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Ewan R Pearson

Publications and source records attributed to Ewan R Pearson.

14 recordsLinked to original sources
PubMed2026

Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review.

BACKGROUND: Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes. METHOD: A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines. RESULTS: A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation. CONCLUSION: The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.

Humans↗
PubMed2026

Five tenets for advancing evidence-based precision medicine.

Precision medicine for complex diseases uses individual-level characteristics to improve prediction of risk, therapeutic response and prognosis. Many precision medicine studies leverage existing data types and analytic methods to reveal new insights; however, beyond oncology, there has been limited success in translating precision medicine research for complex diseases into clinical practice. Thus, there is a need to identify areas for improvement, particularly in translation-oriented analytical methods and study designs. In this perspective article, we outline five fundamental tenets to enhance the efficient clinical translation of precision medicine research. These tenets focus on addressing (1) heterogeneity in risk, response and prognosis; (2) signal robustness; (3) structured statistical benchmarking against key performance indicators; (4) precision trial designs; and (5) risks and benefits to individuals and society. Our intention is to promote clinically meaningful, reproducible, scalable and equitable health outcomes through precision medicine, beyond those possible through contemporary approaches.

Precision Medicine↗
PubMed2006

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

BACKGROUND: Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. METHODS: We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. RESULTS: A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. CONCLUSIONS: Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].).

ATP-Binding Cassette Transporters↗
PubMed2006

Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes.

Defining the molecular genetics of diabetes gives new insight into the underlying etiology and so should help improve treatment. The genetic etiology is now known for most patients with beta-cell monogenic diabetes, allowing genetic classification. We review how this genetic knowledge alters treatment. Patients with a glucose-sensing beta-cell defect due to glucokinase mutations have regulated, mild, fasting hyperglycemia. Oral hypoglycemic agents or low-dose insulin rarely improve glycemic control. Patients with hepatic nuclear factor-1alpha (HNF1alpha) mutations have progressive beta-cell deterioration and require treatment. HNF1alpha patients are 4 times more sensitive to sulfonylureas than matched type 2 diabetic patients. This is partly due to greater insulin secretion, reflecting the fact that the defect in HNF1alpha deficiency precedes the K(ATP) channel where sulfonylureas act. HNF1beta is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells, so patients with HNF1beta mutations have reduced pancreatic development, resulting in early-onset diabetes and exocrine dysfunction. These patients usually rapidly require insulin and are not sensitive to sulfonylureas. Thirty-five to 50% of patients diagnosed with diabetes before 6 months have a mutation in Kir6.2. The mutated KATP channel in these patients does not close in response to increased ATP concentrations, but can be closed when sulfonylureas bind to the sulfonylurea receptor 1 subunit of the channel by an ATP-independent route. These patients are usually insulin dependent, but have excellent glycemic control on high-dose sulfonylureas tablets. In conclusion, the defining of molecular genetic etiology in monogenic diabetes has identified several specific beta-cell defects, and these are critical in determining the response to treatment.

Animals↗
PubMed2006

Conditional expression of hepatocyte nuclear factor-1beta, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic beta-cells.

Mutations in the gene encoding hepatocyte nuclear factor (HNF)1beta result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing beta-cell mass. The functional role of HNF1beta in normal beta-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1beta, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic beta-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1beta was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1beta also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent beta-cells are sensitive to increased expression of WT HNF1beta and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

Apoptosis↗
PubMed2006

Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1beta and -1alpha mutations.

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1alpha and -1beta, HNF-1beta mutation carriers have hyperinsulinemia, whereas HNF-1alpha mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1beta mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU . kg(-1) . min(-1)) and high-dose (1.5 mU . kg(-1) . min(-1)) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-(2)H(2)]glucose, in six subjects with HNF-1alpha mutations, six subjects with HNF-1beta mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1beta subjects but was suppressed by 89% in HNF-1alpha subjects (P = 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at low- and high-dose insulin. Subjects with HNF-1beta mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1beta in the liver and possibly the kidney. This may be mediated through regulation by HNF-1beta of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.

Adult↗
PubMed2005

Relapsing diabetes can result from moderately activating mutations in KCNJ11.

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.

ATP-Binding Cassette Transporters↗
PubMed2004

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

DNA Mutational Analysis↗
PubMed2004

Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and -1beta mutations.

OBJECTIVE: Mutations in the highly homologous transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta cause maturity-onset diabetes of the young types 3 and 5, respectively. Diabetes due to HNF-1alpha mutations is well characterized. However, physiological assessment of the HNF-1beta phenotype is limited. We aimed to test the hypothesis that the diabetes phenotype due to HNF-1beta mutations is similar to that in HNF-1alpha. RESEARCH DESIGN AND METHODS: Fasting biochemistry and a tolbutamide-modified intravenous glucose tolerance test (IVGTT) were compared in matched HNF-1beta, HNF-1alpha, type 2 diabetic, and control subjects. Homeostasis model assessment indexes were determined from fasting insulin and glucose. The peak measures for the insulin increment after tolbutamide and for the insulin increment after glucose were determined from the IVGTT. RESULTS: The HNF-1beta patients showed a 2.4-fold reduction in insulin sensitivity compared with the HNF-1alpha patients (P = 0.001) with fasting insulin concentrations 2.7-fold higher (P = 0.004). HNF-1beta patients had lower HDL cholesterol (1.17 vs. 1.46 mmol/l; P = 0.009) and higher triglyceride (2.2 vs. 1.35 mmol/l; P = 0.015) levels than HNF-1alpha patients. The HNF-1beta patients had similar beta-cell responses to tolbutamide and glucose as the type 2 diabetic patients, but in the HNF-1alpha patients, the tolbutamide response was considerably increased relative to the response to glucose (P = 0.002). CONCLUSIONS: HNF-1beta patients have a different diabetes phenotype than HNF-1alpha patients. Those with HNF-1beta mutations have hyperinsulinemia and associated dyslipidemia consistent with insulin resistance and may have a different beta-cell defect. This suggests that despite considerable homology and a shared binding site, HNF-1alpha and HNF-1beta have a different role in maintaining normal glucose homeostasis. This result suggests a new etiological pathway for insulin resistance involving HNF-1beta.

