Fast Haemoglobin Variant Found in Hawaiian-Chinese-Caucasian Family in Hawaii and a Chinese Subject in Taiwan

Abstract. Haemoglobin J Honolulu, found in members of a family of mixed Hawaiian-Chinese-Caucasian ancestry, has been shown by chemical structure studies to have its structural alteration at position β-59 where a threonyl group replaces the lysyl group normally occupying that position. The same anomaly was found recently in haemoglobin J Kaohsiung, a variant from a Chinese subject living in Taiwan. The relative amounts of haemoglobin A₀ to haemoglobin J Honolulu were 52/48; the corresponding ratio for A₀/J Kaohsiung was 53/47. In both subjects there were no signs of anaemia resulting from the anomalous haemoglobins. Family studies in the Honolulu kindred are not sufficiently complete to provide conclusive evidence concerning which part of the ancestry, Chinese, Hawaiian, or Caucasian, is the source of the variant.     

A polymorphism in the resistin gene promoter and the risk of coronary artery disease in a Chinese population

Objective Resistin, a novel adipocyte‐derived peptide, has been linked to the pathogenesis of atherosclerosis. Recently, –420C>G, a variant located in the promoter region of the resistin gene (RETN) was identified. The aim of this study was to investigate the association between this RETN–420C>G polymorphism and the risk of coronary artery disease (CAD). Design A hospital‐based case–control study. Patients A total of 225 CAD patients and 225 age‐ and sex‐matched control subjects. Measurements Genotyping was performed by polymerase chain reaction (PCR) and restriction enzyme analysis to detect the presence of the RETN–420C>G polymorphism. Results The frequencies of RETN–420C>G genotypes in the CAD group were significantly different from those in the control group (P = 0·024). Subjects with the variant genotypes (CG and GG) had a 62% increased risk of CAD compared to CC carriers [adjusted odds ratio (OR) = 1·62, 95% confidence interval (CI) = 1·09–2·41, P = 0·016]. However, there were no significant differences between the genotypes with respect to weight, body mass index (BMI) and lipid profiles in CAD patients, and no significant association was found between the RETN–420C>G polymorphism and the severity of CAD. Conclusions Our data suggest that the RETN–420C>G polymorphism might be associated with an increased risk of CAD in a Chinese population.     

Polymorphisms of uridine-diphosphoglucuronosyltransferase 1A7 gene in Taiwan Chinese

AIM: Single nucleotide polymorphisms (SNPs) of uridinediphosphoglucuro -nosyltransferase 1A7 (UGT1A7) gene are associated with the development of orolaryngeal cancer, hepatocellular carcinoma, and colorectal cancer. We performed this research to establish the techniques for determining UGT1A7 gene and basic data of this gene for Taiwan Chinese. METHODS: We collected blood samples from 112 healthy adults and 505 subjects carrying different genotypes of UGT1A1, and determined the promoter area and the entire sequence of UGT1A7 exon 1 by polymerase chain reaction. We designed appropriate primers and restriction enzymes to detect variant UGT1A7 genotypes found in the study subjects. RESULTS: Six SNPs at nucleotides 33, 387, 391, 392, 622, and 756 within the coding region of UGT1A7 exon 1 were found. The incidence of UGT1A7*l/*2 (N129R131W208/ K129K131W208) was predominant (35.7%) while that of UGT1A7 *3/*3 (K129K131R208/K129K131R208) was the least (2.7%). The allele frequency of UGT1A7*3, which exists in a considerable proportion of Caucasians (0.361) and Japanese (0.255), was identified only to be 0.152 in our study subjects. A novel variation at nucleotide -57 in the upstream was found, which was associated with SNPs at nucleotides 33, 387, 391, 392, and 622 in one of the variant haplotypes. The nucleotide changes at positions 387, 391, 392 and 756 were in linkage in another variant haplotype. The allele frequency of UGT1A7*3 was 0.018, 0.158, 0.242, 0.433, and 0.920 in subjects carrying wild, A(TA)6TAA/A(TA)7TAA, A(TA)7TAA/A(TA)7TAA, 211G/211A, and 211A/211A variants of UGT1A1 gene, respectively. By using natural or mutagenesis primers, we successfully detected the variations at nucleotides -57, 33, 387, and 622 with the restriction enzymes HpyCH4 Ⅳ, TaqⅠ, AflⅡ, and Rsa Ⅰ, respectively. CONCLUSION: The results indicate that the allele frequencies of UGT1A7 gene in Taiwan Chinese are different from those in Caucasians and Japanese. Carriage of the nucleotide 211- variant UGT1A gene is highly associated with UGT1A7*3. The restriction-enzymedigestion method for the determination of nucleotides-57 (or 33, or 622) and 387 can rapidly identify genotypes of UGT1A7 in an individual.     

