George J Miller

OPPORTUNISTIC LYMPHOPROLIFERATIONS ASSOCIATED WITH EPSTEIN-BARR VIRAL DNA IN INFANTS AND CHILDREN WITH AIDS

Two types of lymphoproliferative disease associated with Epstein-Barr viral (EBV) DNA--central-nervous-system lymphoma and chronic lymphocytic interstitial pneumonitis (LIP)--were recognised in children with human T-lymphotropic virus type III/lymphadenopathy virus infection and the acquired immunodeficiency syndrome (AIDS). Eight of ten lung biopsy specimens from children with LIP contained EBV DNA. EBV DNA was not identified in lung biopsy specimens with Pneumocystis carinii, cytomegalovirus, or atypical mycobacteria but without LIP, nor was EBV found in lung biopsy specimens from five adults with AIDS. Children with these EBV-associated complications had raised serum antibody titres to the replicative EBV antigens, but most of them lacked antibody to the component of the EB nuclear antigen encoded by the Bam HI K fragment. EBV-associated lymphoproliferative disease is a common and important complication of childhood AIDS.

Estrogen Receptor α Gene Variation and the Risk of Stroke

Background and Purpose— Estrogen receptor α (ESR1) gene variation is associated with a range of important estrogen-dependent characteristics, including responses of lipid profile and atherosclerotic severity to hormone replacement therapy, coronary heart disease risk, and migraine. The roles that reproductive steroids play in cerebrovascular pathophysiology and ischemia are an important area of investigation. Given that there is a significantly higher risk of myocardial infarction among men with the CC genotype (PP of PvuII) of c.454-397T>C (rs2234693), we asked whether this genotype is associated with a higher risk of stroke. Methods— Relative risk of stroke by genotype was determined in 2709 participants of the Second Northwick Park Heart Study, white males with a mean baseline age 56 years and follow up 10.5 years. Results— Compared with participants with the ESR1 c.454-397CT or TT genotype, those with the CC genotype had a relative risk of stroke of 1.92 (95% confidence interval, 1.06 to 3.48, P=0.03) after adjustment for age, primary care practice; additional adjustment for body mass index, serum cholesterol and triglyceride levels, hypertension, diabetes, and smoking status. Exclusion of stroke cases with coronary heart disease gave results that were essentially unchanged. Conclusions— In this study, subjects with the common ESR1 c.454-397CC genotype have a substantial increase in risk of stroke. In another publication, other ESR1 variation was associated with migraine. We thus hypothesize that estrogen receptor variation may provide a basis for the established relationship among estrogens, migraine, and stroke.

Estrogen Receptor α Gene Variation Is Associated With Risk of Myocardial Infarction in More Than Seven Thousand Men From Five Cohorts

Understanding the mechanisms by which estrogens affect cardiovascular disease risk, including the role of variation in the gene for estrogen receptor α (ESR1), may be key to new treatment strategies. We investigated whether the CC genotype at ESR1 c.454-397T>C is associated with increased risk among men. Study of more than 7000 whites in 5 cohorts from 4 countries provided evidence that genotype CC, present in roughly 20% of individuals, is a risk factor for nonfatal acute myocardial infarction (odds ratio=1.44; P<0.0001), after adjustment for established cardiovascular risk factors. After exclusion of younger subjects from 2 cohorts, because of age interaction, the odds ratio increased (to 1.63).

Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

The impact of the UCP2 −866G>A and UCP3 −55C>T variants on prospective risk of type 2 diabetes was examined over 15 years in 2,936 healthy middle-aged men (mean age 56 years). Conversion to diabetes (n = 169) was associated with higher BMI, blood pressure, cholesterol, triglycerides and C-reactive protein. The hazard ratio (HR) for diabetes of a BMI >30 kg/m2 was 3.96 (95% CI 2.87–5.47). Homozygosity for the UCP2A or UCP3T alleles accelerated the onset of diabetes, with significant differences in risk of diabetes at 10 years (HR [95% CI] UCP2AA vs. GA+GG 1.94 [1.18–3.19], P = 0.009; UCP3TT vs. CC+ CT 2.06 [1.06–3.99], P = 0.03) but less so at 15 years (UCP2AA 1.42 [0.92–2.19], P = 0.1; UCP3TT 1.57 [0.87–2.04], P = 0.13). Men who were homozygous for both UCP2AA and UCP3TT (1.5% of men) had a risk for diabetes at 10 years of 4.20 (1.70–10.37), P = 0.002. These genotype effects were additive with obesity, and men with a BMI >30 kg/m2 and this genotype combination had a 10-year risk of diabetes of 19.23 [5.63–63.69], P < 0.0001. Functional promoter variants UCP2 and UCP3 increase the prospective risk of diabetes. Although the mechanism of the UCP2 effect is likely to be caused by increased expression in the pancreas and subsequent reduced insulin secretion, the mechanism of the UCP3 effect is currently unknown. Both effects are exacerbated by obesity.

Apolipoprotein AIV Gene Variant S347 Is Associated With Increased Risk of Coronary Heart Disease and Lower Plasma Apolipoprotein AIV Levels

Abstract— The impact of common variants in the apolipoprotein gene cluster (APOC3-A4-A5) on prospective coronary heart disease (CHD) risk was examined in healthy UK men. Of the 2808 men followed over 9 years, 187 had a clinically defined CHD event. Examination of 9 single nucleotide polymorphisms (SNPs) in this group revealed that homozygotes for APOA4 S347 had significantly increased risk of CHD [hazard ratio (HR) of 2.07 (95%CI 1.04 to 4.12)], whereas men homozygous for APOC3 1100T were protected [HR 0.28 (95%CI 0.09 to 0.87)]. In stepwise multiple regression analysis, after entering all the variants and adjusting for established risk factors APOA4 T347S alone remained in the model. Using all nine SNPs, the highest risk-estimate haplotypes carried APOA4 S347 and rare alleles of the two flanking intergenic markers. The protective effect of APOC3 1100T could be explained by negative linkage disequilibrium with these alleles. To determine the association of APOA4 T347S with apoAIV levels, the relationship was examined in 1600 healthy young European men and women. S347 homozygotes had significantly lower apoAIV plasma levels (13.64±0.59 mg/dL) compared with carriers of the T347 allele (14.90±0.12 mg/dL) (P =0.035). These results demonstrate that genetic variation in and around APOA4, independent of the effects of triglyceride, is associated with risk of CHD and apoAIV levels, supporting an antiatherogenic role for apoAIV.

The factor VII activating protease G511E (Marburg) variant and cardiovascular risk

A previous study had shown a strong relationship between a variant in factor VII activating protease (FSAP G511E) and advanced carotid atheroma. In-vitro, the variant has reduced fibrinolytic but normal pro-coagulant activity, which may constitute a prothrombotic state. The current study has addressed risk for coronary heart disease in a prospective study of cardiovascular disorders (Northwick Park Heart Study II). An interactive effect upon risk was found between the 511E allele and elevated levels of cholesterol and triglyceride. Fibrinogen could substitute for triglyceride levels in this risk-interaction analysis. The findings support the proposal that the FSAP 511E allele exacerbates atherosclerosis or its clinical sequelae.

LUNG-FUNCTION OF HEALTHY BOYS AND GIRLS IN JAMAICA IN RELATION TO ETHNIC COMPOSITION, TEST EXERCISE PERFORMANCE, AND HABITUAL PHYSICAL-ACTIVITY

