cost-effectiveness ratio (ICER) was the ratio of the costs differential and the quality adjusted life-years (QALYs) differential for the two strategies. RESULTS: We found that the 4q25 genetic testing strategy, compared with the usual care strategy (aspirin therapy), would be cost-effective (ICER $ 47,148) if 2.1 % or more of the test positive patients were to adhere to warfarin therapy. The test strategy would become a cost saving strategy if 5.3 % or more of the test positive patients were to adhere to warfarin therapy. If 20 % of test positive patients were to adhere to warfarin therapy in a hypothetical cohort of 1000 patients, 7 stroke events would be prevented and 3 extra-cranial major bleeding events would be caused over 5 years, resulting in a cost savings of ~ $250,000 and a net gain of 9 QALYs. DISCUSSION: A clinical study to assess the impact of patient knowledge of genetic risk of AF on adherence to warfarin therapy would be merited because even a modest increase in patient adherence would make a genetic testing strategy cost-effective. CONCLUSION: Providing patients who declined warfarin therapy with information about their genetic risk of AF would be cost effective if this genetic risk information resulted in modest increases in adherence.

Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF. Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need. Here, we investigate whether multiple single nucleotide polymorphisms together as an AF genetic risk score (AF-GRS) can improve prediction of one's risk for AF. METHODS: In 27 471 participants of the Malmö Diet and Cancer Study, a prospective, community-based cohort, we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke. Median follow-up was 14.4 years for incident AF and 14.5 years for ischemic stroke. The AF-GRS comprised 12 single nucleotide polymorphisms that had been previously shown to be associated with AF at genome-wide significance. RESULTS: During follow-up, 2160 participants experienced a first AF event and 1495 had a first ischemic stroke event. Participants in the top AF-GRS quintile were at increased risk for incident AF (hazard ratio, 2.00; 95% confidence interval, 1.73-2.31; P=2.7×10(-21)) and ischemic stroke (hazard ratio, 1.23; 95% confidence interval, 1.04-1.46; P=0.02) when compared with the bottom quintile. Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification (P<0.0001 for both). CONCLUSIONS: An AF-GRS can identify 20% of individuals who are at ≈2-fold increased risk for incident AF and at 23% increased risk for ischemic stroke. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful.

Multiple SNP testing improves risk prediction of first venous thrombosis.

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.

Correlating Stability-Indicating Biochemical and Biophysical Characteristics with In Vitro Cell Potency in mRNA LNP Vaccine.

The development of mRNA vaccines has increased rapidly since the COVID-19 pandemic. As one of the critical attributes, understanding mRNA lipid nanoparticle (LNP) stability is critical in the vaccine product development. However, the correlation between LNPs' physiochemical characteristics and their potency still remains unclear. The lack of regulatory guidance on the specifications for mRNA LNPs is also partially due to this underexplored relationship. In this study, we performed a three-month stability study of heat-stressed mRNA LNP samples. The mRNA LNP samples were analyzed for their mRNA degradation, LNP particle sizes, and mRNA encapsulation efficiency. In vitro cell potency was also evaluated and correlated with these above-mentioned physiochemical characterizations. The mRNA degradation-cell potency correlation data showed two distinct regions, indicating a critical cut-off size limit for mRNA degradation. The same temperature dependence was also observed in the LNP size-cell potency correlation.

A Phase 1 First-in-Human Pharmacokinetic and Pharmacodynamic Study of JNJ-64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase.

JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.

Polymorphisms and noncardioembolic stroke in three case-control studies.

