Context: Six maturity onset diabetes of the young (MODY) genes have been discovered to date but account for a small proportion of MODY among Asians, suggesting the existence of other MODY genes in this racial group. Objective: The aim of this study was to investigate whether or not genetic variants in PAX4, a crucial transcription factor in β-cell development, contribute to MODY in Thais. Design and Methods: We screened PAX4 coding sequences in 46 MODY probands without mutation in known MODY genes and in 74 nondiabetic controls using PCR-single-stranded conformational polymorphism analysis followed by direct sequencing. Genotyping of variants identified was done by PCR-restriction fragment length polymorphism analysis. Results: Eight sequence differences were identified. Two novel variations (R164W and IVS7–1G>A) were found in two different probands. Neither was found in the 74 nondiabetic controls and additional 270 healthy subjects of Thai origin. R164W segregated with diabetes in the family of the proband and in vitro studies showed that it impairs the repressor activity of PAX4 on the insulin and glucagon promoters. The remaining six variants were previously described and observed in both groups. One of them, R192H, was three times more frequent in MODY probands than in 342 nondiabetic controls (minor allele frequency = 0.196 vs. 0.064; P < 0.00001). The same variant was associated with a younger age at diagnosis among 254 Thai subjects with adult-onset type 2 diabetes (44.6 ± 15 vs. 49.7 ± 11 yr; P = 0.048). Conclusions: We have identified two possible pathogenic mutations of PAX4, R164W, and IVS7–1G>A. For one of these, we have shown evidence of segregation with diabetes and a functional impact on PAX4 activity. Single-nucleotide polymorphism R192H might influence the age at onset of diabetes.

Several type 2 diabetes (T2D) susceptibility loci identified via genome-wide association studies were found to be replicated among various populations. However, the influence of these loci on T2D in Thai population is unknown. The aim of this study was to investigate the influence of eight single nucleotide polymorphisms (SNPs) reported in GWA studies on T2D and related quantitative traits in Thai population. Eight SNPs in or near the KCNQ1, CDKN2A/2B, SLC30A8, HHEX, CDKAL1, TCF7L2, MTNR1B, and UBE2E2 genes were genotyped. A case-control association study comprising 500 Thai patients with T2D and 500 ethnically-matched control subjects was conducted. Associations between SNPs and T2D were examined by logistic regression analysis. The impact of these SNPs on quantitative traits was examined by linear regression among case and control subjects. Five SNPs in KCNQ1 (rs2237892), CDK2A/2B (rs108116610, SLC30A8 (rs13266634), TCF7L2 (rs7903146) and MTNR1B (rs1387153) were found to be marginally associated with risk of developing T2D, with odds ratios ranging from 1.43 to 2.02 (p = 0.047 to 3.0 × 10–4) with adjustments for age, sex, and body mass index. Interestingly, SNP rs13266634 of SLC30A8 gene reached statistical significance after correcting for multiple testing (p = 0.0003) (p < 0.006 after Bonferroni correction). However, no significant association was detected between HHEX (rs1111875), CDKAL1 (rs7756992), or UBE2E2 (rs7612463) and T2D. We also observed association between rs10811661 and both waist circumference and waist-hip ratio (p = 0.007 and p = 0.023, respectively). In addition, rs13266634 in SLC30A8 was associated with glycated hemoglobin (p = 0.018), and rs7903146 in TCF7L2 was associated with high-density lipoprotein cholesterol level (p = 0.023). Of the eight genes included in our analysis, significant association was observed between KCNQ1, CDKN2A/2B, SLC30A8, TCF7L2, and MTNR1B loci and T2D in our Thai study population. Of these, CDKN2A/2B, SLC30A8, and TCF7L2 genes were also significantly associated with anthropometric, glycemic and lipid characteristics. Larger cohort studies and meta-analyses are needed to further confirm the effect of these variants in Thai population.

Postoperative hypoparathyroidism is a common complication of total or completion thyroidectomy. The association between preoperative vitamin D deficiency (VDD) and the development of more severe postoperative hypocalcemia is still unclear. Objectives. To evaluate the effect of preoperative VDD on severity of hypocalcemia in patients with hypoparathyroidism following thyroidectomy. Methods. Patients who developed acute hypoparathyroidism after total or completion thyroidectomy, defined as postoperative parathyroid hormone (PTH) level <15 pg/mL and albumin-adjusted calcium level <8.6 mg/dL, were prospectively recruited. Patients were divided into two groups according to their preoperative vitamin D status (VDD group: 25-hydroxyvitamin D (25(OH)D) level <20 ng/mL; non-VDD group: 25(OH) level ≥20 ng/mL). The primary outcome was severity of hypocalcemia in postoperative hypoparathyroidism. Significant hypocalcemia was defined as calcium level ≤7.5 mg/dL. Results. Forty-three patients (21 VDD, 22 non-VDD) were enrolled. Serum total albumin-adjusted calcium level was significantly lower in the VDD group (7.71 ± 0.5 vs. 8.16 ± 0.4 mg/dL, p<0.01), and the incidence of symptomatic hypocalcemia was significantly higher in the VDD group (43% vs. 9%, p=0.01). The median maximal daily supplementary dose of elemental calcium was significantly higher in the VDD group (2,400 vs. 1,500 mg/day, p=0.02). Length of hospital stay was nonsignificantly longer in the VDD group (p=0.06). Preoperative vitamin D level <19.6 ng/mL could predict significant and symptomatic hypocalcemia in postoperative hypoparathyroidism with sensitivity of 90% and 82% and specificity of 70% and 69%, respectively. Conclusion. VDD is an independent risk factor for both significant and symptomatic hypocalcemia in hypoparathyroidism patients after thyroid surgery.