Clinical experience from a regional monogenic diabetes referral centre in Singapore.

AIMS: Monogenic diabetes (also known as maturity-onset diabetes of the young or MODY) affects a subset of individuals with young-onset diabetes. We report our diagnostic work-up experience for such individuals. METHODS: Serving as a regional secondary-care diabetes centre in a multi-ethnic population, we receive referrals to evaluate MODY from endocrinologists in both public and private practice. Key criteria for consideration of genetic-testing are onset age ≤ 35, negative GAD antibody, no history of diabetic ketoacidosis, strong family history of diabetes and BMI < 32.5 kg/m2. A monogenic diabetes registry was set up since 2017 to study their disease trajectories. RESULTS: We identified 30 out of 175 (17.1%) individuals with likely pathogenic/pathogenic variants. Importantly, 29 out of 30 (96.7%) occurred in clinically actionable genes. A continuous scale combining BMI, hs-CRP and HDL provided 80% (P < 0.001) diagnostic accuracy for MODY in our cohort, achieving a negative predictive value of 0.93 and sensitivity at 0.76. Subtyping MODY prior to genetic testing (if desired) will require specialist domain knowledge and additional biomarkers due to its genetic heterogeneity. CONCLUSIONS: Through systematic and structured evaluation, the prevalence of MODY is non-trivial (17.1%) in a referral centre. Diagnostic algorithm combining clinical criteria and readily available biomarkers can support clinical decision for MODY genetic testing.

PAX4 R192H is associated with younger onset of Type 2 diabetes in East Asians in Singapore.

AIMS: Young-onset T2D (YT2D) is associated with a more fulminant course and greater propensity for diabetic complications. The association of PAX4 R192H (rs2233580) variation with YT2D was inconsistent partly because of its Asian-specificity and under-representation of Asians in international consortiums. Interestingly, in our preliminary YT2D (mean = 25 years old) cohort, the prevalence of PAX4 R192H variant was remarkably higher (21.4%) than the general population. Therefore, we sought to determine whether PAX4 R192H is associated with younger onset of T2D in our East Asian (Chinese) population. METHODS: Genotyping of PAX4 R192H was carried out using Illumina OmniExpress BeadChips as part of a genome-wide association study. Data analysis was performed using SPSS Ver. 22. RESULTS: PAX4 R192H genotype was associated with younger onset age (CC: 47.1, CT: 46.0, TT: 42.6) after adjusting for gender, F = 5.402, p = 0.005. Independently, onset of diabetes was younger among males by 2.52 years, 95% CI [-3.45, -1.59], p < 0.0001. HOMA-IR and HOMA-%B were not significantly different across genotypes for a subset (n = 1045) of the cohort. CONCLUSIONS: Minor allele (T) of PAX4 R192H is associated with younger onset diabetes among Chinese in Singapore. Determining this genotype is important for identifying at-risk individuals for earlier onset diabetes and diabetic complications.

A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians.

AIMS: Diabetes is increasing globally and Asia is the epicenter. Among those with young-onset diabetes (<45years), the prevalence of monogenic diabetes is estimated to be non-trivial (∼5%). An accurate diagnosis of monogenic diabetes is important to inform treatment, prognosis and genetic counseling. Therefore, a robust clinical algorithm to identify probands for testing is needed. Our aims are (1) to select probands for genetic testing and variant identification based on their clinical phenotype and (2) to evaluate the MODY probability calculator in our multi-ethnic Asian population. METHODS: Eighty-four potential probands, identified in accordance with clinical practice guidelines, were subjected to re-sequencing of 16 monogenic diabetes genes and targeted genotyping for mitochondrial 3243A>G point-mutation. Variants, confirmed by bi-directional Sanger sequencing, were classified as pathogenic if they fulfilled the criteria adapted from American College of Medical Genetics. Performance of MODY calculator (with positive-predictive threshold set at >62.4%) for those with diabetes-onset ⩽35years (data input-limit) (n=71) was also evaluated. RESULTS: Thirteen subjects (15.5%) harbored likely pathogenic/pathogenic variants: 6 (2 novel) in HNF1A (1 subject concomitantly had another HNF4A variant), 1 in HNF4A, 2 in mt3243A>G and 1 each in GCK, KCNJ11 (novel), ABCC8 (novel) and PAX4 (novel). Performance of the MODY calculator was: sensitivity 0.769, specificity 0.603 and negative predictive value 0.921. When analysis was restricted to MODY1-3, the performance was: 0.875, 0.587 and 0.974, respectively. CONCLUSIONS: The prevalence of MODY is non-trivial (∼15%) among Asians with young-onset diabetes. MODY calculator performs well in our population in nominating probands for genetic testing.

Polymorphisms identified through genome-wide association studies and their associations with type 2 diabetes in Chinese, Malays, and Asian-Indians in Singapore.

CONTEXT: Novel type 2 diabetes mellitus (T2DM) susceptibility loci, identified through genome-wide association studies (GWAS), have been replicated in many European and Japanese populations. However, the association in other East Asian populations is less well characterized. OBJECTIVE: To examine the effects of SNPs in CDKAL1, CDKN2A/B, IGF2BP2, HHEX, SLC30A8, PKN2, LOC387761, and KCNQ1 on risk of T2DM in Chinese, Malays, and Asian-Indians in Singapore. DESIGN: We genotyped these candidate single-nucleotide polymorphisms (SNPs) in subjects from three major ethnic groups in Asia, namely, the Chinese (2196 controls and 1541 cases), Malays (2257 controls and 1076 cases), and Asian-Indians (364 controls and 246 cases). We also performed a metaanalysis of our results with published studies in East Asians. RESULTS: In Chinese, SNPs in CDKAL1 [odds ratio (OR) = 1.19; P = 2 x 10(-4)], HHEX (OR = 1.15; P = 0.013), and KCNQ1 (OR = 1.21; P = 3 x 10(-4)) were significantly associated with T2DM. Among Malays, SNPs in CDKN2A/B (OR = 1.22; P = 3.7 x 10(-4)), HHEX (OR = 1.12; P = 0.044), SLC30A8 (OR = 1.12; P = 0.037), and KCNQ1 (OR = 1.19-1.25; P = 0.003-2.5 x 10(-4)) showed significant association with T2DM. The combined analysis of the three ethnic groups revealed significant associations between SNPs in CDKAL1 (OR = 1.13; P = 3 x 10(-4)), CDKN2A/B (OR = 1.16; P = 9 x 10(-5)), HHEX (OR = 1.14; P = 6 x 10(-4)), and KCNQ1 (OR = 1.16-1.20; P = 3 x 10(-4) to 3 x 10(-6)) with T2DM. SLC30A8 (OR = 1.06; P = 0.039) showed association only after adjustment for gender and body mass index. Metaanalysis with data from other East Asian populations showed similar effect sizes to those observed in populations of European ancestry. CONCLUSIONS: SNPs at T2DM susceptibility loci identified through GWAS in populations of European ancestry show similar effects in Asian populations. Failure to detect these effects across different populations may be due to issues of power owing to limited sample size, lower minor allele frequency, or differences in genetic effect sizes.