Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients.

It is not clear if a Th1/Th2 imbalance in Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) would lead to a particular antigen-specific IgG subclass dominant as had been shown in the mouse model. In new-onset Type 1 diabetics, an autoantibody response to glutamate decarboxylase (GADab) is frequently observed but the GADab subclass repertoire is not well-established. We determined the systemic levels of representative Th1 and Th2 cytokines and the GADab IgG subclass distribution in 41 Chinese IDDM patients of whom 26 were recently diagnosed (< or = 1 year) and 32 had GADab, to ascertain a likely association of antigen-specific antibody isotype and the Th1/Th2 dichotomy. With high-sensitivity ELISA systems that measure sub-picogram cytokine concentrations, 26 of the 41 patients (63.4%) had at least one of the pro-inflammatory Th1 cytokines (TNF-alpha, IFN-gamma and IL-12) detected. Fewer patients (4/41) had the anti-inflammatory Th2 cytokine IL-4 detected. For IL-10, all subjects had measurable quantities but only three diabetics had levels above the upper limit for healthy subjects (n = 20). Grouped according to the profile of detectable cytokines, there were 24 Th1, 2 Th2 and 2 Th0 patterns. GAD-specific IgG1 antibody was more frequently expressed; 22 of 32 GADab[+] patients. The rank order for the GADab subclasses was IgG1 > 4 > 3 > 2; IgG2 was found in 11 GADab[+] patients. Recent-onset diabetics have a similar ranking of the GAD-specific IgG subclasses. In human Type 1 diabetes, a predominance of GAD-specific IgG1 antibody response is observed together with a dominant Th1 cytokine pattern.

Influence of lymphocytic thyroiditis on the prognostic outcome of patients with papillary thyroid carcinoma.

Both the association between lymphocytic thyroiditis (LT) and papillary thyroid carcinoma (PTC), and the prognostic significance of lymphocytic infiltrate in patients with thyroid malignancy, remain controversial. We examine the above relationships by retrospectively reviewing our series of patients treated for differentiated nonmedullary thyroid carcinoma at University of California-San Francisco over a 25-yr period (1970-1995). Of the 631 patients with complete data for analysis, 128 patients (20.3%) showed concomitant histologic evidence of LT and 503 patients (79.7%) had no evidence of LT. Prognostic outcome was assessed using Kaplan-Meier survival plots and analysis of risk factors by Cox's proportional-hazard modeling. The cohort with LT revealed a higher frequency of PTC (97.7% vs. 87.3%) and female patients (85.2% vs. 66.8%), a lower frequency of extrathyroidal invasion (7.8% vs. 23.3%) and nodal metastases (25.8% vs. 43.3%), and absence of distant metastases (0% vs. 4.8%), respectively, compared with those without LT. At initial surgery, a significantly greater proportion of patients with LT belonged to lower pathological tumor-node-metastasis stages, compared with those without LT (stage 1, 86.7% vs. 73%; stage 2, 4.7% vs. 8.3%; stage 3, 8.6% vs. 15.3%; and stage 4, 0% vs. 3.4%). Over a mean +/- SE follow-up period of 11.1 +/- 0.4 yr, patients with LT had significantly lower cancer recurrence rate (6.3% vs. 24.1%; P < 0.0001) and cancer mortality rate (0.8% vs. 8.0%; P = 0.001), respectively, compared with those without LT. In summary, our series showed a relatively common occurrence of LT in patients with PTC, and we believed that lymphocytic infiltration developed mainly in response to the tumor itself. We also found a more favorable course of PTC in the presence of LT; this supports the hypothesis that lymphocytic infiltration represents a form of immune reaction to control tumor growth and proliferation.

Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients.

