Citations

Familial Hypercholesterolemia (FH) is an inherited disorder associated with increased cardiovascular risk that requires patients to make multiple impactful decisions regarding the management of their condition. Patient decision aids (PDAs) can facilitate shared decision-making (SDM) and enable patients to make choices that are concordant with their goals and values. To inform the development of a PDA for patients with FH, we employed a qualitative inductive approach and focus group discussions with patients, physicians, and genetic counselors. We explored and analyzed the perceptions and understanding of these stakeholders related to a PDA for FH and identified important concepts to include in the PDA. Categories emerging from focus group discussions included: (a) perceptions of a PDA related to FH; (b) discussion about the content of a PDA related to FH; and (c) SDM. In general, stakeholders were in favor of developing tools which can inform and individualize discussion about genetic testing and treatment options for FH. Physicians valued a tool that facilitates knowledge transfer to FH patients. Patients desired a tool to help them understand the genetic aspects of and treatment options related to FH. Genetic counselors emphasized the inclusion of visual aids to support discussion with patients. Potential barriers to and facilitators of PDA implementation were identified. The input of various stakeholders will inform the development of a prototype tool that will be iteratively tested before implementation in the clinical setting.

To inform guidelines for screening family members of patients with familial hypercholesterolemia (FH), we designed a clinical trial to compare the yield of cascade screening in FH patients with and without an identifiable pathogenic variant. Participants with hypercholesterolemia (Low-density lipoprotein cholesterol (LDL-C) > 155 mg/dL) underwent sequencing of LDLR, APOB, and PCSK9 and genotyping of six single nucleotide polymorphisms associated with LDL-C followed by calculation of a polygenic score for LDL-C. We identified 24 patients with definite FH (pathogenic variant in one of the three FH genes), 76 patients with probable FH (Dutch lipid clinic network (DLCN) score ≥ 6, no pathogenic variant), and 262 patients with possible FH (DLCN score 3–5, no pathogenic variant). We will enroll 50 patients with definite FH by recruiting an additional 26 from the FH Clinic at Mayo and 50 patients each with probable and possible FH, matching on age and sex. Family members of patients with definite FH will undergo testing for the relevant pathogenic variant using saliva kits and family members of those with probable/possible FH will have a lipid profile checked. We will assess the number of new cases detected (defined as presence of a pathogenic variant in the family member of definite FH patient or LDL-C > 155 mg/dL (>130 mg/dL in children) in family members of probable/possible FH patients, and the cost of detecting a new case. The proposed clinical trial will compare the yield and cost of cascade screening for FH patients with/without an identifiable pathogenic variant, and thereby inform guidelines for cascade screening for FH.

Background: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

AbstractThe eMERGE Network is establishing methods for electronic transmittal of patient genetic test results from laboratories to healthcare providers across organizational boundaries. We surveyed the capabilities and needs of different network participants, established a common transfer format, and implemented transfer mechanisms based on this format. The interfaces we created are examples of the connectivity that must be instantiated before electronic genetic and genomic clinical decision support can be effectively built at the point of care. This work serves as a case example for both standards bodies and other organizations working to build the infrastructure required to provide better electronic clinical decision support for clinicians.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.

The burden and predictors of hospitalization over time in community-based patients with peripheral artery disease (PAD) have not been established. This study evaluates the frequency, reasons and predictors of hospitalization over time in community-based patients with PAD. We assembled an inception cohort of 1798 PAD cases from Olmsted County, MN, USA (mean age 71.2 years, 44% female) from 1 January 1998 through 31 December 2011 who were followed until 2014. Two age- and sex-matched controls ( n = 3596) were identified for each case. ICD-9 codes were used to ascertain the primary reasons for hospitalization. Patients were censored at death or last follow-up. The most frequent reasons for hospitalization were non-cardiovascular: 68% of 8706 hospitalizations in cases and 78% of 8005 hospitalizations in controls. A total of 1533 (85%) cases and 2286 (64%) controls ( p < 0.001) were hospitalized at least once; 1262 (70%) cases and 1588 (44%) controls ( p < 0.001) ≥ two times. In adjusted models, age, prior hospitalization and comorbid conditions were independently associated with increased risk of recurrent hospitalizations in both groups. In cases, severe PAD (ankle–brachial index < 0.5) (HR: 1.25; 95% CI: 1.15, 1.36) and poorly compressible arteries (HR: 1.26; 95% CI: 1.16, 1.38) were each associated with increased risk for recurrent hospitalization. We demonstrate an increased rate of hospitalization in community-based patients with PAD and identify predictors of recurrent hospitalizations. These observations may inform strategies to reduce the burden of hospitalization of PAD patients.

SummaryPurposeSpexin, a novel peptide, has potential implications in obesity, satiety and energy homeostasis. The current study examined the relationship of spexin with various biomarkers of cardiovascular disease and endothelial function in adolescents with obesity.MethodsNineteen adolescents with obesity (age, 15.8 ± 1.7 years) were studied. Spexin, leptin and various cardiovascular disease biomarkers were measured. Endothelial function was assessed by high‐resolution Doppler ultrasonography of the right brachial artery.ResultsSpexin concentration (median [interquartile range] 0.38 ng/mL [0.29–0.59 ng/mL]) was inversely correlated (r = −0.50, P = 0.03) with leptin. When participants were clustered into two groups (‘high spexin and low leptin’ vs. ‘low spexin and high leptin’), the odds of having ‘low spexin and high leptin’ in participants with higher hs‐CRP (≥ 3 mg/L) were 12.25 times (95 per cent CI −1 to139, P = 0.026) higher than those of participants with lower hs‐CRP (<3 mg/L). Spexin levels, however, were not associated with measures of endothelial function.ConclusionsThe inverse association between spexin and leptin and the presence of higher concentrations of hs‐CRP in adolescents with obesity in the setting of ‘low spexin and high leptin’ suggest a potential role for spexin in the regulation of satiety and certain cardiovascular risk factors in children with obesity.