Wallaya Jongjaroenprasert

Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis

Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.

Similarity of the allele frequency and linkage disequilibrium pattern of single nucleotide polymorphisms in drug-related gene loci between Thai and northern East Asian populations: implications for tagging SNP selection in Thais

AbstractThe similarity of the marker allele frequency and linkage disequilibrium structure between two populations are major factors for the determination of the transferability and efficiency of haplotype tagging SNP derived from one population to use for an indirect association study in another population. To prove the similarity between northern East Asian populations in Hapmap and Thais, 861 SNP in 166 drug-related genes shared between Thais, Han Chinese and Japanese were analyzed for their correlation statistics. Allele frequency, Fst statistics and linkage disequilibrium statistics (r2) showed a high correlation between these populations. TagSNP sets derived by an aggressive tagging algorithm from these 861 SNP in Japanese and Chinese were used to test the coverage of East Asia-derived tagSNP in Thais. TagSNP derived from Japanese and Chinese are comparable in the percentage of coverage of the alleles captured with tagSNP at r2≥0.8 (93% vs. 93%) in these drug-related gene loci. Additional tagSNP sets derived from the combination of Japanese- and Chinese-derived tagging SNP sets were used to test the coverage in Thais. The later set improved the percentage of coverage of alleles captured with tagSNP at r2≥0.8-98% for these sites. High similarity between Thais and northern East Asian allele frequency and linkage disequilibrium statistics supported that tagSNPs derived from the northern East Asian population should be useful for an indirect association study in Thais. The combination of non-overlapping Japanese derived tagSNP and Chinese-derived tagSNP improved the percentage of genomic coverage in Thais, at least in these drug-related gene loci.

A genome-wide association study identifies novel susceptibility genetic variation for thyrotoxic hypokalemic periodic paralysis

Several lines of evidence have pointed out that genetic components have roles in thyrotoxic hypokalemic periodic paralysis (TTPP). In this study, for the first time we performed genome-wide association study (GWAS) in male hyperthyroid subjects in order to identify genetic loci conferring susceptibility to TTPP. We genotyped 78 Thai male TTPP cases and 74 Thai male hyperthyroid patients without hypokalemia as controls with Illumina Human-Hap610 Genotyping BeadChip. Among the SNPs analyzed in the GWAS, rs312729 at chromosome 17q revealed the lowest P-value for association (P=2.09 × 10−7). After fine mapping for linkage disequilibrium blocks surrounding the landmark SNP, we found a significant association of rs623011; located at 75 kb downstream of KCNJ2 on chromosome 17q, reached the GWAS significance after Bonferronis adjustment (P=3.23 × 10−8, odds ratio (OR)=6.72; 95% confidence interval (CI)=3.11–14.5). The result was confirmed in an independent cohort of samples consisting of 28 TTPP patients and 48 controls using the same clinical criteria diagnosis (replication analysis P=3.44 × 10−5, OR=5.13; 95% CI=1.87–14.1; combined-analysis P=3.71 × 10−12, OR=5.47; 95% CI=3.04–9.83).

Reference ranges of serum TSH, FT4 and thyroid autoantibodies in the Thai population: the national health examination survey

Data on reference intervals of thyroid functions in Southeast Asia are limited. The aim of this study was to provide reference ranges of thyroid functions and thyroid autoantibodies in Thais.

Association of genetic variants in GABRA3 gene and thyrotoxic hypokalaemic periodic paralysis in Thai population

Background  Genetic predisposition has been suggested to play role in the pathogenesis of thyrotoxic hypokalaemic periodic paralysis (THPP).

The association of soluble IGF2R and IGF2R gene polymorphism with type 2 diabetes.

The aim of this study is to investigate the insulin-like growth factor type 2 (IGF2R) gene and circulating soluble IGF2R in relation to type 2 diabetes (T2DM). Six hundred fifty-four subjects without history of diabetes were screened for diabetes by oral glucose tolerance test. In addition, 145 subjects with known diabetes were recruited from a local diabetes clinic. Circulating IGF2R levels were measured by ELISA method; plasma glucose was measured by colorimetric method; insulin levels were determined by chemiluminescent method; IGF2R gene rs416572 was genotyped using real-time PCR. The distributions of IGF2R genotypes were 69.2% CC, 27.8% CT, and 3.0% TT. The C allele was more commonly found in diabetes subjects, with a significant difference (P < 0.01). In the presence of the T allele, circulating IGF2R levels were significantly lower (P < 0.05). There was no significant difference in other potential confounders including age, sex, and BMI. Only circulating IGF2R, age, and BMI were independently associated with the degree of insulin resistance, as assessed by the HOMA model. It was found that age, sex, and BMI were associated with beta cell function. In conclusion, IGF2R gene polymorphism and circulating IGF2R are associated with T2DM.

