Fanconi anemia complementation group C protection against oxidative stress­induced ß­cell apoptosis.

Diabetes mellitus (DM) and other glucose metabolism abnormalities are commonly observed in individuals with Fanconi anemia (FA). FA causes an impaired response to DNA damage due to genetic defects in a cluster of genes encoded proteins involved in DNA repair. However, the mechanism by which FA is associated with DM has not been clearly elucidated. Fanconi anemia complementation group C (FANCC) is a component of FA nuclear clusters. Evidence suggests that cytoplasmic FANCC has a role in protection against oxidative stress­induced apoptosis. As oxidative stress­mediated ß­cell dysfunction is one of the contributors to DM pathogenesis, the present study aimed to investigate the role of FANCC in pancreatic ß­cell response to oxidative stress. Small interfering RNA­mediated FANCC suppression caused a loss of protection against oxidative stress­induced apoptosis, and that overexpression of FANCC reduced this effect in the human 1.1B4 ß­cell line. These findings were confirmed by Annexin V­FITC/PI staining, caspase 3/7 activity assay, and expression levels of anti­apoptotic and pro­apoptotic genes. Insulin and glucokinase mRNA expression were also decreased in FANCC­depleted 1.1B4 cells. The present study demonstrated the role of FANCC in protection against oxidative stress­induced ß­cell apoptosis and established another mechanism that associates FANCC deficiency with ß­cell dysfunction. The finding that FANCC overexpression reduced ß­cell apoptosis advances the potential for an alternative approach to the treatment of DM caused by FANCC defects.

DNAJC3 mutation in Thai familial type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2D) is a heterogeneous disease, with certain cases presenting an autosomal dominant type. The rare coding variants of disease­causing genes in T2D remain mostly unclear. The present study aimed to identify the disease­causing gene conducting whole exome sequencing in a Thai T2D family with an autosomal dominant transmission of T2D with no evidence of mutations in known maturity­onset diabetes of the young (MODY) genes. Candidate variants were selected according to certain criteria of mutation prediction programs, followed by segregation analysis with diabetes in the family. The results demonstrated that, of the 68,817 variants obtained, 122 were considered as candidate variants subsequent to the filtering processes. Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family. This mutation was also identified in another proband from the autosomal dominant T2D family without mutation in known MODY genes and was segregated with diabetes. This variant was also identified in 14/1,000 older­onset T2D patients [minor allele frequency (MAF)=0.007], 2/500 non­diabetic controls (MAF=0.002) and 3 prediabetic individuals who were previously classified as non­diabetic controls. In silico mutagenesis and protein modeling of p.H238N revealed changes of the polar contacts across the tetratricopeptide repeat (TPR) motif and TPR subdomains, which may affect the protein tertiary structure. Furthermore, the expression of DNAJC3 H238N protein was 0.68±0.08 fold (P<0.05) lower when compared with that of the wild­type, possibly due to protein instability. Thus, DNAJC3 p.H238N is likely to be a variant causing diabetes.

Prevalence of plasma small dense LDL is increased in obesity in a Thai population.

