Bahram Jafar-Mohammadi

Genetics of type 2 diabetes mellitus and obesity : a review

Type 2 diabetes (T2D) and obesity are recognized as conditions of growing biomedical importance to societies worldwide. Despite this, lack of understanding concerning the processes which normally serve to maintain weight and to regulate glucose concentrations, and ignorance about the mechanisms by which these homeostatic processes fail, remains a significant obstacle to the development of improved tools for management and prevention. There has been a long‐standing belief that the identification of the specific genes influencing development of these conditions has the potential to reveal these fundamental processes, thereby providing vital clues to support clinical advances. Furthermore, there has been the hope that this information will translate into the capacity to deliver more ‘personalized’ medical care, whereby management can be tailored in accordance with an appreciation of individual molecular pathogenesis. As this review indicates, these developments are already a reality for selected monogenic forms of diabetes and obesity. Recent advances in the identification of genes underlying multifactorial forms of these conditions will accelerate efforts to effect similar clinical translation across the full spectrum of disease.

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility

Aims/hypothesisRare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)—known to influence downstream HNF-4A target gene expression—are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis.MethodsWe genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls.ResultsWe found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08–1.28]; p = 1.5 × 10−4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10–1.30]; p = 2.1 × 10−5).Conclusions/interpretationOur data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Genetic association analysis of LARS2 with type 2 diabetes

Aims/hypothesisLARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk.MethodsWe combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent.ResultsNo association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95–1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90–1.08], p = 0.78, n = 35,715 respectively).Conclusions/interpretationIn this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.

Routine genetic screening with a multi-gene panel in patients with pheochromocytomas

PurposeSeveral new gene mutations have been reported in recent years to be associated with a risk of familial pheochromocytoma. However, it is unclear as to whether extensive genetic testing is required in all patients.MethodsThe clinical data of consecutive patients operated for pheochromocytoma over a decade in a tertiary referral center were reviewed. Genetic screening was performed using a 10-gene panel: RET, VHL, SDHB, SDHD, SDHA, SDHC, SDHAF2, MAX, TMEM127 and FH.ResultsA total of 166 patients were analyzed: 87 of them had genetic screening performed (39 M: 44.8%, 48 F: 55.2%, age range 6–81 years, mean 45±16.8 years). In total, 22/87 (25.3%) patients had germline mutations, while 65/87 (74.7%) patients presented with apparently sporadic tumors. Germline VHL mutations were identified in 11.7% of patients, RET in 6.8% (five MEN2A/MEN2 and one MEN2B/MEN3), SDHD in 2.3%, MAX in 2.3%, SDHB in 1.1%, and TMEM127 in 1.1% of patients. At diagnosis, 15.1% of patients with unilateral non-syndromic pheochromocytoma showed germline mutations. We identified 19.7% of mutations in patients with unilateral-non-recurrent pheochromocytomas within 5 years vs. 50% in the recurrent-bilateral-metastatic group (p = 0.01). Germline mutations were more frequently seen with bilateral pheochromocytomas (p = 0.001): 80% of patients with bilateral disease had germline mutations (4 VHL, 3 RET, 1 MAX).ConclusionsThe advent of rapid genetic screening using a gene-panel makes it feasible to screen large cohorts of patients and provides a valuable tool to contribute to the prediction of bilateral and malignant disease and to screen family members.

Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes

Background There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8–10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1–7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8–10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D. Methodology and Principal Findings We performed targeted capillary resequencing of HNF1A exons 8–10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤45 years) and/or family history of T2D (≥1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9−24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. Conclusions and Significance We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.

Baseline morning cortisol level as a predictor of pituitary–adrenal reserve: a comparison across three assays

The short ACTH stimulation test (250 μg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds.

PITUITARY STALK THICKENING: THE ROLE OF AN INNOVATIVE MRI IMAGING ANALYSIS WHICH MAY ASSIST IN DETERMINING CLINICAL MANAGEMENT

CONTEXT Disease processes that affect the pituitary stalk are broad; the diagnosis and management of these lesions remains unclear. OBJECTIVE The aim was to assess the clinical, biochemical and histopathological characteristics of pituitary stalk lesions and their association with specific MRI features in order to provide diagnostic and prognostic guidance. DESIGN AND METHODS Retrospective observational study of 36 patients (mean age 37years, range: 4-83) with pituitary stalk thickening evaluated at a university hospital in Oxford, UK, 2007-2015. We reviewed morphology, signal intensity, enhancement and texture appearance at MRI (evaluated with the ImageJ programme), along with clinical, biochemical, histopathological and long-term follow-up data. RESULTS Diagnosis was considered certain for 22 patients: 46% neoplastic, 32% inflammatory and 22% congenital lesions. In the remaining 14 patients, a diagnosis of a non-neoplastic disorder was assumed on the basis of long-term follow-up (mean 41.3months, range: 12-84). Diabetes insipidus and headache were common features in 47 and 42% at presentation, with secondary hypogonadism the most frequent anterior pituitary defect. Neoplasia was suggested on size criteria or progression with 30% sensitivity. However, textural analysis of MRI scans revealed a significant correlation between the tumour pathology and pituitary stalk heterogeneity in pre- and post-gadolinium T1-weighted images (sensitivity: 88.9%, specificity: 91.7%). CONCLUSIONS New techniques of MRI imaging analysis may identify clinically significant neoplastic lesions, thus directing future therapy. We propose possible textural heterogeneity criteria of the pituitary stalk on pre- and post-gadolinium T1 images with the aim of differentiating between neoplastic and non-neoplastic lesions with a high degree of accuracy.