The TNM classification (tumor-node-metastasis) was adopted by the American Joint Committee on Cancer and the International Union against Cancer a decade ago to avoid heterogeneity of prognostic classification schemes used for differentiated thyroid cancers. To date, however, clinical data based on this classification are lacking. We retrospectively evaluate the prognosis of 700 patients (208 men and 492 women) with papillary (89%) and follicular (11%) thyroid cancers according to the pathological TNM (pTNM) staging system, treated over a 25-yr period (1970-1995). Patients who received primary treatment at our center constituted 87.4% of the cases; the majority underwent total thyroidectomy, followed by 131I ablative therapy in high risk groups, as standard treatment. Clinical and follow-up data were obtained from the medical records and our cancer registry. Disease-free and cancer-specific survival data were analyzed by Kaplan-Meier product limit estimates and Cox proportional hazard models. Patient distribution by the pTNM system were: stage I, 516 patients; stage II, 57 patients; stage III, 104 patients; and stage IV, 23 patients. Over a mean +/- SE follow-up of 11.3 +/- 0.3 yr, the overall cancer recurrence and mortality rates were 20.5% and 8.4%, respectively. However, the respective cancer recurrence and mortality rates were distinctly different in the various pTNM stages: 15.4% and 1.7% in stage I, 22% and 15.8% in stage II, 46.4% and 30% in stage III, and 66.7% and 60.9% in stage IV tumors. Using actuarial survival plots, a clear separation in both disease-free survival and cancer-specific survival was noted among all the stages (P < 0.0001). Risk factors analyses showed a significant association between all the prognostic variables used in TNM staging (age, tumor size, extent of primary tumor, and presence of nodal or distant metastases) and the observed end points of recurrence or death from thyroid cancer. After correcting for TNM stages, the risk of cancer recurrence was halved in female compared to male patients, whereas this was 1.7-fold higher in multifocal than unifocal tumors. Conversely, cancer mortality was 3.4-fold higher in follicular than papillary thyroid cancer. In the analysis of effect of primary treatment among 492 patients with tumor more advanced than the T1N0M0 category, patients who underwent less extensive surgery (lobectomy or subtotal thyroidectomy) had a 2.5-fold risk of cancer recurrence (P < 0.0001) and a 2.2-fold risk of death (P < 0.01) compared to those who underwent total or near-total thyroidectomy. Patients not treated with 131I ablation had a 2.1-fold greater risk of cancer recurrence (P < 0.0001) than those given 131I ablation, although no difference was noted in deaths from thyroid cancer. Based on our data, the pTNM classification is useful in distinguishing patients with different prognostic outcomes. However, the small patient numbers in pTNM stages other than stages I precludes us from evaluating its usefulness as a guide for therapy. Until prospective data could be accrued from controlled treatment trials, we support the standard practice of total thyroidectomy followed by 131I ablative therapy (if focal iodide uptake was noted) in patients with papillary thyroid cancer more advanced than the T1N0M0 category or of multicentric nature and in the majority of patients with follicular thyroid cancer.

Familial papillary thyroid cancer: a case report.

Familial occurrence of medullary thyroid cancer is well known in families as an isolated malignancy or in association with multiple endocrine neoplasia syndrome type II. Conversely, papillary thyroid cancer almost always presents sporadically except for reports of familial clustering in individuals with radiation exposure, inherited syndromes of colonic polyposis or multiple harmatomas, and rarely in monozygotic twins. We report a case of papillary thyroid cancer diagnosed incidentally in a 53-year-old woman who underwent surgery for excision of an adenomatous nodule. It was noted that her mother suffered from a similar thyroid malignancy some 33 years ago, and several of her maternal relatives had either Graves' disease or hypothyroidism. The possible existence of this familial entity and its likely genetic basis is discussed.

Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature.

Three patients who developed symptomatic, autoimmune-mediated thyroid dysfunction during treatment with interferon-alpha (IFN-alpha) for chronic active hepatitis C with liver cirrhosis, age-related macular degeneration with foveal involvement, and chronic myelogenous leukemia, respectively, are described. The first two patients developed autoimmune hypothyroidism that required thyroxine replacement, and the third developed autoimmune thyroiditis with transient thyrotoxicosis. The clinical manifestations were protean, and required a high index of suspicion for diagnosis, the failure of which led to significant morbidity. A literature review revealed that the mean incidence of IFN-alpha induced thyroid dysfunction was 6%. Spontaneous resolution occurred in more than half with discontinuation of IFN-alpha treatment. Hypothyroidism was induced more frequently than hyperthyroidism. At least one positive thyroid autoantibody titer was found in 17% of patients receiving IFN-alpha. Risk factors for developing thyroid dysfunction with IFN-alpha treatment were female sex, underlying malignancy or hepatitis C, higher doses of IFN-alpha for longer durations, combination immunotherapy (especially with interleukin-2), and the presence of thyroid autoantibodies prior to or during treatment.

