Kullo, Iftikhar J

Background Atherosclerosis in >1 vascular bed (ie, polyvascular disease), often a feature of peripheral artery disease (PAD), is associated with high morbidity and mortality. We sought to identify risk factors for polyvascular involvement in patients with PAD. Methods and Results We performed 2‐sample Mendelian randomization using an inverse‐variance‐weighted approach, to assess 60 exposures including size and lipid content of atherogenic lipoproteins, blood pressure, glycated hemoglobin, and smoking as causal mediators for polyvascular disease in patients with PAD. Genetic instruments for these exposures were obtained from prior genome‐wide association studies. Patients with PAD were from the Mayo Vascular Disease Biorepository, and polyvascular disease (ie, concomitant coronary heart disease, cerebrovascular disease, and/or abdominal aortic aneurysm) was ascertained by validated phenotyping algorithms. Of 3279 patients with PAD, 61% had polyvascular disease. Genetically predicted levels of the lipid content and/or particle measures of very small and small size very low‐density lipoprotein, intermediate‐density lipoprotein, and large low‐density lipoprotein were associated with polyvascular disease: odds ratios (OR) of 1.80 (95% CI, 1.23–2.61), 1.70 (95% CI, 1.17–2.61), and 1.40 (95% CI, 1.09–1.80) per 1 SD increase in genetically determined levels, respectively. Both genetically predicted diastolic and systolic blood pressure were associated with polyvascular disease; OR per 10 mm Hg genetic increase in diastolic and systolic blood pressure were 1.66 (95% CI, 1.19–2.33) and 1.31 (95% CI, 1.07–1.60), respectively. Conclusions Lifetime exposure to increased lipid content and levels of very small and small very low‐density lipoprotein, intermediate‐density lipoprotein, and large low‐density lipoprotein particles as well as elevated blood pressure are associated with polyvascular involvement in patients with PAD. Reduction in levels of such exposures may limit progression of atherosclerosis in patients with PAD.

AbstractPopulation‐based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life‐altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and “lessons learned” across institutions. A 60‐item survey that consisted of both multiple choice and open‐ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results.

AbstractBackgroundA 61‐year‐old woman underwent direct to consumer genetic testing and was found to be homozygous for the C282Y HFE variant (c.845G>A :p.Cys282Tyr) which is classified as pathogenic/likely pathogenic for hereditary hemochromatosis. However, no action was taken by the individual.MethodsThe individual took part in the Mayo Clinic Return of Actionable Variants Empiric (RAVE) study and the actionable finding was confirmed and results disclosed in person by a genetic counselor with subsequent referral to a hepatologist.ResultsFurther testing revealed iron overload with an elevated ferritin level (560 ng/ml) and increased ferritin saturation (74%). Phlebotomy was initiated with subsequent normalization of the ferritin levels (252 ng/ml).ConclusionThis case highlights that actionable genetic results may not be acted on after direct to consumer testing and the need for effective genetic counseling after such testing.