Angelika Erwin

PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease

OBJECTIVES:The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity.METHODS:Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I2 statistics and publication bias using Egger’s test and Begg and Mazumdar’s test. Individual participant data obtained from five studies were used for subgroup analyses.RESULTS:Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24–1.69) and 2.22 (1.50–3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79–2.44) and 3.37 (2.49–4.58) and among AC patients with HCC was 2.87 (1.61–5.10) and 12.41 (6.99–22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73–3.97) and 8.45 (2.52–28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24–3.17) and 3.86 (1.18–12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76–2.72) and 2.81 (1.57–5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients.CONCLUSIONS:PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services

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.

PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum.

Abstract Background and Aims: Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease. Methods: Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) and NAFLD were included. Pooled data are reported as odds ratios (ORs) with 95% confidence intervals. Results: Of 393 potentially relevant studies, 35 on NAFLD were included in the analysis. Compared to healthy controls, the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL) were 1.46 (1.16–1.85) and 2.76 (2.30–3.13), and were 1.75 (1.24–2.46) and 4.44 (2.92–6.76) among patients with non-alcoholic steatohepatitis respectively. The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90–6.13) and 5.05 (1.47–17.29) when comparing non-alcoholic hepatocellular carcinoma to NAFL patients. Among the NAFLD patients, the ORs for G allele frequency when comparing steatosis grade 2–3 to grade 0–1 NAFL, when comparing the NAFLD activity score of ≥ 4 to score ≤ 3, when comparing NASH to NAFLD, when comparing the presence of lobular inflammation to absence, and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43–3.80), 1.80 (1.36–2.37), 1.66 (1.42–1.94), 1.58 (1.19–2.10), and 2.63 (1.87–3.69) respectively. Subgroup analysis based on ethnicity showed similar results. Conclusions: PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs. PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.

Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care

Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients’ wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The percent of patients with a predicted phenotype associated with a gene‐based CPIC dosing recommendation was determined. Ninety‐nine patients (93.4%) elected to receive secondary pharmacogenomic findings. For each gene–drug pair analyzed, the number of patients with an actionable phenotype ranged from two (2%) to 43 patients (43.4%). Combining all gene–drug pairs, 84 unique patients (84.8%) had an actionable phenotype. A prospective multidisciplinary practice model was developed for integrating secondary pharmacogenomic findings into clinical practice. Our model highlights a unique collaboration between physician‐geneticists, pharmacists, and genetic counselors.

Corrigendum: PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease.

Corrigendum: PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease

De novo missense variants in MEIS2 recapitulate the microdeletion phenotype of cardiac and palate abnormalities, developmental delay, intellectual disability and dysmorphic features

Gross deletions involving the MEIS2 gene have been described in a small number of patients with overlapping phenotypes of atrial or ventricular septal defects, cleft palate, and variable developmental delays and intellectual disability. Non‐specific dysmorphic features were noted in some patients, including broad forehead with high anterior hairline, arched eyebrows, thin or tented upper lip, and short philtrum. Recently, a patient with a de novo single amino acid deletion, c.998_1000delGAA (p.Arg333del), and a patient with a de novo nonsense variant, (c.611C>G, p.Ser204*), were reported with a similar, but apparently more severe phenotypes. Clinical whole exome sequencing (WES) performed at our clinical molecular diagnostic laboratory identified four additional patients with predicted damaging de novo MEIS2 missense variants. Our patients’ features closely resembled those previously reported in patients with gross deletions, but also included some less commonly reported features, such as autism spectrum disorder, hearing loss, and short stature, as well as features that may be unique to nucleotide‐level variants, such as hypotonia, failure to thrive, gastrointestinal, skeletal, limb, and skin abnormalities. All of the observed missense variants, Pro302Leu, Gln322Leu, Arg331Lys, and Val335Ala, are located in the functionally important MEIS2 homeodomain. Pro302Leu is found in the region between helix 1 and helix 2, while the other three are located in the DNA‐binding helix 3. To our knowledge, these are the first described de novo missense variants in MEIS2, expanding the known mutation spectrum of the newly recognized human disorder caused by aberrations in this gene.