Neonatal jaundice and molecular mutations in glucose-6-phosphate dehydrogenase deficient newborn infants

Molecular mutations of the glucose-6-phosphate dehydrogenase (G6PD) gene and clinical manifestations of neonatal jaundice in 112 male and 50 female Chinese neonates with G6PD deficiency were studied. In the 112 males, the nucleotide (nt) 1376 (G→T) mutation was the dominant type (50.0%), followed by nt 1388 (G→A) (16.1%), nt 493 (A→G) (8.0%), nt 1024 (C→T) (6.2%), nt 95 (A→G) (5.4%), nt 392 (G→T) (1.8%), nt 487 (G→A) (1.8%), nt 871 (G→A) (0.9%), and nt 1360 (C→T) (0.9%). The nt 871 variant has not been reported in Taiwan before. The occurrence rates for nt 1376, nt 1388, nt 493, nt 95, and nt 1024 mutations in the 50 females were 44.0%, 18.0%, 12.0%, 6.0%, and 6.0%, respectively. The type of G6PD mutation in 10 male and 7 female neonates has not been identified yet. Although G6PD deficient neonates had higher frequency of phototherapy than G6PD normal neonates in both sexes, a significant difference in the prevalence of hyperbilirubinemia (peak bilirubin ≥ 15.0 mg/dl) between G6PD deficient and normal neonates was found only in males. Further analysis showed that duration of phototherapy was longer in G6PD deficient male neonates than in the control group, while the outcome of phototherapy was better in subjects with non-nt 1376 mutations than subjects with the nt 1376 mutation. Most (78.3%) of the 23 G6PD deficient neonates who subsequently suffered from neonatal hyperbilirubinemia carried the nt 1376 mutation. The results of this study indicate that the nucleotide substitution at 1376 is the most common and important mutation for G6PD deficiency in Chinese neonates in Taiwan. © 1996 Wiley-Liss, Inc.     

Alteration of Glutamyltranspeptidase Binding Proteins in Postmortem Brains of Heroin Addicts

Glutamyltranspeptidase binding (G) proteins play an important role in intracellular signal transduction downstream from many receptors, including opioid receptors. Moreover, it was recently reported that the β-subunits of G proteins, in addition to the α-subunits, regulate effector pathways. In this study, membrane G protein immunoreactivity was estimated by Western blotting with polyclonal antibodies (RM/1, AS/7, GC/2, QL, and SW/1) against specific G proteins (Gαs, Gαi-1,2, Gαo, Gαq, and Gβ, respectively) in postmortem temporal cortex obtained from 6 heroin addicts and 6 control subjects without a history of drug abuse. Immunoreactivities of the Gβ-subunit increased significantly ( p < 0.05) in heroin addicts, compared with controls, and that of Gαi-1,2 tended to increase in heroin addicts. Present findings suggest that the alterations in G protein-mediated signal transduction may be involved in the mechanism of opiate addiction.     

Haemoglobin F Texas II (α2γ26 Glu→Lys), the Second of the Haemoglobin F Texas Variants

S ummary A survey of 13 ,000 cord bloods in Great Britain yielded an electrophoretically abnormal variant of Haemoglobin F which resembled Haemoglobin F Texas. Haemoglobin F Texas might be either α₂γ₂^5G1u→Lys or α₂γ₂^6Glu→Lys. The first has been described and was named Haemoglobin F Texas I. The present variant has the same substitution in the sixth residue of the γ chain and is designated as Haenioglobin F Texas II.     

