Search

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in pre-diabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in metformin (MET, n=876) and placebo (PBO, n=887) arms. Multiple linear regression assessed association with one-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (p

HypothesisThe prevalence of type 2 diabetes is higher in Latino populations compared with other major ancestry groups. Not only has the Latino population been systematically underrepresented in large-scale genetic analyses, but previous studies relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation reference panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The NHLBI Trans-Omics for Precision Medicine (TOPMed) reference panel represents a unique opportunity to analyze rare genetic variations in the Latino population.MethodsWe evaluate the TOPMed imputation performance using genotyping array and whole-exome sequence data in 6 Latino cohorts. To evaluate the ability of TOPMed imputation of increasing the identified loci, we performed a Latino type 2 diabetes GWAS meta-analysis in 8,150 type 2 diabetes cases and 10,735 controls and replicated the results in 6 additional cohorts including whole-genome sequence data from the All of Us cohort.ResultsWe show that, compared to imputation with 1000G, the TOPMed panel improves the identification of rare and low-frequency variants. We identified 26 distinct signals including a novel genome-wide significant variant (minor allele frequency 1.6%, OR=2.0, P=3.4×10−9) near ORC5. A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improves the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance.ConclusionsOur results demonstrate the utility of TOPMed imputation for identifying low-frequency variation in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores.

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and BMI. A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year hemoglobin A1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study (P = 0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.

BackgroundCharacterization of genetic variation that influences response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes (T2D). SUGAR-MGH examined the acute response to two anti-diabetes medications in order to understand the functional relevance of known T2D- and glycaemic trait-associated genetic loci.Methods1,000 participants at risk for T2D from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between variants and primary endpoints of drug response. We evaluated the influence of 804 unique T2D and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalization analyses to identify shared genetic signals.FindingsFive genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency=0·026) at rs149403252 and lower fasting glucose following metformin, adjusted for baseline glucose (p=1·9×10−9), with a 0·94 mmol/L larger decrease in fasting glucose after metformin. We identified associations between T2D-associated variants and glycaemic response, including the T2D-protective C allele of rs703972 near ZMIZ1 and increased levels of active GLP-1 (p=1·6×10−5), supporting the role of alterations in incretin levels in T2D pathophysiology.InterpretationWe present a well phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common anti-diabetes medications, and provide insight into mechanisms of action of T2D-related variation.FundingUS National Institutes of Health.

Objective: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However there exists significant variability in glycaemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. Research design and methods: As an initiative of the Metformin Genetics Plus (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia, 5,485 white Europeans with type 2 diabetes treated with sulfonylurea were recruited from 6 referral centres in Europe and North America. We first estimated heritability using generalized restricted maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis-eQTLs and functional validation in cellular models. Finally, we examined for a possible drug-drug-gene interactions. Results: After establishing that sulfonylurea response is heritable (37±11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (p < 5×10-8). The C-allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), p=2.39×10−8) lower reduction in HbA1c. Similarly, the C-allele was associated with higher glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3, 029 human whole blood samples, the C-allele is a cis-eQTL for increased expression of GXYLT1 (β=0.21, p=2.04×10-58). The C-allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (p=4.80×10−8). In 1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced SLCO1B1 expression (p=1.61×10−7) which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use, sulfonylurea response and SCLO1B1 genotype was observed (p=0.001). In statin non-users, C-allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48±0.12% (5.2±1.26 mmol/mol)), equivalent to initiating a DPP4 inhibitor. Conclusion: We have identified clinically important genetic effects at genome wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important when prescribing glucose-lowering drugs.

Genome-wide significant (GWS) loci for glycemic response to MET in type 2 diabetes (T2D) reported elsewhere have not replicated in the DPP. Thus, to assess whether pharmacogenetic interactions may differ in impaired glucose tolerance (IGT), we conducted a GWAS in the DPP for MET response, defined by diabetes incidence and change in quantitative traits (fasting glucose, 2-hour glucose on oral glucose tolerance test, hemoglobin A1c [HbA1c], fasting insulin, insulin sensitivity index, and weight). Samples were genotyped on the Illumina HumanCore Exome array and imputed on the 1000 Genomes Phase3 panel. Cox proportional hazards models tested associations with diabetes incidence in MET (n=876) and placebo (PBO, n=887) arms. Multiple linear regression using an additive model evaluated for association with 1-year change in quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-environment (G×E) interaction between MET and PBO. Results were filtered to minor allele frequency (MAF) >1% and imputation score >0.7. We identified 3 GWS variants after correcting for correlated traits (P In summary, a GWAS for MET response in participants with IGT revealed novel associations that require validation in ancestry-specific populations and may have implications for tailored therapy. Disclosure J. H. Li: None. R. L. Hanson: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. D. Research group: None. J. A. Perry: None. K. A. Jablonski: None. L. Chen: None. S. Srinivasan: None. J. N. Todd: None. M. Harden: None. J. M. Mercader: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)