BACKGROUND: Plasma low density lipoprotein (LDL) particles vary in size, density, electrical charge and chemical composition. An increased presence of small dense LDL (sdLDL), along with raised triglyceride concentrations and decreased high density lipoprotein (HDL) cholesterol concentrations is commonly known as the atherogenic triad and has been observed in some cases of obesity, principally in Europe and America. This study examines the prevalence of sdLDL in the plasma of an obese (BMI≥25 kg/m2) Thai population. METHODS: Plasma from fasted obese (n=48) and non-obese (n=16) Thai participants was subjected to density gradient ultracentrifugation in iodixanol to separate lipoproteins. Gradients were unloaded top-to-bottom into 20 fractions which were assayed for cholesterol, triglyceride, apo B and apo A-1 to identify lipoprotein types and subtypes. RESULTS: LDL cholesterol was subfractionated into LDL I+II (fractions 3-6, ρ=1.021-1.033 g/ml) which was considered to represent large buoyant LDL (lbLDL), LDL III (fractions 7-9, ρ=1.036-1.039 g/ml) which was considered to represent sdLDL, and, LDL IV (fractions 10-12, ρ=1.044-1.051 g/ml) which was considered to represent very sdLDL. Concentrations of LDL III and IV were increased by 15-20% in obese participants whilst that of LDL I+II was concomitantly decreased by 10%. This was accompanied by a 50% increase in plasma triglyceride concentrations and 15% decrease in HDL cholesterol concentrations. Only 3/16 (19%) non-obese participants had a pattern B LDL cholesterol profile (peak density of >1.033 g/ml), whilst 28/48 (58%) obese participants were pattern B. When expressed as a fraction of the LDL concentration, total sdLDL (i.e. LDL III+IV) showed highly significant correlations to plasma triglyceride concentrations and the triglyceride/HDL cholesterol ratio. CONCLUSIONS: The prevalence of sdLDL is increased in obesity in a Thai population such that they demonstrate a similar atherogenic triad to that previously observed in European and American populations.

Effects of PCSK1 genetic variants on obesity among Thai children and their family members: in relation to health risk, and biochemical and anthropometric parameters.

Single nucleotide polymorphisms (SNPs) in PCSK1, namely, rs6234, rs6235, and rs271939 have been linked to obesity in European population; and rs3811951 has also been connected to type 2 diabetes and obesity parameters in Chinese population. In this family-based case-control study, we analyzed links between PCSK1 genetic variants and obesity in Thai children and their families. Eleven obese children with a percent weight for height > or = 140 who had family history of obesity and 69 family members were recruited. SNPs rs6234, rs6235, rs3811951, and rs271939 of PCSK1 were analyzed using PCR and gene sequencing methods. DNA of 200 normal weight subjects was used as control. Participants with variant genotypes in the rs6234-6235 pair are at significantly more risk of being obese [OR = 2.44 (1.35-4.43), p = 0.003], and also at increased risk of being severely obese (obese class III) [OR = 3.03 (1.20-7.66), p = 0.015]. Variant rs3811951 showed no association with being obese, but is significantly linked to an increased risk of being severely obese [OR = 3.59 (1.42-9.08) p = 0.005]. Moreover, high density lipoprotein (HDL)-C levels between normal and variant rs3811951 group differed considerably, with patients with variant genotype having a lower HDL-C level (p = 0.037). Thus, Thais carrying SNPs rs6234-5 are at increased risk of being obese, and the risk of severe obesity increases when carrying both rs6234-5 and rs3811951, but not with rs271939. Furthermore, patients with genetic variations at rs3811951 are at risk of having low HDL-C levels.

ID4 gene polymorphism and osteoporosis in Thai menopausal women.

BACKGROUND: The inhibitor of DNA binding 4 (ID4) protein regulates osteogenic and adipogenic cell fate and lack of lD4 gene expression decreased osteoblast differentiation. Variant in the ID4 gene polymorphism has not been reported with osteoporosis. OBJECTIVE: To identify whether ID4 can be a marker gene for osteoporosis in Thai menopausal women. MATERIAL AND METHOD: The 3 'UTR of lD4 (rs3798339) single nucleotide polymorphism was examined bypolymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP), together with lumbar spine bone mineral density (BAMD) in 160 Thai menopausal women. RESULTS: Lumbar spine 3 (L3) had a significantly lower BMD score in women with the TT genotype, compared with the CT+CC genotypes (p = 0.037). This disappeared after the adjustment of various factors. CONCLUSION: The polymorphism at 3'UTR of lD4 gene can alter ID4 mRNA stability, and may be linked to the function of proteins. However, this needs confirmation in larger populations. The present study is useful as an initial investigation into ID4 gene polymorphism in osteoporosis.