First Report of a Chinese Family Carrying a Double Heterozygosity for Hb Q-Thailand and Hb J-Bangkok

The double heterozygosity for α and β chain variants leads to the formation of abnormal heterodimer hybrids, which could render laboratory diagnostics in a routine setting difficult. The following is the first report of a double heterozygosity for Hb Q-Thailand [α74(EF3)Asp→His; HBA1: c.223G>C] with α⁺-thalassemia (α⁺-thal) and Hb J-Bangkok [β56(D7)Gly→Asp; HBB: c.170G>A] found in a Chinese family. Both subjects were healthy with normal or borderline hematological parameters. Hemoglobin (Hb) analyses showed a novel variant, Hb Q-Thailand and Hb J-Bangkok. Family studies helped in the initial recognition and in making presumptive diagnoses, but definitive diagnoses of these cases with complex α and β chain variants could only be obtained after DNA analysis.     

The Genetic Basis of Hb Q-H Disease

A Chinese family has been studied in which two siblings have haemoglobin Q-H disease. Using a combination of haematological and haemoglobin analysis, globin chain synthesis, analysis of α/β globin messenger RNA ratios and restriction endonuclease mapping, it has been shown that each of these siblings has received one chromosome on which both α chain genes have been deleted and another on which there is only a single α chain locus which carries the α^Q mutation. Their genotype is thus ——/ — α^Q. Despite the fact that the haemoglobin Q mutation in this family is carried on a chromosome with a single α chain locus, heterozygous carriers for the variant have only 25% or less haemoglobin Q. Our observations indicate that the molecular basis for haemoglobin Q-α thalassaemia is similar to that for the common form of haemoglobin H disease in Orientals. Furthermore, they provide clear evidence that the level of an α chain variant in heterozygous carriers is not a reliable reflection of the number of α globin genes.     

Genetic polymorphisms of adiponectin and tumor necrosis factor-alpha and nonalcoholic fatty liver disease in Chinese people

Background and Aim:  Hypoadiponectinemia and high tumor necrosis factor-alpha (TNF-α) levels are associated with the development of nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the genetic polymorphisms of adiponectin and TNF-α in Chinese NAFLD patients and their association with disease severity.
Methods:  Seventy-nine patients with histology-proven NAFLD (61 with simple steatosis and 18 with stage 2–4 fibrosis) and 40 controls were tested for the nucleotide polymorphisms at adiponectin −11 391, −11 377, +45, and +276 and TNF-α promoters −863, −308, and −238.
Results:  There was no significant deviation in the adiponectin and TNF-α gene polymorphisms between NAFLD patients and controls, or between patients with simple steatosis and those with stage 2–4 fibrosis. NAFLD patients with −11377G and +45G at the adiponectin gene were more likely to have hypertriglyceridemia. On multivariate analysis, older age, higher body mass index, and higher fasting glucose were independent factors associated with stage 2–4 fibrosis in NAFLD patients.
Conclusions:  Adiponectin and TNF-α gene polymorphisms were not shown to be associated with NAFLD or significant fibrosis in Chinese people. The adiponectin −11377G and +45G alleles were associated with hypertriglyceridemia in NAFLD patients. Since the current study is not adequately powered to detect smaller differences in allele frequencies, larger-sized studies in different ethnic groups are required.     

Molecular characterisation of red cell glucose-6-phosphate dehydrogenase deficiency in Singapore Chinese

Sixty-two G6PD deficient Chinese males have been investigated for the presence of seven mutations of the coding region of the G6PD gene by natural and artifically created amplified restriction sites. The results show that the G to T substitution at nucleotide (nt) 1376 and G to A substitution at nt 1388 represent 24% and 21% of G6PD deficiency, respectively, in the Singapore Chinese; 37% of the sample could not be characterised. The remaining samples were identified as follows: 10% C→T at nt 563, 5% A→G at nt 95, and 3% C→T at nt 1024. The G to A substitution (nt 487) and the substitution A→G (nt 493) were not present in this sample. None of the subjects with the Mediterranean mutation (563 C→T) had the silent mutation at 1311 (C→T). This study confirms the extreme molecular heterogeneity of the G6PD gene in the Chinese. © 1994 Wiley-Liss, Inc.     