Local optometrists are a major source of referrals to a pituitary tumour clinic

Pituitary adenomas can be identified pathologically in some 20-25% of autopsy specimens, 12 but only around 1/1000 of the population have clinically significant tumours (Daly et al 13 2006, Fernandez et al 2010). As the tumour expands, the optic chiasm may be compressed 14 from below, causing visual field abnormalities including the classic bitemporal hemianopia. 15 These visual symptoms are the most common objective manifestations of non-functioning 16 pituitary adenomas, and demand urgent decompression to increase the probability of a 17 complete normalisation of visual function. Delayed diagnosis may lead to irreversible visual 18 loss, especially if the chiasmal compression is associated with more evident field defects 19 (Lee et al 2013) or has been of long duration (Dutta et al 2016), although improvement may 20 continue sometime after surgery (Harris et al 1989). In a multivariate analysis, only 21 preceding visual defect predicted the degree of recovery, although this could continue for at 22 least 5 years (Gnanalingham et al 2005). In general, it is anticipated that patients will 23 present to either their general practitioner or to an ophthalmologist complaining of visual 24 changes, but patients may undergo considerable visual loss without realisation of the 25 disorder. The onset of the visual deficit is usually gradual such that many patients might not 26 seek medical consultation for months or even years. Thus, early diagnosis is critical but may 27 be significantly delayed by a failure of concern by the patient or their clinicians. 28

The Short Synacthen (Corticotropin) Test Can Be Used to Predict Recovery of Hypothalamo-Pituitary-Adrenal Axis Function

Context The 250-μg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. Objective To use the SST results to predict adrenal recovery. Design A retrospective analysis of 1912 SSTs data. Patients Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Main Outcome Measures Recovery of HPA axis function. Results SST 30-minute cortisol levels above or below 350 nmol/L (12.7 μg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels <350 nmol/L. In the subgroup analysis, delta cortisol (30-minute-basal) best predicted the recovery (AUC ROC = 0.77; median recovery time: 262 vs 974 days, P = 7.0 × 10-6). No patient with a delta cortisol <100 nmol (3.6 μg/dL) and a subsequent 1-year random cortisol <200 nmol/L (7.3 μg/dL) recovered HPA axis function. Conclusions Cortisol levels across an SST can be used to predict recovery of AI and may guide the frequency of repeat testing and inform both clinicians and patients as to the likelihood of restoration of HPA axis function.

INITIATION OF PATIENTS ONTO LONG-ACTING SOMATOSTATIN ANALOGUE THERAPY FOR NEUROENDOCRINE TUMORS: A SINGLE-CENTER REVIEW OF PRACTICE

OBJECTIVE Neuroendocrine tumors (NETs) are being seen increasingly frequently, and recent data show that long-acting somatostatin analogues have become a major initial treatment, regardless of whether the tumors are functioning or not. However, test dosing with subcutaneous (sc) octreotide is usually advised to assess longer-term tolerability, although this advice is mainly based on results with functioning tumors. The aim of the study was to assess the value of an initiating test dose of sc octreotide on the prediction of subsequent adverse events after treatment with the long-acting analogue. METHODS In a single, large Centre of Excellence for NETs, a first cohort of patients (n = 24) was admitted overnight after an sc injection of octreotide, and then administered the analogue; a subsequent group (n = 53) had the test dose performed on an outpatient basis. Side effects were recorded after the test dose and subsequent treatment with the long-acting analogue. RESULTS The test dose injection was of little value in predicting adverse events following the long-acting somatostatin analogue. CONCLUSION Unless there are serious symptoms associated with a functioning NET, it is unnecessary to carry out a test dose; a change to this procedure will improve resource allocation and should enhance early initiation onto maintenance therapy. ABBREVIATIONS CLARINET = Controlled study of lanreotide antiproliferative response in neuroendocrine tumors LAR = long-acting repeatable NET = neuroendocrine tumor PROMID = Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with meta-static neuroendocrine midgut tumors.