The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients.

Iodine-131 metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical agent used for scintigraphic localization of pheochromocytomas, has been employed to treat malignant pheochromocytomas since 1983 in a few specialized centers around the world. We review our clinical experience together with the published experience of 23 other centers in 10 countries, regarding the use of 1311-MIBG for treating patients with malignant adrenal pheochromocytomas or extra-adrenal paragangliomas. There were a total of 116 evaluable patients: 3 were from our current report and another 113 were reported in the literature from 1983 to 1996. A majority of the patients were selected for treatment based upon positive tracer uptake studies. The cumulative dose of 131I-MIBG administered ranged from 96 to 2,322 mCi (3.6 to 85.9 GBq), with a mean (+/-SD) of 490+/-350 mCi (18.1+/-13.0 GBq). The subjects received a mean single therapy dose of 158 mCi (5.8 GBq) and the number of doses administered ranged from 1 to 11, with a mean of 3.3+/-2.2 doses. Initial symptomatic improvement was achieved in 76% of patients, tumor responses in 30%, and hormonal responses in 45%. Five patients had complete tumor and hormonal responses, ranging from 16 to 58 months, which were sustained at the time of reporting. Patients with metastases to soft tissue had more favorable responses to treatment than those with metastases to bone. No difference was noted in the age between the responders and non-responders. Adverse effects, recorded in 41% of the treated patients, were generally mild except for one fatality from bone marrow aplasia. Among 89 patients with follow-up data, 45% of the responders had relapsed with recurrent or progressive disease after a mean interval of 29.3+/-31.1 months (median 19 months). Of patients with an initial response to 1311-MIBG, death was reported in 33% after a mean of 23.2+/-8.1 months (median 22 months) following treatment. Of non-responders, death was reported in 45% after a mean of 14.3+/-8.3 months (median 13 months). In conclusion, this review suggests that 131I-MIBG therapy may be a useful palliative adjunct in selected patients with malignant pheochromocytoma or paraganglioma. Although controlled studies are lacking, our review raises the hope that this therapeutic modality may prolong survival with an occasional sustained complete remission or possible cure.

Soluble T-cell markers and serum cytokines in type I (insulin-dependent) diabetes mellitus.

Markers of cell-mediated immune activation were studied in 32 Chinese patients with recent-onset insulin-dependent diabetes mellitus (IDDM) as compared with 12 patients with recent-onset non-insulin-dependent diabetes mellitus (NIDDM) and 34 normal subjects. Sera were assessed for soluble markers of T-cell activation (sCD4, sCD8, sIL-2R); the cytokines (IL-1 beta, TNF-alpha, IL-2, IL-6), and T-cell subsets were also determined. Only 1 of the 32 IDDM patients had increased sCD4 levels, 5 had increased sCD8, and 3 had increased sIL-2R. None of the sera from NIDDM patients and control subjects showed such increased levels of soluble markers. Three IDDM patients had detectable IL-1 beta and this weakly so (< 3.5 pg/ml). However, the other cytokine data and the frequency of activated T-cells, CD4+, CD8+ T-cell subsets and CD4:CD8 ratio showed no significant differences among the IDDM, NIDDM and normal subjects. Our data suggest that in addition to a low frequency of islet cell antibodies, Chinese patients with recent onset IDDM also showed a lack of serum markers of cellular activation.

Relationships between cigarette smoking, blood pressure and serum lipids in the Singapore general population.