Efficacy of Intermittent Low Dose Alendronate in Thai Postmenopausal Osteoporosis

Alendronate has been proven to be effective in the prevention and treatment of postmenopausal osteoporosis with the recommended daily dose of 10 mg. However, a constraining requirement for dosing limited its general acceptance in treatment. Since alendronate is potent and has a long half‐life, weekly administration of alendronate in lower total doses might be safer and more convenient. The purpose of this study was to determine the efficacy of low dose once‐weekly 20 mg alendronate in Thai postmenopausal women with osteoporosis. Thirty‐nine postmenopausal women with osteoporosis received alendronate 20 mg once a week plus 750 mg elemental calcium daily. Bone mineral density (BMD) was measured by dual energy X‐ray absorptiometry (DXA) at baseline and 6 and 12 months after treatment. Serum C‐terminal telopeptide of type I collagen (CTx‐I) was measured by electrochemiluminescence immunoassay at baseline and 3 months after treatment. By the end of 1 year, once weekly 20 mg alendronate significantly increased vertebral BMD ( + 6.2%, p < 0.001 vs baseline) from baseline whereas there was a reduction of 60.7% in serum CTx‐I at 3 months. However, the BMD at femur did not increase significantly ( + 0.64%). Conclusion: Low‐dose intermittent once‐weekly 20 mg alendronate was effective, cost saving and had a good safety profile in increasing vertebral BMD and stabilizing BMD at the femoral neck in postmenopausal osteoporosis.

Copy Number Variation in Thai Population

Copy number variation (CNV) is a major genetic polymorphism contributing to genetic diversity and human evolution. Clinical application of CNVs for diagnostic purposes largely depends on sufficient population CNV data for accurate interpretation. CNVs from general population in currently available databases help classify CNVs of uncertain clinical significance, and benign CNVs. Earlier studies of CNV distribution in several populations worldwide showed that a significant fraction of CNVs are population specific. In this study, we characterized and analyzed CNVs in 3,017 unrelated Thai individuals genotyped with the Illumina Human610, Illumina HumanOmniexpress, or Illumina HapMap550v3 platform. We employed hidden Markov model and circular binary segmentation methods to identify CNVs, extracted 23,458 CNVs consistently identified by both algorithms, and cataloged these high confident CNVs into our publicly available Thai CNV database. Analysis of CNVs in the Thai population identified a median of eight autosomal CNVs per individual. Most CNVs (96.73%) did not overlap with any known chromosomal imbalance syndromes documented in the DECIPHER database. When compared with CNVs in the 11 HapMap3 populations, CNVs found in the Thai population shared several characteristics with CNVs characterized in HapMap3. Common CNVs in Thais had similar frequencies to those in the HapMap3 populations, and all high frequency CNVs (>20%) found in Thai individuals could also be identified in HapMap3. The majorities of CNVs discovered in the Thai population, however, were of low frequency, or uniquely identified in Thais. When performing hierarchical clustering using CNV frequencies, the CNV data were clustered into Africans, Europeans, and Asians, in line with the clustering performed with single nucleotide polymorphism (SNP) data. As CNV data are specific to origin of population, our population-specific reference database will serve as a valuable addition to the existing resources for the investigation of clinical significance of CNVs in Thais and related ethnicities.

Prevalence of Thyroid Dysfunction in Thai HIV-Infected Patients

Increasing prevalence of thyroid function abnormality has been reported in HIV-infected patients. We aim to evaluate the prevalence and assess risk factors of thyroid dysfunction in Thai HIV-infected patients. A cross-sectional study was conducted. Serum thyroid hormone concentrations (FT4, FT3, and TSH) and thyroid autoantibodies (TgAb and TPOAb) were measured by electrochemiluminescence immunoassay. A total of 200 HIV-infected outpatients were included. Ninety-seven patients (48.5%) were men (mean age of 36.3 +/- 8.3 years). Duration of HIV infection was 49.6 +/- 35.1 months and 53% had previous opportunistic infections (OI). Mean CD4 cell count was 340.6 +/- 173.1 cells/mm(3). Of these, 167 patients (83.5%) received antiretroviral therapy (ARV). Abnormal thyroid function test was detected in 32 patients (16%). Twenty-seven patients (13.5%) had decreased thyroid function (primary hypothyroidism 3, subclinical hypothyroidism 12, and low FT4 with low or normal TSH 12) whereas 5 patients had increased thyroid function (overt hyperthyroidism 1, subclinical hyperthyroidism 1, and isolated high FT3 3). None had clinical features of thyroid hormone dysfunction. Thirteen patients (6.5%) had thyroid antibody positive. Patients who received ARV had higher mean FT3 levels than those who were naïve to ARV (p = 0.017). History of previous OI was found to be an independently significant risk factor for decreased thyroid function with the odds ratio of 3.28 (95% CI =1.183-9.099; p = 0.022). Hypothyroidism was common among Thai HIV-infected patients, especially in those who had history of previous OI. It is therefore suggested that screening and/or monitoring of thyroid hormone in HIV-infected patients should be considered.

Identifying Disease Susceptible DNA Regions Using Underlying Odds Ratio Contour Analysis

Odds ratio plays important roles in identifying and assessing disease susceptible SNPs in the case-control association study. However, the contour of odds ratio has too much variation to identify the disease susceptible DNA region. This paper proposes the odds ratio contour analysis (ORCA), a method for analyzing of odds ratio contour in genome-wide SNP association study. This method smoothes the odds ratio contour and discriminates disease susceptible regions out of the others. We have preliminarily tested ORCA with SNPs data from pooled DNA genome-wide SNP association study of type 2 diabetes mellitus (T2DM), including four pools as cases and five pools as controls. Each DNA pool was assayed on Affymetrix GeneChipreg mapping 10 K Array. With an optimal threshold level, ORCA can effectively highlight disease-associated regions, which reduce the false positive rate that has been one of the major problems in high-throughput case-control association study.