Thiopurine methyltransferase polymorphisms in a multiracial asian population and children with acute lymphoblastic leukemia.

The purpose of this study was to determine the frequency of thiopurine methyltransferase (TPMT) polymorphisms in a multiracial Asian population and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Six hundred unrelated cord blood samples from 200 Chinese, Malay, and Indian healthy newborns were collected at the National University Hospital, Singapore; an additional 100 children with ALL were analyzed for five of the commonly reported TPMT variant alleles using polymerase chain reaction/restriction fragment length polymorphism and allele-specific polymerase chain reaction-based assays. In the cord blood study, the TPMT*3C variant was detected in all three ethnic groups; Chinese, Malays, and Indians had allele frequencies of 3%, 2.3%, and 0.8%, respectively. The TPMT*3A variant was found only among the Indians at a low allele frequency of 0.5%. The TPMT*6 variant was found in one Malay sample. Among the children with ALL, two white and one Chinese were heterozygous for the TPMT*3A variant and showed intermediate sensitivity to 6-mercaptopurine during maintenance therapy. Three Chinese patients and one Malay patient were heterozygous for the TPMT*3C variant. Mercaptopurine sensitivity could be validated in only one out of four TPMT*3C heterozygous patients. The overall allele frequency of the TPMT variants in this multiracial population was 2.5%. The TPMT*3C was the most common variant allele; TPMT*3A and TPMT*6 were rare. These results support the feasibility of performing TPMT genotyping in all children diagnosed with acute leukemia to minimize toxicity from thiopurine chemotherapy.

Genetic susceptibility to asthma and atopy among Chinese in Singapore--linkage to markers on chromosome 5q31-33.

BACKGROUND: Asthma and atopy are complex genetic traits, influenced by the interaction of multiple genes and environmental factors. Linkage of these traits to chromosome 5q31-33 has been shown in other populations, but has not been well studied in the Chinese. We studied linkage between asthma and atopy with markers on chromosome 5q31-33 in the Singapore Chinese. This region contains many candidate genes, including the cytokine gene cluster. METHODS: We recruited 88 Chinese families with at least two affected offspring, totaling 373 subjects, with 125 and 119 sib-pairs for atopy and asthma, respectively. All individuals were genotyped with 19 polymorphic microsatellite markers spanning a distance of 41 cM along chromosome 5q31-33. Affected sib-pair and multipoint linkage analysis was performed. RESULTS: There was evidence for linkage of the asthma and atopy phenotypes with three markers, D5S2110, D5S2011, and D5S412 (P values of 0.001 to 0.00001). Multipoint analysis further substantiated this (nonparametric linkage scores of 1.8-2.9). These findings suggest that susceptibility genes for asthma and atopy are found in this region in the Chinese. CONCLUSION: This study has shown linkage of atopy and asthma to chromosome 5q31-33 in a heterogeneous Chinese population. These findings further substantiate the notion that chromosome 5q31-33 contains "universally" important susceptibility genes for these traits.

Tardive dyskinesia is not associated with the serotonin gene polymorphism (5-HTTLPR) in Chinese.

Neuroleptics are the mainstay of treatment for schizophrenia, but one of the complications is the development of tardive dyskinesia (TD). The pathophysiology of TD may involve dopamine-serotonin interaction. The serotonin transporter participates in the reuptake and termination of serotonin neurotransmission, and the gene that codes for this protein is thus a candidate gene for the development of TD. There is a functional polymorphism in the transcriptional control region of the serotonin transporter gene, and we investigated the association between this polymorphism and TD in Chinese schizophrenic patients. The patients who did not differ in age and sex distribution did not show variation on the rates of TD and Abnormal Involuntary Movements Scale (AIMS) scores with genotypes. Our findings suggest that 5-HTTLPR polymorphism is not a risk factor for TD in Chinese. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:712-715, 2000.

Ethnic differences in genetic susceptibility to atopy and asthma in Singapore.