In a cross-sectional random survey of the whole of Singapore (2143 subjects aged 18-69 years), cardiovascular risk factors were measured by standardized techniques. For the analysis in the 18-69 year age group there was adjustment for ethnic group, age, body mass index, alcohol consumption and physical activity. Among serum lipids, high density lipoprotein (HDL-) cholesterol and fasting triglyceride were inversely related with partial correlation coefficients (r) of males -0.34 (P < 0.001) and females -0.26 (P < 0.001). There were no relationships between blood pressure and serum lipids except for direct ones with fasting triglyceride, being males (systolic r = 0.06, P = 0.066 and diastolic r = 0.12, P < 0.001) and females (systolic r = 0.11, P < 0.001 and diastolic r = 0.13, P < 0.001). Cigarette smoking, in males, was related to systolic blood pressure (inversely), with, compared to non-smokers, a reduction of 1.3 mm Hg (1.1%) in light smokers, 3.8 mm Hg (3.1%) in moderate smokers and 4.6 mm Hg (3.7%) in heavy smokers; there was no clear relation with diastolic blood pressure. Cigarette smoking, in males, was related to HDL-cholesterol (inversely), even after further adjustment for fasting triglyceride, with compared to non-smokers reductions of 0.03 mmol/l (3.4%) in light smokers, 0.09 mmol/l (10.3%) in moderate smokers and 0.12 mmol/l (13.8%) in heavy smokers. Cigarette smoking was related to fasting triglyceride (directly) but this was removed by further adjustment for HDL-cholesterol. Cigarette smoking was not related to low density lipoprotein cholesterol. These results are compared to those of other surveys.

Non-restricted immunoglobulin-G subclass islet cell antibodies in Chinese.

Islet cell antibodies (ICAs) in Chinese (23 IDDM, 13 NIDDM and 6 non-diabetic) were characterized for immunoglobulin isotypes and light chain specificity. All ICAs were IgG-type and none were IgM- or IgA-type (median titre: 20 JDF units; range 10-160). Light chain specificity showed that 25/36 (69.4%) of the diabetic patients had lambda and kappa chains. Half of the non-diabetic subjects had both lambda and kappa chains. The rest had only lambda chains. Isotyping for ICA-IgG subclass combination with IUIS/WHO reference monoclonal antibodies in the diabetic patients gave the following: IgG1 alone-9 (25%), IgG1+2+3-8 (22.2%), IgG1+2-11 (30.6%), IgG1+3-6 (16.7%), IgG2+3-2 (5.6%). No ICA-IgG4 was detected. The frequency of the subclasses would be: IgG1-94.4%, IgG2-58.3% and IgG3-44.4%. The distribution of ICA-IgG subclasses was not affected by diabetes type (IDDM or NIDDM) or duration of disease. Of the 6 non-diabetic subjects only one had a single ICA-IgG subclass (IgG1). Serum levels of IgG subclasses in a subgroup of the patients (n = 16) were not significantly different from normal individuals. Biochemical modification of pancreatic tissue prior to ICA testing showed that acetylneuraminic acid residues, lipid and protein components were associated with binding of ICAs. The co-existence of other autoantibodies was also tested in these 42 ICA-positive sera. Twelve individuals (1 non-diabetic) had thyroid autoantibodies. Antibodies to thyrotrophin receptor, gastric parietal cell and rheumatoid factor were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive hemifacial atrophy--a report of 2 cases.

Idiopathic hemifacial atrophy (Parry-Romberg Syndrome) is characterised by progressive wasting or loss of subcutaneous tissue in half of the face, starting usually in childhood, and often associated with skin changes. Two adult onset cases are described. They did not demonstrate skin changes but one had complicated hemiplegic migraine with headaches always ipsilateral to the facial wasting.

Diabetes mellitus and its chronic complications in Singapore: an increasing healthcare problem.

We studied the prevalence of diabetes mellitus in Singapore and compared it to the study conducted ten years previously. A rise in prevalence rates from 2.0% to 4.7% was demonstrated. Impaired glucose tolerance (IGT) was studied for the first time, and a prevalence rate of 0.9% was found. Findings on chronic complications of diabetes were also reported. A high frequency of coronary heart disease and hypertension were detected in both diabetic and IGT subjects. Obesity and hyperlipidaemia were identified as important risk factors. This study demonstrates the scope and impact of diabetes mellitus as a major healthcare problem in Singapore. Strategies directed at prevention and control of this disease needs to be implemented so as to check its rising trend.

Physical activity in Chinese, Malays and Indians in Singapore.

A population based survey has measured levels of physical activity by questionnaire in persons aged 18 to 69 years in Singapore. Levels of physical activity were classified into high, medium and low based on activity in leisure and at work. The only ethnic difference was that for males a higher proportion were classified as "high" activity in Malays (24.8%) than Chinese (16.0%) and Indians (18.1%). For the overall 18 to 69 age group, it was found that for males, the proportions in the "low" category were Chinese 80%, Malays 70% and Indians 75% while for females it was 95% in all three ethnic groups. As physical activity of sufficient intensity is important in disease prevention and health promotion, more needs to be done on educating the public in Singapore about the benefits of regular exercise.