SUGAR-MGH is a pharmacogenetic resource for characterizing genetic influences on pharmacological perturbations relevant to type 2 diabetes (T2D). 1,000 participants who were naïve to T2D treatment received 5 mg glipizide, followed by 4 doses of 500 mg metformin and a 75-g oral glucose tolerance test (OGTT) a week later. Glucose and insulin were measured at pre-specified endpoints after glipizide and during the OGTT. Incretin levels were measured in a subset. We calculated physiologic endpoints reflecting insulin secretion, insulin sensitivity, and incretin secretion. The mean age was 47 years, 54% were women, >35% were non-white, and the mean BMI was 30.2 kg/m2. 890 participants underwent genome-wide genotyping using the Illumina Multi-Ethnic Genotyping Array, and high-quality imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and endpoints. We identified 21 genome-wide significant variants, of which 3 met experiment-wide significance (P Disclosure J. H. Li: None. V. Kaur: None. L. Brenner: Research Support; Self; Apple. J. M. Mercader: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. Funding National Institutes of Health (R01DK088214, R03DK077675, P30DK036836, M01RR01066, 1UL1RR025758-04, 8UL1TR000170-05, T32DK007028)

Background: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However there exists significant variability in glycaemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. Methods: As an initiative of the Metformin Genetics Plus (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia, 5,485 white European adults with type 2 diabetes treated with sulfonylurea were recruited from 6 referral centres in Europe and North America. We first estimated heritability using generalized restricted maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy in each cohort using linear regression followed by meta-analysis. These results were supported by cis-eQTLs and functional validation in cellular models. Findings: After establishing that sulfonylurea response is heritable (37±11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction. The C-allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), p=2.4×10−8) lower HbA1c reduction. Similarly, the C-allele was associated with higher glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). The C-allele of rs10770791, near SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater HbA1c reduction (p=4.8×10 −8 ). In 1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced SLCO1B1 expression (p=1.61×10−7) which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use, sulfonylurea response and SCLO1B1 genotype was observed (p=0.001). In statin non-users (but not users), C-allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48±0.12% (5.2±1.26 mmol/mol)), equivalent to initiating a DPP4 inhibitor. Interpretation: We have identified clinically important genetic effects at genomewide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important when prescribing glucose-lowering drugs. Funding Statement: Innovative Medicines Initiative, the National Institutes of Health, the Geisinger Health Plan Quality Pilot Fund. Declaration of Interests: ERP has received honoraria for speaking from Lilly and Sanofi. JCF has received honoraria for speaking at scientific conferences from Novo, and for consulting from Goldfinch Bio. All other authors declare no competing interest. Ethics Approval Statement: This study was approved by respective research ethics review boards and participants provided written informed consent.

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to anti-diabetes medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose (FG), and fasting insulin (FI), comprised of 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic endpoints, adjusting for age, sex, race, and body mass index (BMI). A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year HbA1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research, Tayside and Scotland (GoDARTS) study (p=0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.

A variety of inflammatory disorders, generically classified as "thyroiditis," can affect the thyroid gland diffusely, generating distinctive radiographic patterns. While a precise diagnosis can seldom be made based on sonographic appearance alone, interpreting these patterns in the correct clinical and biochemical context will help support the most appropriate diagnosis. We believe that the generic term "thyroiditis" is often not helpful and often may be incorrect. Therefore, it is important for radiologists to understand the sonographic and functional correlations to provide the most appropriate differential diagnosis in their reports. This brief review is designed to provide information and guidance for radiologists when dealing with various thyroid disorders which cause diffuse changes in the thyroid and underline the pitfalls most often encountered in clinical practice.

AIMS: To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naïve to diabetes medications. METHODS: In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), 786 individuals genotyped for rs1799853/rs41291560 (*2) and rs1057910/rs9332214 (*3) were treated with 5 mg glipizide in the fasting state. Glucose and insulin levels were measured at baseline, 30, 60, 90, 120, 180 and 240 min for calculation of phenotypic endpoints of glipizide response. The challenge was aborted as a result of hypoglycaemia, defined as glucose

