ABSTRACT
AIMS/HYPOTHESIS: Evolving research suggests that common and rare alleles jointly constitute the genetic landscape of complex disease. We studied the association between 43 pathway-related candidate genes with 'intermediate phenotype' (i.e. corresponding plasma protein) and diabetic nephropathy in a customised microarray of 1,536 SNPs. METHODS: In this case-control study of type 2 diabetic Chinese individuals with and without diabetic nephropathy, cases (n = 545) were defined on the basis of a spot urinary albumin/creatinine ratio (ACR) > 113 mg/mmol; the value for controls (n = 503) was ACR < 3.3 mg/mmol. Genotyping was performed using Illumina GoldenGate assay. RESULTS: No single nucleotide polymorphism (SNP) remained significant in single locus analysis after correction for multiple testing. Therefore, we explored the best approximately 1% SNPs. Of these 13 SNPs, four clustered to a 5' end NADPH oxidase homologue 4 (NOX4) haplotype (GGCC frequency = 0.776) with estimated OR for diabetic nephropathy of 2.05 (95% CI 1.04-4.06) (heterozygous) and 2.48 (1.27-4.83) (homozygous) (p = 0.0055). The haplotype was correlated with plasma Cu/Zn superoxide dismutase (SOD) concentration, suggesting increased oxidative burden. Endothelin-1 SNP (rs1476046G>A, frequency = 0.252) was correlated with plasma C-terminal pro-endothelin-1 concentrations with an estimated OR for diabetic nephropathy of (heterozygous) 1.26 (0.96-1.66) and (homozygous) 1.87 (1.13-3.12) (p = 0.0072). Nitric oxide synthase 1 (NOS1) 5' haplotype (TGTC frequency = 0.38) also revealed a suggestive association with diabetic nephropathy: heterozygous 1.26 (0.95-1.67), homozygous 1.57 (1.04-2.35) (p = 0.0073). A rare NADPH oxidase homologue 1 (NOX1)-coding non-synonymous SNP (Arg315His, frequency = 0.006) was found exclusively among cases. CONCLUSIONS/INTERPRETATION: Our preliminary observations suggest that common haplotypes from NOX4 and endothelin-1 SNP correlated with plasma Cu/Zn SOD and C-terminal pro-endothelin-1 concentrations, respectively, and might have conferred diabetic nephropathy susceptibility. Common NOS1 and rare NOX1 variants also revealed a suggestive association with diabetic nephropathy. Future studies to validate our observation are needed.
Subject(s)
Asian People/genetics , Diabetes Mellitus, Type 2/genetics , Diabetic Nephropathies/genetics , Endothelin-1/genetics , NADPH Oxidases/genetics , Nitric Oxide Synthase Type I/genetics , Aged , Blood Proteins/genetics , Case-Control Studies , Diabetes Mellitus, Type 2/ethnology , Diabetic Nephropathies/ethnology , Female , Genetic Predisposition to Disease/ethnology , Haplotypes , Humans , Male , Middle Aged , NADPH Oxidase 4 , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Singapore/epidemiologySubject(s)
Cardiovascular Diseases/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Carrier Proteins/genetics , Cholesterol Ester Transfer Proteins , Clofibric Acid/therapeutic use , Diabetes Mellitus/drug therapy , Gemfibrozil/therapeutic use , Glycoproteins/genetics , Humans , Mutation , Risk FactorsABSTRACT
Thyrotrophin (TSH)-secreting pituitary adenomas, although rare, should be recognised as a possible cause of normal or elevated serum TSH in the presence of elevated serum free thyroid hormone levels. Clinical hyperthyroidism may be mild or absent. Early recognition provides the best chance for surgical cure. We report a patient with a TSH-secreting pituitary tumour with cavernous sinus invasion. This case illustrates that multiple modalities of treatment are often necessary and complementary in achieving control of tumour growth and hormonal hypersecretion when these tumours are diagnosed late.
Subject(s)
Adenoma/pathology , Cavernous Sinus/pathology , Pituitary Neoplasms/pathology , Thyrotropin/metabolism , Adenoma/metabolism , Adenoma/therapy , Humans , Male , Middle Aged , Neoplasm Invasiveness , Pituitary Neoplasms/metabolism , Pituitary Neoplasms/therapyABSTRACT
INTRODUCTION: We report the first case of hypoglycaemia from beta cell hyperplasia with nesidioblastosis in an Asian adult with pre-existing type 2 diabetes. CLINICAL PICTURE: A 57-year-old Chinese woman presented with hyperinsulinaemic hypoglycaemia despite discontinuation of oral hypoglycaemic agents 4 months after diagnosis of type 2 diabetes. Preoperative portal venous sampling suggested regionalisation to the neck of the pancreas. Intraoperative ultrasound and palpation of the fully mobilised pancreas were non-localising. TREATMENT: A subtotal 85% pancreatectomy was performed with success. OUTCOME: Histology showed no evidence of tumour, but revealed islet hyperplasia and nesidioblastosis. Her diabetes was subsequently well controlled on metformin therapy. CONCLUSION: Endogenous hyperinsulinism from beta cell hyperplasia with nesidioblastosis may rarely occur in type 2 diabetics. However, this remains a diagnosis of exclusion that is confirmed only on surgical pathology. In affected individuals, preoperative portal venous sampling may be falsely localising, especially if selective sampling of the smaller peri-pancreatic veins is omitted. Definite treatment involves pancreatectomy, although the extent of surgical resection is not well established.