BACKGROUND: Gene variants associated with disease could reveal novel mechanisms. We searched for single nucleotide polymorphisms (SNPs) associated with noncardioembolic stroke (nonCES). METHODS: We tested 24,926 SNPs in or near genes for association with nonCES in the Vienna Study (551 cases, 815 controls) and then evaluated the associated SNPs in the UCSF-CC Study (570 cases, 1,604 controls) first in pooled DNA samples and then in individual DNA samples. We then asked whether the risk alleles of the SNPs associated with increased risk in both studies were also associated with increased risk of nonCES in the German Study (728 cases, 1,041 controls). RESULTS: Six of the 46 SNPs that were associated with nonCES in both the Vienna and the UCSF-CC Studies were also associated with nonCES in the German Study: rs362277 in HTT (OR 1.39, 90% CI 1.12-1.71), rs2924914 near CSMD1 (OR 1.22, 90% CI 1.04-1.43), rs1264352 near DDR1 (OR 1.20, 90% CI 1.02-1.41), rs544115 in NEU3 (OR 1.63, 90% CI 1.02-2.62), rs12481805 in UMODL1 (OR 1.31, 90% CI 1.01-1.81), and rs2857595 near NCR3 (OR 1.15, 90% CI 1.00-1.32). Accounting for multiple testing of 46 SNPs, these 6 SNPs had a false discovery rate of 0.69. CONCLUSIONS: Some of the 6 SNPs may be associated with nonCES but most may be false positives. These 6 SNPs merit investigation in additional nonCES study populations.

Genetic variants in the KIF6 region and coronary event reduction from statin therapy.

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (P (interaction) < 01 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (P (interaction) < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from -4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r (2) > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy.

Monozygotic twins reveal germline contribution to allelic expression differences.

Variation in the level of gene expression is a major determinant of a cell's function and characteristics. Common allelic variants of genes can be expressed at different levels and thus contribute to phenotypic diversity. We have measured allelic expression differences at heterozygous loci in monozygotic twins and in unrelated individuals. We show that the extent of differential allelic expression is highly similar within monozygotic twin pairs for many loci, implying that allelic differences in gene expression are under genetic control. We also show that even subtle departures from equal allelic expression are often genetically determined.

Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses.

BACKGROUND: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly. METHODS: The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification. RESULTS: Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results. CONCLUSION: With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.

The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study.

BACKGROUND: Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. METHODS: Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). RESULTS: Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). CONCLUSIONS: While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.

Assessment of the Association of Vitamin D Level With SARS-CoV-2 Seropositivity Among Working-Age Adults.

Importance: Low vitamin D levels have been reported to be associated with increased risk of SARS-CoV-2 infection. Independent, well-powered studies could further our understanding of this association. Objective: To examine whether low levels of vitamin D are associated with SARS-CoV-2 seropositivity, an indicator of previous infection. Design, Setting, and Participants: This is a cohort study of employees and spouses who elected to be tested for SARS-CoV-2 IgG as part of an annual employer-sponsored health screening program conducted in August to November 2020. This program includes commonly assessed demographic, biometric, and laboratory variables, including total vitamin D measurement. Baseline (prepandemic) levels of vitamin D and potential confounders were obtained from screening results from the previous year (September 2019 to January 2020). Data analysis was performed from December 2020 to March 2021. Exposures: Low total serum 25-hydroxyvitamin D, defined as either less than 20 ng/mL or less than 30 ng/mL. Main Outcomes and Measures: The main outcome was SARS-CoV-2 seropositivity, as determined with US Food and Drug Administration emergency use-authorized assays. The association of SARS-CoV-2 seropositivity with vitamin D levels was assessed by multivariable logistic regression analyses and propensity score analyses. Results: The 18 148 individuals included in this study had test results for SARS-CoV-2 IgG in 2020 and vitamin D levels from the prepandemic and pandemic periods. Their median (interquartile range) age was 47 (37-56) years, 12 170 (67.1%) were women, 900 (5.0%) were seropositive, 4498 (24.8%) had a vitamin D level less than 20 ng/mL, and 10 876 (59.9%) had a vitamin D level less than 30 ng/mL before the pandemic. In multivariable models adjusting for age, sex, race/ethnicity, education, body mass index, blood pressure, smoking status, and geographical location, SARS-CoV-2 seropositivity was not associated with having a vitamin D level less than 20 ng/mL before (odds ratio [OR], 1.04; 95% CI, 0.88-1.22) or during (OR, 0.93; 95% CI, 0.79-1.09) the pandemic; it was also not associated with having a vitamin D level less than 30 ng/mL before (OR, 1.09; 95% CI, 0.93-1.27) or during (OR, 1.05; 95% CI, 0.91-1.23) the pandemic. Similar results were observed in propensity score analyses. SARS-CoV-2 seropositivity was associated with obesity (OR, 1.26; 95% CI, 1.08-1.46), not having a college degree (OR, 1.40; 95% CI, 1.21-1.62), and Asian (OR, 1.46; 95% CI, 1.13-1.87), Black (OR, 2.74; 95% CI, 2.25-3.34), Hispanic (OR, 2.65; 95% CI, 2.15-3.27), American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander (OR, 2.01; OR, 1.54-2.62) race/ethnicity, and was inversely associated with high blood pressure (OR, 0.82; 95% CI, 0.70-0.96), smoking (OR, 0.60; 95% CI, 0.47-0.78), and residing in the US Northeast (OR, 0.75; 95% CI, 0.62-0.92) and West (OR, 0.54; 95% CI, 0.44-0.67). Conclusions and Relevance: In this cohort study, SARS-CoV-2 seropositivity was not associated with low levels of vitamin D independently of other risk factors.