Larger body mass index and waist circumference are associated with lower mortality in Chinese long-term care facility residents

OBJECTIVES: To investigate the association between body mass index (BMI) and waist circumference (WC) and all‐cause mortality of Chinese residents in long‐term care facilities in Taiwan. DESIGN: Prospective cohort study. SETTING: Eight long‐term care facilities in Taiwan. PARTICIPANTS: Three hundred fifty‐four residents aged 60 and older (median 78.4, range 60–101; 156 men, 198 women) were recruited during the study period. MEASUREMENTS: Anthropometrics and metabolic parameters were measured at baseline. Mean BMI was 21.7±4.2 kg/m² (range 11.6–35.3 kg/m², and mean WC was 82.4±10.9 cm (range 55.0–124.0 cm). Mortality data were from the Department of Health in Taiwan. RESULTS: There were 219 deaths during the 5 years of follow‐up. After adjusting for age, sex, albumin, Karnofsky performance status scale, hypertension, and diabetes mellitus, subjects in the highest quartile of BMI (27.3± 2.8 kg/m²) and WC (96.7±7.4 cm) had a significantly lower mortality rate than did subjects in the lowest quartile (BMI, 16.7±1.7 kg/m²; WC, 69.6±4.2 cm). After further stratification according to central obesity status, the subjects in the two highest BMI quartiles had a lower mortality rate than those in the lowest BMI quartile but only in the central obesity group (≥90 cm in men or ≥80 cm in women). The adjusted relative risk for all‐cause mortality in the highest versus lowest BMI quartile was 0.17 (95% confidence interval=0.05–0.57). CONCLUSION: BMI and WC were negative predictors for all‐cause mortality in older Chinese adults living in long‐term care facilities. Participants with higher WC and BMI had lower all‐cause mortality.     

Hb Indianapolis [beta112 (G14) Cys-->Arg] as the probable cause of moderate hemolytic anemia and renal damage in a Brazilian patient

Hemoglobin (Hb) Indianapolis [beta112 (G14) Cys-->Arg] is a rare and slightly unstable beta-globin variant. All carriers described to date were clinically normal with only mild reticulocytosis. We report here a case of a Brazilian patient in whom hemolytic anemia and acute renal failure were probably caused by the presence of this variant.     

Haemoglobin Siriraj, β-7 (βA4) Glu→ Lys, in a Chinese Subject in Taiwan

Abstract. Haemoglobin Siriraj, β-7 Glu→Lys, was reported in members of a Thai family by Tuchinda, Beale and Lehmann [Brit. med. J. 1 : 1583–1585, 1965]. The same variant now is reported in a normal Chinese subject originating from the Chinese province of Honan. Relative amounts of haemoglobins A_o and Siriraj were 67 to 33. Incidence of Siriraj in Chinese subjects is low; only one subject was found among 160,000 Chinese tested.     

Hemoglobin Chongqing [alpha 2(NA2)Leu----Arg] and hemoglobin Harbin [alpha 16(A14)Lys----Met] found in China

Hemoglobin Chongqing is a new slowly-moving and unstable hemoglobin variant with a high oxygen affinity, that was discovered in five members of a Chinese family in the suburb of Chongqing. Hemoglobin Harbin is another new rapidly-moving hemoglobin variant with slightly reduced stability and slightly increased oxygen affinity, found in a Chinese woman living in Harbin. The relative amounts of these two variants in the propositi were about 9% and 18%, respectively. Sequence analyses identified a Leu----Arg substitution at position alpha 2(NA2) of Hb Chongqing, and a Lys----Met substitution at position alpha 16(A14) of Hb Harbin.     