INTRODUCTION: Asthma and atopy are complex traits, the phenotypes being influenced by the interaction of both genetic and environmental factors. In view of the growing evidence for inter-ethnic differences in genetic susceptibility to complex diseases such as asthma and atopy, we have assessed genetic factors for these diseases in the local population. METHODS: The genetic analysis of asthma and atopy is being approached by candidate gene analysis as well as linkage studies for mapping of susceptibility loci. We reviewed published studies, which include data from our population on some candidate genes, as well as our preliminary data on susceptibility locus mapping for linkage to chromosome 5q31-33. RESULTS: In local studies of the interleukin-4 receptor and tumour necrosis factor polymorphisms, we failed to find associations with genetic variants previously implicated to be associated with asthma and atopy. Evaluation of markers on chromosome 5q31-32 identified novel loci for susceptibility to asthma and atopy in addition to loci already described by others. CONCLUSION: Both the published literature and our own findings indicate that there are inter-ethnic differences in genetic susceptibility to asthma and atopy.

Membranous nephropathy with anti-tubular basement membrane antibody may be X-linked.

The association of membranous nephropathy with Fanconi syndrome and anti-tubular basement antibodies appears to be a distinct subset of familial membranous nephropathy. We studied two Chinese families with four affected boys to evaluate the mode of inheritance of disease. HLA haplotype analysis of the family members in these two pedigrees did not reveal any significant linkages. However, microsatellite analysis of both pedigrees using markers on the X chromosome suggested linkage to the long arm of the X chromosome between the microsatellite markers DXS1001 and DXS1227. Identification and analysis of additional pedigrees may allow more precise mapping of the disease gene for anti-tubular basement membrane antibody-associated membranous nephropathy.

An atypical kindred with X-linked adrenal hypoplasia congenita, normal puberty, and normal Dax-1 promoter and coding sequence.

We report a Chinese kindred with an atypical sex-linked form of isolated adrenal hypoplasia without hypogonadotropic hypogonadism. Evidence of sex linkage was supported by DNA analysis using three polymorphic markers from the X-chromosome: a restriction fragment length polymorphism 200 kb centromeric of the DAX-1 gene, a tetranucleotide repeat marker in the DAX-1 promoter (DAX-P), and a microsatellite in the Duchenne muscular dystrophy locus (3'-19). This pedigree therefore presents the novel phenotype of sex-linked hypoadrenalism without hypogonadotropic hypogonadism, with evidence of possible linkage to the DAX-1 gene. However, all three affected individuals were examined for mutations in the DAX-1 gene, and found to have no sequence anomalies in the coding region, splice sites or 5' non-coding region. This presentation may be due to a defect in the DAX-1 gene outside its known coding region, possibly modulated by functional polymorphisms at other loci, and/or environmental effects, or to a defect in a novel gene on the X chromosome which selectively influences adrenal development.

Attempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia.

Abnormalities of serotonin synthesis and metabolism may be associated with suicidality. The serotonin transporter gene (5-HTT) is one of the important genes involved in the regulation of serotonin neurotransmission. We examined the association of suicidal behavior in Chinese schizophrenic patients with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). The 5-HTTLPR genotype was determined by polymerase chain reaction for 76 suicidal and 262 non-suicidal patients with a diagnosis of schizophrenia (DSM-IV criteria). All subjects were unrelated to each other, and all were Chinese. There was no significant genotypic or allelic association of the 5-HTTLPR polymorphism with history of attempted suicide. From our results, this 5-HTTLPR polymorphism is unlikely to have a major effect on suicidal behavior in Chinese patients with schizophrenia.

Ethnic differences in genetic susceptibility to atopy and asthma.

The genetics of asthma and atopy is complex, but can be approached by studies of both candidate genes and mapping of susceptibility loci. Genetic factors conferring susceptibility to disease may vary among ethnic groups. We present our experience with some candidate gene studies for asthma and atopy and susceptibility locus mapping for linkage to chromosome 5q.

Association between allele 1 of T102C polymorphism, 5-hydroxytryptamine 2a receptor gene and schizophrenia in Chinese males in Singapore.

The T102C polymorphism at the 5-hydroxytryptamine 2a receptor (5HTR2a) gene was studied in 101 Chinese male schizophrenics and 103 controls. Genotyping revealed a predominance of allele 1 among schizophrenics. This is in contrast to previous reports in Caucasians and Japanese which showed an association of allele 2 of this polymorphism with schizophrenia.