Alcohol consumption in Chinese, Malays and Indians in Singapore.

A population based survey has measured alcohol consumption by questionnaire in persons aged 18 to 69 years in Singapore. The majority were "occasional/none" drinkers, being males (Chinese 87%, Malays 99% and Indians 80%) and females (Chinese 98%, Malays 100% and Indians 100%). "Heavy" consumption was uncommon in males (Chinese 0.6%, Malays 0% and Indians 1.3%) and absent in females, while "heavy/moderate" drinking was males (Chinese 5.7%, Malays 0.5% and Indians 3.8%) and females (Chinese 0.3%, Malays 0% and Indians 0%). For males, "light" drinking was highest in Indians (15.9%), then Chinese (7.8%) and then Malays (0.5%). This survey indicates that alcohol consumption is not yet a major public health problem in Singapore.

Obesity and body mass indices in Chinese, Malays and Indians in Singapore.

A population based cross-sectional survey has measured body mass indices (BMIs) in Singapore and compared their means and the proportions who are overweight and obese amongst Chinese, Malays and Indians. For males there was little ethnic differences; for the 18-69 age group, the age-adjusted mean BMIs being Chinese 22.3, Malays 23.1 and Indians 22.5. However for females, Malays and Indians were considerably more obese than Chinese; for the 18-69 age group the age-adjusted mean BMIs in Malays (25.1) and Indians (24.6) were significantly greater (p less than 0.001) than in Chinese (22.2). The proportions categorised as overweight or obese (BMI equal to or more than 26 in males and 25 in females) were males (Chinese 16.7%, Malays 22.4%, and Indians 14.0%) and females (Chinese 21.2%, Malays 51.5%, and Indians 42.0%). Health education on the harmful effects of obesity should be targeted especially on Malay and Indian females.

Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. II. Differences in risk factor levels.

STUDY OBJECTIVE: The aim of the study was to examine cardiovascular risk factors to see how these might explain differences in cardiovascular disease mortality among Chinese, Malays, and Indians in the Republic of Singapore. DESIGN: The study was a population based cross sectional survey. Stratified systematic sampling of census districts, reticulated units, and houses was used. The proportions of Malay and Indian households were increased to improve statistical efficiency, since about 75% of the population is Chinese. SETTING: Subjects were recruited from all parts of the Republic of Singapore. SUBJECTS: 2143 subjects aged 18 to 69 years were recruited (representing 60.3% of persons approached). There were no differences in response rate between the sexes and ethnic groups. MEASUREMENTS AND MAIN RESULTS: Data on cardiovascular risk factors were collected by questionnaire. Measurements were made of blood pressure, serum cholesterol, low and high density lipoprotein cholesterol, fasting triglycerides and plasma glucose. In males the age adjusted cigarette smoking rate was higher in Malays (53.3%) than in Chinese (37.4%) or Indians (44.5%). In both sexes, Malays had higher age adjusted mean systolic blood pressure: males 124.6 mm Hg v 121.2 mm Hg (Chinese) and 121.2 mm Hg (Indians); females 122.8 mm Hg v 117.3 mm Hg (Chinese) and 118.4 mm Hg (Indians). Serum cholesterol, low density lipoprotein cholesterol and triglyceride showed no ethnic differences. Mean high density lipoprotein cholesterol in males (age adjusted) was lower in Indians (0.69 mmol/litre) than in Chinese (0.87 mmol/litre) and Malays (0.82 mmol/litre); in females the mean value of 0.95 mmol/litre in Indians was lower than in Chinese (1.05 mmol/litre) and Malays (1.03 mmol/litre). Rank prevalence of diabetes for males was Indians (highest), Malays and then Chinese; for females it was Malays, Indians, Chinese. CONCLUSIONS: The higher mortality from ischaemic heart disease found in Indians in Singapore cannot be explained by the major risk factors of cigarette smoking, blood pressure and serum cholesterol; lower high density lipoprotein cholesterol and higher rates of diabetes may be part of the explanation. The higher systolic blood pressures in Malays may explain their higher hypertensive disease mortality.

Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. I. Differences in mortality.