Whether genetics can help predict response to type 2 diabetes (T2D) drugs is unknown. We set out to examine whether genetic risk scores (GRSs) composed of single nucleotide polymorphisms (SNPs) known to be associated with glycemic traits and T2D are associated with glycemic traits and the acute response to metformin and glipizide in SUGAR-MGH. We measured plasma glucose, insulin, glucagon, proinsulin, c-peptide, GLP-1, and GIP levels in 1,000 participants naïve to antidiabetes medications at 0, 30, 60, 90, 120, 180, and 240 minutes following administration of 5 mg glipizide (Visit 1, day 1), and during a 75-g oral glucose tolerance test following a short metformin course (Visit 2, day 8). We constructed a T2D, fasting glucose (FG), and fasting insulin (FI) GRS (with 65, 43 and 13 SNPs respectively) by summing the number of risk alleles carried by each person based on known genome-wide significant associations. Linear regression tested for associations between GRSs and glycemic traits as well as pharmacodynamic endpoints, adjusting for age, sex, race, and BMI. The FG GRS predicted FG in our cohort (β=0.46 increase in FG in mg/dL*allele, P Disclosure J.H. Li: None. L. Szczerbinski: None. V. Kaur: None. J. Todd: None. J.C. Florez: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK-088214, R03DK-077675, P30-DK-036836); Joslin Clinical Research Center; Harvard Catalyst; National Center for Research Resources/National Center for Advancing Translational Sciences (M01-RR-01066, 1UL1-RR-025758-04, 88UL1-TR-000170-05; Harvard University

BACKGROUNDIn 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine.CONTENTIn this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants. These genetic variations have pharmacodynamic and pharmacokinetic effects and have been shown to explain differences in drug response such as lipid lowering, prevention of cardiovascular disease, and prevention of stroke, as well as incidence of adverse events such as musculoskeletal side effects and bleeding. Several groups have begun to implement pharmacogenetics testing as part of routine clinical care with the goal of improving health outcomes. Such strategies identify both patients at increased risk of adverse outcomes and alternative strategies to mitigate this risk as well as patients with “normal” genotypes, who, armed with this information, may have increased confidence and adherence to prescribed medications. While much is known about the genetic variants that underlie these effects, translation of this knowledge into clinical practice has been hampered by difficulty in implementing cost-effective, point-of-care tools to improve physician decision-making as well as a lack of data, as of yet, demonstrating the efficacy of using genetic information to improve health.SUMMARYMany genetic variants that affect individual responses to drugs used in cardiovascular disease prevention and treatment have been described. Further study of these variants is needed before successful implementation into clinical practice.

Radioactive iodine (RAI) ablation is a beneficial, adjuvant therapy for the management of differentiated thyroid cancer (DTC) after thyroidectomy. The goal of RAI is to destroy remnant thyroid and microscopic cancerous tissue. Radioactive iodine uptake is enhanced by elevating TSH levels and initiating a low iodine diet (LID) prior to ablation. An ideal LID should preferably not exceed 50 mcg/day of dietary iodine for 1-2 weeks, although the duration may be shortened to a week with a structured patient education programme. A pre-ablation spot urinary iodine concentration (UIC) of

Aim: SLCO1B1 variants are associated with intermediate outcomes that may increase risk of death/myocardial infarction (MI) in statin-treated patients. Patients & methods: In high-risk Caucasians undergoing cardiac catheterization, we tested the association between rs4149056/625T>C and rs2306283/492A>G with low-density lipoprotein cholesterol (LDL-c) over 3 years (n = 1402) and death/MI over 6 years (n = 2994), accounting for statin use or type during follow-up. Results: Carriers of the rs4149056 C allele had 6.2 ± 1.7 mg/dl higher LDL-c per C allele (p < 0.001) but were not at higher risk for death/MI (p = 0.9). We found no associations between rs2306283 and LDL-c or death/MI (p > 0.6). Conclusion: Functional SLCO1B1 variants are not associated with death/MI in patients commonly treated with statins, despite higher LDL-c in carriers of the rs4149056 C allele. Original submitted 3 November 2014; Revision submitted 5 January 2015

Background & Aims Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-λ genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients. Methods A cross-sectional study of 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n = 178), African Americans (n = 53), and HCV genotypes 1 (n = 186) and 2/3 (n = 45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended. Results The rs12979860 CC genotype (found in ∼40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio, 5.79; 95% confidence interval, 2.67–12.57; P = 9.0 × 10−6), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1). Conclusions rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.