Adult↗
PubMed2003

Genetic cause of hyperglycaemia and response to treatment in diabetes.

BACKGROUND: Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1alpha diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity. METHODS: We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1alpha mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance. FINDINGS: Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4.7 vs 0.9 mmol/L, p=0.0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0.002). Patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups. INTERPRETATION: The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1alpha diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.

ATP-Binding Cassette Transporters↗
PubMed2003

Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is a dominantly inherited condition characterized by young-onset hyperuricemia, gout, and renal disease. The etiologic genes are unknown, although a locus on chromosome 16 has been identified in some kindreds. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with dominant inheritance of a variety of disorders of renal development, particularly renal cystic disease and early onset diabetes; hyperuricemia has been reported in some kindreds. METHODS: To assess a possible role for the HNF-1beta gene in some FJHN kindreds we sequenced the HNF-1beta gene in subjects from three unrelated FJHN families with atypical features of renal cysts or abnormalities of renal development. We also compared serum urate levels in subjects with HNF-1beta mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1beta mutations. RESULTS: A splice-site mutation in intron 2, designated IVS2+1G>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1beta subjects compared with the normal control subjects (384 micromol/L vs. 264 micromol/L, P = 0.002) and the type 2 diabetic subjects (397 micromol/L vs. 271 micromol/L, P = 0.01). Comparison of serum urate levels in the HNF-1beta subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 micromol/L vs. 352 micromol/L, P = 0.2). CONCLUSION: Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.

Adult↗
PubMed2003

Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels.

Hepatocyte nuclear factor-1a (HNF-1alpha) is a transcription factor that plays an important role in regulation of gene expression in pancreatic beta-cells, intestine, kidney, and liver. Heterozygous mutations in the HNF-1alpha gene are responsible for maturity-onset diabetes of the young (MODY3), which is characterized by pancreatic beta-cell-deficient insulin secretion. HNF-1alpha is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-1alpha mutations. In this study, we show that Hnf-1alpha is a potent transcriptional activator of the gene encoding apolipoprotein M (apoM), a lipoprotein that is associated with the HDL particle. Mutant Hnf-1alpha(-/-) mice completely lack expression of apoM in the liver and the kidney. Serum apoM levels in Hnf-1alpha(+/-) mice are reduced approximately 50% compared with wild-type animals and are absent in the HDL and HDLc fractions of Hnf-1alpha(-/-). We analyzed the apoM promoter and identified a conserved HNF-1 binding site. We show that Hnf-1alpha is a potent activator of the apoM promoter, that a specific mutation in the HNF-1 binding site abolished transcriptional activation of the apoM gene, and that Hnf-1alpha protein can bind to the Hnf-1 binding site of the apoM promoter in vitro. To investigate whether patients with mutations in HNF-1alpha mutations (MODY3) have reduced serum apoM levels, we measured apoM levels in the serum of nine HNF-1alpha/MODY3 patients, nine normal matched control subjects (HNF-1alpha(+/+)), and nine HNF-4alpha/MODY1 subjects. Serum levels of apoM were decreased in HNF-1alpha/MODY3 subjects when compared with control subjects (P < 0.02) as well as with HNF-4alpha/MODY1 subjects, indicating that HNF-1alpha haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum apoM protein concentrations. This study demonstrates that HNF-1alpha is required for apoM expression in vivo and that heterozygous HNF-1alpha mutations lead to an HNF-1alpha-dependent impairment of apoM expression. ApoM levels may be a useful serum marker for the identification of MODY3 patients.

Adult↗
PubMed2002

Severe hyperglycemia after renal transplantation in a pediatric patient with a mutation of the hepatocyte nuclear factor-1beta gene.

After renal transplantation for congenital cystic kidney disease of unknown origin, a 14-year-old boy, who was previously normoglycemic, had "steroid-induced" diabetes mellitus, which was treated with insulin. Transplant failure from chronic rejection and subsequent transplant nephrectomy allowed discontinuation of corticosteroids, the gradual withdrawal of insulin and normoglycemia. The recent description of renal cysts and diabetes (RCAD) syndrome and a strong paternal family history of early-onset diabetes mellitus prompted genetic screening of the hepatocyte nuclear factor-1beta gene. A novel heterozygous frameshift mutation in exon 1 was identified, adding to the 12 kindreds thus far described. This case highlights the unmasking of the hyperglycemic component of the RCAD syndrome in the immediate postoperative period after renal transplantation and emphasizes the pleiotropic manifestations of this important genetic kidney disease.

Adolescent↗