STUDY OBJECTIVE: The aim of the study was to analyse differences in mortality from the main cardiovascular diseases (ischaemic heart disease, hypertensive disease, and cerebrovascular disease) among Chinese, Malays, and Indians in Singapore. DESIGN: The study was a survey using national death registration data in Singapore for the five years 1980 to 1984. The underlying cause of death, coded according to the ninth revision of the International Classification of Diseases, was taken for the analyses. SETTING: The study was confined to the independent island state of Singapore, population 2.53 million (Chinese 76.5%, Malays 14.8%, Indians 6.4%, Others 2.3%). Death registration is thought to be complete. SUBJECTS: All registered deaths in the age range 30-69 years during the study period were analysed by ethnic group. MEASUREMENT AND MAIN RESULTS: Indians had higher mortality from ischaemic heart disease than the other ethnic groups in both sexes, with age-standardised relative risks of Indian v Chinese (males 3.8, females 3.4), Indian v Malay (males 1.9, females 1.6), and Malay v Chinese (males 2.0, females 2.2). The excess mortality in Indians declined with age. For hypertensive disease Malays had the highest mortality, with age-standardised relative risks of Malay v Chinese (males 3.4, females 4.4), Malay v Indian (males 2.0, females 2.5), and Indian v Chinese (males 1.6, females 1.6). For cerebrovascular disease there was little ethnic difference except for lower rates in Chinese females, with age-standardised relative risks of Malay v Chinese (males 1.1, females 1.9), Malay v Indian (males 1.0, females 1.1), and Indian v Chinese (males 1.1, females 1.7). CONCLUSIONS: There are significant differences in mortality from the three main cardiovascular diseases in the different ethnic groups in Singapore.

IgG-class insulin autoantibodies in autoimmune thyroid disease.

We studied the incidence of insulin autoantibodies (IAA) in 97 patients with autoimmune thyroid disease with an enzyme-linked immunosorbent assay. The sera were also tested for islet cell antibodies (ICA) and thyrotropin receptor antibodies (TRAb). IAA as assessed by a standard deviation score were present in 7 patients (7.2%). None of the patients were seropositive for ICA. Data from this random sampling and a retrospective study of 12 patients on antithyroid drug treatment indicated that the presence of IAA was not associated with TRAb.

Relative predispositional effects (RPEs) of marker alleles with disease: HLA-DR alleles and Graves disease.

A method is described to reveal the relative predispositional effects (RPEs) (predisposing, protective, or neutral) of the HLA alleles or of any other marker system that is associated with a disease. When the disease is associated with two or more alleles of a locus, the RPE method identifies the associations sequentially according to their strength; thus the problem that a strong association with one allele can create misleading deviations in the frequencies of other alleles is alleviated. Using this method, we have examined the relative effects of HLA-DR alleles in susceptibility to Graves disease in the Caucasian population. The well-established positive association with DR3 was confirmed as the strongest effect. In addition, a negative association was found between DR5 and Graves disease. The reduced frequency of DR5 among patients is statistically significant and is not a result of the increase in DR3. Finally, when patients were divided according to the presence or absence of eye disease, the latter showed a significant increase in the frequency of DR4. With family data, linkage to HLA of Graves disease was established in both Caucasian and Chinese families by the sib-pair method.

HLA Bw46 and DR9 associations in Graves' disease of Chinese patients are age- and sex-related.

The HLA-A, -B antigens in 159 Chinese patients with Graves' disease were compared with those of 330 controls. The HLA-DR antigens of the patients were also studied in 100 normals. Analysis of the increased prevalence of Bw46, according to the sex and age of onset of disease of the patients, showed that the strong association of Bw46 resided with male patients (n = 58), Pc = 0.0000052, RR = 4.2. Although the frequency of Bw46 was also increased in female patients (n = 101), it was statistically not significant. For the DR9 antigens, the strong association with male patients was also observed, viz. Pc = 0.019, RR = 3.2. Males also had higher risks of Graves' disease if they had homozygous Bw46 at presentation. Further analysis by age of onset of disease revealed the segregation of significant association with Bw46 for the males at 1-19 yr, Pc = 0.0011, RR = 17.5 HLA associations (Bw46 and DR9) with Graves' disease in Chinese are observed primarily in males, especially those whose known ages of onset of the disease are between 1-19 yr (Bw46).