Association of changes in lipid levels with changes in vitamin D levels in a real-world setting.

In clinical trials, vitamin D supplementation has been reported to reduce serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) but not high-density lipoprotein cholesterol (HDL-C). In this cohort study we evaluated the association between changes in vitamin D (25-hydroxyvitamin D) and changes in lipid levels in a real-world setting. Changes in lipid levels over a 1-year period were evaluated among individuals whose vitamin D levels increased (group 1) or decreased (group 2) by ≥ 10 ng/mL in year 2018 versus 2017 (cohort 1; n = 5580), in 2019 versus 2018 (cohort 2, n = 6057), or in 2020 versus 2019 (cohort 3, n = 7249). In each cohort, levels of TC, LDL-C, and TG decreased in group 1 and increased in group 2. Between-group differences in average changes in the 3 cohorts ranged from 10.71 to 12.02 mg/dL for TC, from 7.42 to 8.95 mg/dL for LDL-C, and from 21.59 to 28.09 mg/dL for TG. These differences were significant after adjusting for age, sex, race, education, body mass index, blood pressure, smoking status, geographical location, and baseline levels of vitamin D and lipids (P < 0.001). Changes in vitamin D levels were not significantly associated with changes in HDL-C levels.

KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study.

BACKGROUND: Statin therapy has been found to substantially and significantly reduce coronary events in carriers of the KIF6 719Arg variant (rs20455) but not in noncarriers. We investigated whether, among the elderly, statin therapy also significantly reduced coronary events in carriers but not in noncarriers. DESIGN AND METHODS: Among 5,752 patients of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study, we assessed the effect of pravastatin, compared with placebo, on coronary events according to 719Arg carrier status using proportional hazards models. RESULTS: Since benefit from statin therapy in elderly patients has been primarily shown among those with prior vascular disease, we performed analyses in PROSPER patients with prior disease and found that pravastatin therapy significantly reduced events in 719Arg carriers [hazards ratio (HR): 0.66, 95% confidence interval (CI): 0.52-0.86] but not in noncarriers (HR: 0.94, 95% CI: 0.69-1.28), P=0.09 for interaction between treatment and carrier status. Among those without prior disease, no significant benefit was observed in either carriers or noncarriers. Among those with prior vascular disease in the placebo arm, Trp719Arg heterozygotes were at significantly greater risk, compared with noncarriers (HR: 1.36, 95% CI: 1.03-1.81, P=0.03); the HR of 719Arg carriers, compared with noncarriers, was 1.28 (95% CI: 0.98-1.69, P=0.07). CONCLUSION: Elderly carriers of the KIF6 719Arg variant with prior vascular disease received significant benefit from pravastatin therapy; no benefit was observed in noncarriers with prior disease or in those without prior disease (carriers or noncarriers).

Genetic analysis of genome-wide variation in human gene expression.

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.