Daphne Gardner

Genetic Variation in KCNQ1 Associates With Fasting Glucose andβ-Cell Function A Study of 3,734 Subjects Comprising Three Ethnicities Living in Singapore

OBJECTIVE The potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) has been found through a genome-wide association study to be a strong candidate for conferring susceptibility to type 2 diabetes in East Asian and European populations. Our objective was to describe the association between polymorphisms at the KCNQ1 locus with insulin resistance, beta-cell function, and other type 2 diabetes-related traits in a sample of Chinese, Malays, and Asian Indians living in Singapore. RESEARCH DESIGN AND METHODS We examined the associations between four previously reported KCNQ1 single-nucleotide polymorphisms (SNPs) with type 2 diabetes-related traits in 3,734 participants from the population-based 1998 Singapore National Health Survey cohort (2,520 Chinese, 693 Malay, and 521 Asian Indians). Insulin resistance was calculated from fasting insulin and glucose using the homeostasis model assessment method, whereas pancreatic beta-cell function was assessed using the corrected insulin response at 120 min (CIR(120)). RESULTS SNPs rs2237897, rs2237892, and rs2283228 were significantly associated with type 2 diabetes (odds ratio [OR] 1.48, P = 3 x 10(-4); OR 1.38, P = 0.002; OR 1.31, P = 0.012, respectively). Within the Chinese population, the risk alleles for rs2237897, rs2237892, and rs2283228 were significantly associated with higher fasting glucose levels (P = 0.014, 0.011, and 0.034, respectively) and reduced CIR(120)(P = 0.007, 0.013, and 0.014, respectively). A similar trend was observed among the Malay and Asian Indian minority groups, although this did not reach statistical significance because of limited sample sizes. CONCLUSIONS The increased risk for type 2 diabetes associated with KCNQ1 is likely to be caused by a reduction in insulin secretion. Further studies will be useful to replicate these findings and to fully delineate the role of KCNQ1 and its related pathways in disease pathogenesis.OBJECTIVE The potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) has been found through a genome-wide association study to be a strong candidate for conferring susceptibility to type 2 diabetes in East Asian and European populations. Our objective was to describe the association between polymorphisms at the KCNQ1 locus with insulin resistance, β-cell function, and other type 2 diabetes–related traits in a sample of Chinese, Malays, and Asian Indians living in Singapore. RESEARCH DESIGN AND METHODS We examined the associations between four previously reported KCNQ1 single-nucleotide polymorphisms (SNPs) with type 2 diabetes–related traits in 3,734 participants from the population-based 1998 Singapore National Health Survey cohort (2,520 Chinese, 693 Malay, and 521 Asian Indians). Insulin resistance was calculated from fasting insulin and glucose using the homeostasis model assessment method, whereas pancreatic β-cell function was assessed using the corrected insulin response at 120 min (CIR120). RESULTS SNPs rs2237897, rs2237892, and rs2283228 were significantly associated with type 2 diabetes (odds ratio [OR] 1.48, P = 3 × 10−4; OR 1.38, P = 0.002; OR 1.31, P = 0.012, respectively). Within the Chinese population, the risk alleles for rs2237897, rs2237892, and rs2283228 were significantly associated with higher fasting glucose levels (P = 0.014, 0.011, and 0.034, respectively) and reduced CIR120(P = 0.007, 0.013, and 0.014, respectively). A similar trend was observed among the Malay and Asian Indian minority groups, although this did not reach statistical significance because of limited sample sizes. CONCLUSIONS The increased risk for type 2 diabetes associated with KCNQ1 is likely to be caused by a reduction in insulin secretion. Further studies will be useful to replicate these findings and to fully delineate the role of KCNQ1 and its related pathways in disease pathogenesis.

Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes

Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition, but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients’ prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM) (diagnosis <6 months). We performed exome sequencing in a patient with NDM and autoimmune lymphoproliferative syndrome and his unrelated, unaffected parents and identified compound heterozygous null mutations in LRBA. Biallelic LRBA mutations cause common variable immunodeficiency-8; however, NDM has not been confirmed in this disorder. We sequenced LRBA in 169 additional patients with diabetes diagnosed <1 year without mutations in the 24 known NDM genes. We identified recessive null mutations in 8 additional probands, of which, 3 had NDM (<6 months). Diabetes was the presenting feature in 6 of 9 probands. Six of 17 (35%) patients born to consanguineous parents and with additional early-onset autoimmunity had recessive LRBA mutations. LRBA testing should be considered in patients with diabetes diagnosed <12 months, particularly if they have additional autoimmunity or are born to consanguineous parents. A genetic diagnosis is important as it can enable personalized therapy with abatacept, a CTLA-4 mimetic, and inform genetic counseling.