Recently, genetic polymorphisms occurring in the interferon (IFN)-lambda gene region were associated with response to IFN-based treatment of hepatitis C infection. Both infection with the hepatitis C virus and IFN therapy are associated with decreased serum cholesterol and high cholesterol has been associated with increased likelihood to respond to IFN. We sought to determine if the IFN-lambda gene variant was also associated with serum lipid levels in chronic hepatitis C patients. We compared genotypes of the rs12979860 polymorphism, located proximal to the IL28 gene, with serum lipid and apolipoprotein levels in 746 subjects with chronic hepatitis C virus infection, not currently undergoing treatment, using multivariable analysis of variance. Levels of total cholesterol (P = 6.0 x 10(-4)), apolipoprotein B (P = 1.3 x 10(-6)) and low-density lipoprotein (LDL) cholesterol (P = 8.9 x 10(-10)) were significantly higher in subjects carrying the rs12979860 CC responder genotype compared with those with the CT or TT genotype. Levels of triglycerides (P = 0.03), apolipoprotein A-I (P = 0.06), and apolipoprotein E (P = 0.01) were slightly lower in the rs12979860 CC genotype group, whereas levels of high-density lipoprotein cholesterol (P = 0.78) and apolipoprotein C-III (P = 0.74) did not vary by rs12979860 genotype.Our results suggest that low levels of LDL cholesterol in chronic hepatitis C patients may be a marker of host endogenous IFN response to hepatitis C and that subjects with the rs12979860 CC responder genotype may have a lower endogenous IFN response to the virus.

Statin adherence is often limited by side effects. The SLCO1B1*5 variant is a risk factor for statin side effects and exhibits statin-specific effects: highest with simvastatin/atorvastatin and lowest with pravastatin/rosuvastatin. The effects of SLCO1B1*5 genotype guided statin therapy (GGST) are unknown. Primary care patients (n = 58) who were nonadherent to statins and their providers received SLCO1B1*5 genotyping and guided recommendations via the electronic medical record (EMR). The primary outcome was the change in Beliefs about Medications Questionnaire, which measured patients’ perceived needs for statins and concerns about adverse effects, measured before and after SLCO1B1*5 results. Concurrent controls (n = 59) were identified through the EMR to compare secondary outcomes: new statin prescriptions, statin utilization, and change in LDL-cholesterol (LDL-c). GGST patients had trends (p = 0.2) towards improved statin necessity and concerns. The largest changes were the “need for statin to prevent sickness” (p < 0.001) and “concern for statin to disrupt life” (p = 0.006). GGST patients had more statin prescriptions (p < 0.001), higher statin use (p < 0.001), and greater decrease in LDL-c (p = 0.059) during follow-up. EMR delivery of SLCO1B1*5 results and recommendations is feasible in the primary care setting. This novel intervention may improve patients’ perceptions of statins and physician behaviors that promote higher statin adherence and lower LDL-c.

Objective: To report an unusual case of concurrent pancreatic adenocarcinoma and metastatic insulinoma causing severehypoglycemia in a patient with diabetes.Methods: The clinical presentation, biochemical studies, and relevant imaging of this patient are presented and the pertinentliterature is reviewed.Results: A 59-year-old man with a history of unresectable pancreatic adenocarcinoma and diabetes was admitted for persistenthypoglycemia, meeting all criteria for Whipple’s triad and requiring high-dose dextrose infusion. Prior outpatient abdominalimaging had revealed hepatic lesions that were biopsied and found to be a high-grade neuroendocrine carcinoma. On admission, laboratory evaluation revealed inappropriately suppressed beta-hydroxybutyrate levels, and inappropriately elevated insulin, C-peptide, and proinsulin levels. An octreotide scan revealed uptake in the hepatic lesions but not in the pancreatic head mass. Immunohistochemistry staining of prior liver biopsy samples was negative for insulin. Diazoxide therapy was initiated, butdiscontinued after the onset of hypotension. The hypoglycemia resolved only after trans-arterial chemoembolization of lesionsboth in the left and the right liver lobes, in combination with continued octreotide. Unfortunately, he subsequently developedrecurrent hypoglycemia three weeks later and ultimately passed away after transitioning to hospice care.Conclusions: Insulinomas are rare neoplasms of the pancreas that are characterized by insulin hypersecretion, which can bedebilitating and potentially life-threatening. The diagnosis of metastatic insulinoma is difficult to make in the setting of multiplecomorbidities and requires precise biochemical studies. Multiple medical treatments are available but the overall prognosis ispoor.

Background & Aims IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naive patients with CHC. Methods Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. Results CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs . 22.5% (9/40; p =0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p =0.001) of CC patients in the Duke cohort. Conclusions IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.

20 G2) were included. SVR was defined as undetectable HCVRNA at 24 weeks of follow up. The SNP analysis of rs12979860 variant was determined in 50ng of DNA by RT-PCR using specific oligonucleotide primers and probes to amplify the sequence target in DNA (Tib MoLBIOL GmbH, Berlin Germany). All HCV patients were genotyped as CC, CT or TT. Results: CT and TT variants were present in 45 and 18 subjects (56% and 23%, respectively) of the studied population. CC polymorphism had the lowest frequency in our cohort (21%, CI 95%: 12.89–31.83%) and it was strongly associated with response to standard treatment (OR 2.95); 76% of CC carriers achieved SVR compared with 55.5% and 44.4% of SVR in patients with CT and TT variants.