Pathology of urinary tract malformations in a paediatric autopsy series.

In a series of 3172 consecutive autopsies of stillbirths, infants and children performed over a 12-year period from 1978 to 1989 at the Department of Pathology, Outram Road, Singapore, urinary tract malformations were found in 78 cases (2.5%). The urinary tract abnormalities were of 6 major groups: hydronephrosis and/or hydroureter (35.9%), cystic disorders (29.5%), renal agenesis (26.9%), horseshoe kidney (11.5%), renal hypoplasia (5.1%) and pelvic kidney (1.3%). Other series have reported incidences of urinary tract malformations ranging between 2.7% and 11%, depending on the source of the study material. Our local incidence appears to fall below the lower end of the scale, but may not reflect an accurate comparison because of the differences in the denominational base.

Epidermal growth factor and phorbol myristate acetate increase expression of the mRNA for cytosolic phospholipase A2 in glomerular mesangial cells.

We have previously shown that phospholipase A2 (PLA2) activity is rapidly activated by epidermal growth factor (EGF) and phorbol 12-myristate 13-acetate (PMA) in renal mesangial cells and other cell systems in a manner that suggests a covalent modification of the PLA2 enzyme(s). This PLA2 activity is cytosolic (cPLA2) and is distinct from secretory forms of PLA2, which are also stimulated in mesangial cells in response to cytokines and other agonists. However, longer-term regulation of cPLA2 in renal cells may also occur at the level of gene expression. Cultured rat mesangial cells were used as a model system to test the effects of EGF and PMA on the regulation of cPLA2 gene expression. EGF and PMA both produced sustained increases in cPLA2 mRNA levels, with a parallel increase in enzyme activity over time. Inhibition of protein synthesis by cycloheximide increased basal cPLA2 mRNA accumulation in serum-starved mesangial cells, and the combination of EGF and cycloheximide resulted in super-induction of cPLA2 gene expression compared with EGF alone. Actinomycin D treatment entirely abrogated the effect of EGF on cPLA2 mRNA accumulation. These findings suggest that regulation of cPLA2 is achieved by factors controlling gene transcription and possibly mRNA stability, in addition to previously characterized posttranslational modifications.

Comparison of progression of renal failure in children with hypoplastic-dysplastic kidneys and chronic glomerulonephritis.

A comparative study was made on two groups of children comprising 20 patients with renal hypoplasia/dysplasia in one group and 12 patients with chronic glomerulonephritis (GN) in the other, presenting with chronic renal failure (CRF) in the Department of Paediatrics, Singapore General Hospital and National University Hospital between 1975 and 1989. The age of onset of CRF, the progression of renal failure and the presence of various clinical complications were analysed and compared. The mean age of onset of CRF was earlier in patients with renal hypoplasia/dysplasia (p less than 0.001) but the progression of renal failure in these patients were slower (p less than 0.005). Hypertension occurred more frequently in the chronic GN group (p less than 0.001) while urinary tract infection (UTI) occurred more frequently in the renal hypoplasia/dysplasia group (p less than 0.004). With the early onset of renal failure and slow deterioration of renal function in patients with renal hypoplasia/dysplasia, the provision of good conservative treatment for renal failure is most important in the management of these patients. In the chronic GN patients however, with the rapidity of deterioration of renal function, early preparation for replacement therapy becomes more imminent. However, renal replacement therapy in end-stage renal failure (ESRF) is costly and not readily available, it is more prudent to delay the onset of ESRF by providing effective conservative treatment of renal failure which includes the early recognition and treatment of hypertension in chronic GN and UTI in renal hypoplasia/dysplasia.

The red cell charge in steroid--responsive nephrotic syndrome.

It has been suggested that the negative charge on the surface of red blood cells (RBC) may reflect the charge on the glomerular capillaries. Measurements were made of RBC charge in patients with steroid-responsive nephrotic syndrome (SRNS) based on the binding of a cationic dye, alcian blue. There was no difference found between patients in relapse and in normal controls. We conclude that RBC charge measurements are not a reliable indicator of the glomerular charge barrier and a more specific method is required.