Incremental cost-effectiveness of algorithm-driven genetic testing versus no testing for Maturity Onset Diabetes of the Young (MODY) in Singapore

Background Offering genetic testing for Maturity Onset Diabetes of the Young (MODY) to all young patients with type 2 diabetes has been shown to be not cost-effective. This study tests whether a novel algorithm-driven genetic testing strategy for MODY is incrementally cost-effective relative to the setting of no testing. Methods A decision tree was constructed to estimate the costs and effectiveness of the algorithm-driven MODY testing strategy and a strategy of no genetic testing over a 30-year time horizon from a payer’s perspective. The algorithm uses glutamic acid decarboxylase (GAD) antibody testing (negative antibodies), age of onset of diabetes (<45 years) and body mass index (<25 kg/m2 if diagnosed >30 years) to stratify the population of patients with diabetes into three subgroups, and testing for MODY only among the subgroup most likely to have the mutation. Singapore-specific costs and prevalence of MODY obtained from local studies and utility values sourced from the literature are used to populate the model. Results The algorithm-driven MODY testing strategy has an incremental cost-effectiveness ratio of US

Traditional clinical criteria outperform high-sensitivity C-reactive protein for the screening of hepatic nuclear factor 1 alpha maturity-onset diabetes of the young among young Asians with diabetes:

93 663 per quality-adjusted life year relative to the no testing strategy. If the price of genetic testing falls from US

Erratum. Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes. Diabetes 2017;66:2316–2322

1050 to US

Psychometric validation of the Hypoglycemia Fear Survey-II (HFS-II) in Singapore

530 (a 50% decrease), it will become cost-effective. Conclusion Our proposed algorithm-driven testing strategy for MODY is not yet cost-effective based on established benchmarks. However, as genetic testing prices continue to fall, this strategy is likely to become cost-effective in the near future.

Translating Advances in Our Understanding of the Genetics of Diabetes into the Clinic

Background: Young adults with diabetes in Asia represent a heterogeneous group. Using traditional clinical criteria to preselect individuals for testing for maturity-onset diabetes of the young (MODY) may exclude a large proportion from testing. High-sensitivity C-reactive protein (hs-CRP) has shown promise as a biomarker to differentiate hepatic nuclear factor 1 alpha (HNF1A)-MODY from type 2 diabetes. We aimed to compare the use of hs-CRP as a biomarker versus traditional criteria, to guide testing for HNF1A-MODY among a cohort of young adults with diabetes in Singapore. Methods: A total of 252 adults (age of onset ⩽45 years) and 20 children with diabetes were recruited. Using traditional criteria (family history of diabetes and onset of diabetes ⩽25 years) and an hs-CRP cut off of ⩽0.5 mg/l, 125 and 37 adults, respectively, were identified for HNF1A gene testing. All children underwent HNF1A gene testing. Results: Five adults (5/143, 3.5%) with HNF1A-MODY were identified. There were no HNF1A gene mutations among the children. Traditional criteria correctly identified all five HNF1A-MODY individuals (5/125, 4%), while applying an hs-CRP level of ⩽0.5 mg/l selected just 1 of these 5 for HNF1A gene testing (1/37, 2.7%). None of those with a positive GAD antibody or undetectable C-peptide level had HNF1A-MODY. Conclusion: The use of hs-CRP to guide screening for HNF1A-MODY among Asian young adults with diabetes did not improve the diagnostic yield. Applying a combination of age of onset of diabetes under 25 years and a family history of diabetes alone could guide targeted HNF1A-MODY screening in Asians, with an expected yield of 4% diagnosed with HNF1A-MODY among those screened.

A rare cause of hyperthyroidism: functioning thyroid metastases

In the article listed above, Ayla Guven, of the Pediatric Endocrinology Clinic, Goztepe Educational and Research Hospital, Istanbul, …

Stigmatization of Adults with Type 1 Diabetes in Asia

Objective We conducted a cross-sectional study to adapt and validate the Hypoglycemia Fear Survey-II (HFS-II) for use in Singapore among persons with type 1 and 2 diabetes mellitus. Research design and methods A total of 144 patients with type 1 or 2 diabetes on insulin therapy for at least a year completed the HFS-II between September and December 2013 in the Diabetes Center at Singapore General Hospital. We examined the validity (content, concurrent and discriminant validity, and construct validity) and reliability (internal consistency and test–retest reliability) of the instrument. Content validity was established using cognitive interviews. Construct validity was assessed using confirmatory factor analysis (CFA) followed by exploratory factor analysis (EFA) after the hypothesized two-factor structure was not confirmed by CFA. Measures of anxiety (Generalized Anxiety Disorder-7 (GAD-7)) and depression (Patient Health Questionnaire-9 (PHQ-9)) were used to establish concurrent validity; history of severe hypoglycemia and status of glycemic control were used to establish discriminant validity. Internal consistency was measured by Cronbachs α; test–retest reliability was measured by intracluster correlation coefficient (ICC). Results Scores of the adapted HFS-II had moderate positive correlations with measures of anxiety and depression scores (ranxiety=0.41, p<0.01; rdepression=0.37, p<0.01). Patients with a recent history of severe hypoglycemia had higher HFS-II scores than those without (mean difference=9, p<0.01). Patients with poor glycemic control had higher HFS-II scores than those with good control (p<0.05). The original two-factor structure was not confirmed in our sample. EFA results suggested a three-factor solution with the original Behavior subscale splitting into two dimensions. The adapted HFS-II displayed good internal consistency (Cronbachs α=0.93) and test–retest reliability (ICC=0.75). Conclusions The adapted HFS-II has good content, concurrent and discriminant validity, and reliability, but its constructvalidity was not proven with the Behavior subscale turning out to be non-unidimensional.

Incremental Cost-Effectiveness of Algorithm-Driven Genetic Testing Versus no Testing for Maturity Onset Diabetes of the Young (Mody) in Singapore

The high worldwide prevalence of type 2 diabetes (T2D) is driving major efforts to understand the genetic basis of the disorder, with the expectation that this will increase our understanding of disea