Interaction between the Glucose-6-Phosphate Dehydrogenase Deficiency and Thalassaemia Genes at Phenotype Level

Summary. No significant differences were observed in the mean values of Hb A₂ levels and red cell indices between G6PD^- and G6PD+β thalassaemia carriers apart from the MCV, which was significantly higher in β thalassaemia G6PD^- subjects, but still in the thalassaemia carrier range. No difference was seen between G6PD+ and G6PD^-α thalassaemia carriers. G6PD+β thalassaemia carriers show a significant increase in G6PD levels expressed as activity per g of Hb and to lesser extent as activity per number of red cells x 10⁹; in G6PD+α thalassaemia carriers this increase is statistically significant only when the enzyme levels are expressed as activity per g of Hb. G6PD^-β thalassaemia carriers had enzyme levels higher than non-thalassaemic G6PD^- subjects only when the activity is expressed per g of Hb. G6PD activity was found to be increased in G6PD+ and G6PD^- Hb H disease patients.     

Lack of association between perlecan gene intron 6 BamHI polymorphism and risk of mitral valve prolapse in Taiwan Chinese

Abnormalities of proteoglycan, collagen, and elastic fibers were found in floppy mitral valves. Perlecan is one of the three major classes of heparan sulfate proteoglycans within the cardiovascular system. The role of perlecan genetic variant in mitral valve prolapse (MVP) has not been studied. We therefore performed a case-controlled study investigating the possible relation between the perlecan gene intron 6 BamHI polymorphism and MVP among the Chinese population in Taiwan. We studied 100 patients with MVP diagnosed by echocardiography and 100 age- and sex-matched normal control subjects. The perlecan gene intron 6 BamHI polymorphism was identified by polymerase chain reaction-based restriction analysis. There were no significant differences in either the genotype distribution or allelic frequencies between MVP cases and controls for perlecan gene intron 6 BamHI polymorphism (P = 0.20 and 0.76, respectively). Further categorization of the MVP patients into mild and severe subgroups also revealed no statistical difference from controls for perlecan gene intron 6 BamHI polymorphism. It is concluded that perlecan gene intron 6 BamHI polymorphism is not a suitable genetic marker of MVP in Taiwan Chinese.     

Haemoglobin A1c is associated with carotid intima-media thickness in a Chinese population

Background The association between haemoglobin A1c (HbA1c) levels and subclinical atherosclerosis in carotid arteries in Chinese populations is unknown. Aim, design and methods The objective of this study was to investigate this relationship and evaluate the ability of HbA1c levels to predict carotid atherosclerosis in a Chinese population. This was a cross‐sectional study, which included 541 subjects without known diabetes (Taiwan Lifestyle Study). About 67 (9·2%) subjects were newly diagnosed with diabetes during the study. Carotid intima–media thickness (IMT) and the presence of carotid plaques were determined using ultrasonography. Results The HbA1c level in all subjects was positively correlated with carotid IMT (β = 0·018, P = 0·03) after being adjusted for age, gender, smoking, low‐density lipoprotein cholesterol level, hypertension and body mass index. HbA1c level was higher in subjects with plaques in carotid arteries (P = 0·01). There was a positive and linear relationship between HbA1c levels and the probability of having plaques, thickened carotid IMT or both (P for all comparisons, <0·05). The ability of HbA1c levels to predict thickened carotid IMT or the presence of plaques was only modest {the optimal cutoff of HbA1c level [5·7%] was determined from the receiver operating characteristic (ROC) curve (sensitivity = 67%, specificity = 61%) and the area under the ROC curve [0·666]}. Conclusions Thus, HbA1c level is associated with subclinical atherosclerosis in carotid arteries in a Chinese population. The relationship is linear without an inflection point. However, HbA1c criterion is not a useful marker for the identification of subclinical atherosclerosis.     

