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The number of clinically relevant gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug-prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics. We describe the development of pharmacist-managed pharmacogenomic services within a large health system. The Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B*57:01-abacavir, HLA-B*15:02-carbamazepine, and TPMT-thiopurines (i.e., azathioprine, mercaptopurine, and thioguanine) were systematically integrated into patient care. Sixty-three custom rules and alerts (20 for TPMT-thiopurines, 8 for HLA-B*57:01-abacavir, and 35 for HLA-B*15:02-anticonvulsants) were developed and deployed to the EHR for the purpose of providing point-of-care pharmacogenomic decision support. In addition, a pharmacist and physician-geneticist collaboration established a pharmacogenomics ambulatory clinic. This clinic provides genetic testing when warranted, result interpretation along with pharmacotherapy recommendations, and patient education. Our processes for developing these pharmacogenomic services and solutions for addressing implementation barriers are presented.

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Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal-dominant disorder due to the half-normal activity of the heme biosynthetic enzyme, hydroxymethylbilane (HMB) synthase (1). Symptomatic heterozygotes, most (~90%) of which are women, experience episodic life-threatening acute neurovisceral attacks that typically begin with severe abdominal pain and may include hypertension, tachycardia, constipation, motor weakness and seizures. These attacks are precipitated by certain drugs, dieting and hormonal factors that increase the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1) (1). When hepatic ALAS1 is induced, the half-normal activity of HMB synthase becomes ratelimiting, leading to decreased heme biosynthesis and depletion of the hepatic "free" heme pool. Depletion of the"free" heme pool leads to further induction of Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3-and 5-fold, and ALA and PBG concentrations were increased ~3-and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.

This study assessed physician attitudes toward adopting genome-guided prescribing through clinical decision support (CDS), prior to enlisting in the Clinical Implementation of Personalized Medicine through Electronic Health Records and Genomics pilot pharmacogenomics project (CLIPMERGE PGx). We developed a survey instrument that includes the Evidence Based Practice Attitude Scale, adapted to measure attitudes toward adopting genome-informed interventions (EBPAS-GII). The survey also includes items to measure physicians’ characteristics (awareness, experience, and perceived usefulness), attitudes about personal genome testing (PGT) services, and comfort using technology. We surveyed 101 General Internal Medicine physicians from the Icahn School of Medicine at Mount Sinai (ISMMS). The majority were residency program trainees (~88%). Prior to enlisting into CLIPMERGE PGx, most physicians were aware of and had used decision support aids. Few physicians, however, were aware of and had used genome-guided prescribing. The majority of physicians viewed decision support aids and genotype data as being useful for making prescribing decisions. Most physicians had not heard of, but were willing to use, PGT services and felt comfortable interpreting PGT results. Most physicians were comfortable with technology. Physicians who perceived genotype data to be useful in making prescribing decisions, had more positive attitudes toward adopting genome-guided prescribing through CDS. Our findings suggest that internal medicine physicians have a deficit in their familiarity and comfort interpreting and using genomic information. This has reinforced the importance of gathering feedback and guidance from our enrolled physicians when designing genome-guided CDS and the importance of prioritizing genomic medicine education at our institutions.

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

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