Screening colonoscopy in Chinese and Western patients: a comparative study

OBJECTIVES: The aim of this study was to compare findings on screening colonoscopy in a Chinese cohort versus a concurrent Western cohort. METHODS: Asymptomatic adults aged 40 years or older concurrently underwent screening colonoscopy in two hospitals, one in Taiwan and the other in Seattle. The prevalence and distribution of colonic neoplasia and advanced neoplasia (defined as an adenoma >or=10 mm or with villous, high-grade dysplastic, or malignant features) were compared between the two groups. RESULTS: The Taiwan cohort was composed of 1,456 subjects. Colonic neoplasms were found in 214 (14.7%), advanced neoplasms in 58 (4%), and colon cancers in 4 subjects (0.3%). The Seattle cohort was composed of 3,403 subjects. Neoplasms were found in 705 (20.7%), advanced neoplasms in 166 (4.9%), and cancers in 11 subjects (0.3%). Age and male sex were risk factors for neoplasia in both groups. The adjusted risk ratio was 1.30 (95% confidence interval: 1.08-1.57) in Western versus Chinese patients. However, the prevalence of advanced neoplasms was not statistically different between the two cohorts. The Chinese cohort had a higher proportion of distal neoplasia (66.4%vs 52.6%; p= 0.0004). The sensitivity of a sigmoidoscopic screening strategy for detecting advanced neoplasia was higher in Chinese (79.3%) than in Western patients (67.5%). CONCLUSIONS: Compared to Westerners, Chinese patients have a slightly lower prevalence of colon neoplasia (but not advanced neoplasia), more distal distribution of neoplasia, and higher likelihood of concomitant proximal advanced neoplasia and distal neoplasia. Colonoscopy is safe, well-tolerated, and a viable screening option in Chinese patients, but its advantage over sigmoidoscopy as a screening tool may be smaller.     

THE LABORATORY DIAGNOSIS OF HAEMOGLOBINOPATHIES,

The laboratory diagnosis of haemoglobinopathies, including the thalassaemias, is of growing importance, particularly because of an increasing requirement for antenatal diagnosis of significant disorders of globin chain synthesis. This guideline discusses the laboratory tests which are most useful in the diagnosis of haemoglobinopathies and describes their role in specific clinical circumstances. Of the newer technical methods, high-performance liquid chromatography (HPLC) is of considerable importance whereas isoelectric focusing (IEF) and immunoassay for variant haemoglobins have a more minor role.
Specific recommendations have been formulated for testing in relation to genetic counselling and for neonatal diagnosis. Methods used in specialized laboratories for fetal diagnosis have been tabulated. Genetic counselling requires: (i) identification of haemoglobins S, C, D-Punjab, O-Arab, E, Lepore and H, and (ii) the detection of carriers of α° and β thalassaemia. It is recommended that subjects of all ethnic groups be screened for β-thalassaemia trait, all except Northern European Caucasians for variant haemoglobins, and selected ethnic groups for α°-thalassaemia trait. Testing for β-thalassaemia trait should be carried out when the mean cellular haemoglobin (MCH) is < 27 pg and testing for α°-thalassaemia trait should be considered when the MCH is < 25 pg. Appropriate methods include HPLC or haemoglobin electrophoresis for identification of variant haemoglobins and HPLC or microcolumn chromatography for quantification of haemoglobin A2.     

Unstable hemoglobin Rush [beta 101(G3) Glu>Gln, HBB:c.304G>C] in a Brazilian family with moderate hemolytic anemia

Hemoglobin Rush is an unstable variant generated by a mutation of the β-globin gene which causes amino acid replacement Glu>Gln in the central cavity of hemoglobin (G3). Many members of a Brazilian family of Italian descent have hemoglobin Rush. This is the second report in world literature. Clinical and laboratory features were retrieved and gene mutation was characterized. Hemoglobin electrophoresis, gene sequencing, and restriction fragment length polymorphism with Hpy188I were used to characterize it. In 13 affected members, hemoglobin ranged from 9.3 to 13.0?g/dL and reticulocyte count up to 12.8%. The intensity of hemolysis appeared to be linked to increased stress. The mutation was proved to be HBB:c.304G>C, beta 101(G3) Glu>Gln. Heterozygous hemoglobin Rush should be suspected when alkaline electrophoresis shows three bands, whereas isoelectric focusing and acid electrophoresis show only two. Adequate genetic counseling to avoid intermarriage should be provided because homozygous hemoglobin Rush is predicted to be clinically severe.