Miller, G. J., Saunders, M. J., Gilson, R. J. C., and Ashcroft, M. T. (1977).Thorax, 32, 486-496. Lung function of healthy boys and girls in Jamaica in relation to ethnic composition, test exercise performance, and habitual physical activity. The relationships of forced expiratory volume and forced vital capacity on height, age, sex, area of residence, and ethnic composition were assessed in 622 children in Jamaica. Rural children in hill-farming communities were judged to have a higher habitual physical activity than urban children. Allowing for differences in body size, forced vital capacity averaged 3% greater in rural children than in urban children, 7% less in girls than in boys, and 16% greater in children of European origin than in children of African descent. Lung volumes, indices of gas transfer, and submaximal-exercise responses were measured in a subgroup of 108 children of African descent believed to be of common genetic stock. Total lung capacity and vital capacity averaged respectively 6% greater and 7% greater in rural than in urban children of equal height but residual volume and transfer factor did not differ significantly between localities. Rural children had a lower average cardiac frequency during test exercise than did urban children. Sex differences and locality differences in vital capacity and total lung capacity disappeared when allowance was made for standardised exercise cardiac frequency. At standard body size and age transfer factor increased with decreasing cardiac frequency for standard work. The results suggest an harmonious development of the cardiac and respiratory components of the oxygen transport system, consonant with the demand for muscular work. Increased habitual physical activity and improved exercise performance appear to be associated with increases in vital capacity, total lung capacity, and transfer factor.

A community survey of respiratory disease among East Indian and African adults in Guyana

The belief that chronic bronchitis is more prevalent among Indians than Africans in the Caribbean area was investigated by a community survey in Guyana. Respiratory symptoms were assessed by a standard questionnaire, ventilatory capacities were measured, and chest radiographs were taken of some 800 African and Indian men and women aged 35 to 54 years living in adjacent and similar communities. Histories of morning cough, chronic cough, morning phlegm, and chronic phlegm (chronic bronchitis) were more common in Indians than Africans. Although these respiratory symptoms were much more common in smokers than non-smokers, the higher prevalence rates in Indians could not be explained by smoking habits which were similar in the two races. Chronic bronchitis occurred in 17·3% of Indian and 2·4% of African male smokers and in 16·1% and 2·2% of Indian and African female non-smokers respectively. Judging by the history, lung function, and clinical signs, chronic bronchitis was more severe in Indians than Africans. The condition was more common among field labourers on sugar estates but, although the majority of field labourers were Indian, this occupational difference only partially explained the difference in prevalence between Indians and Africans. Indians, for reasons unknown, appear to have a greater susceptibility than Africans to chronic bronchitis.

High density lipoprotein cholesterol concentration as a predictor of coronary heart disease in West Indian men.

STUDY OBJECTIVE--The aim of the study was to determine whether the inverse association between high density lipoprotein cholesterol concentration and risk of coronary heart disease described in people of European stock was also present in other racial groups. DESIGN--The study was a prospective population survey. Cardiovascular risk factors were examined, including fasting serum lipid estimation (obtained at recruitment). SETTING--This was a community based study within a defined survey area in Trinidad. PARTICIPANTS--All men aged between 35 and 69 years within the survey area were identified and followed between 1977 and 1986. Analysis was confined to those of African, Asian Indian, and mixed descent who were free of coronary heart disease at entry (n = 960, 69% of age eligible men in the survey population). MEASUREMENTS AND MAIN RESULTS--64 men developed coronary heart disease during the study period. A strong inverse curvilinear relation was found between high density lipoprotein cholesterol and coronary heart disease incidence (p less than 0.005), independent of age or other relevant characteristics including low density lipoprotein cholesterol. CONCLUSIONS--A low serum concentration of high density lipoprotein cholesterol is a risk factor for coronary heart disease in non-whites as well as in whites.

Reappraisal of cardiovascular surveys in Jamaica. Use of submaximal exercise tests for clinical investigation.

Assertions that idiopathic cardiomegaly or an obscureform of ischaemic heart disease are common in Jamaica have been based on a high prevalence in community surveys of unexplained electrocardiographic abnormalities and ofpositive responses to a questionnaire for ischaemic heart pain. Thirty-one men, aged 42-62 years, in whom these abnormalities had been found in a previously surveyed rural community, were recalledfor clinical examination and exercise tests and compared with I8 control subjects. No clinical abnormalities were found. The heart rates during standard work and maximum oxygen uptake ofsubjects and controls were similar, and indicated, on average, excellent exercise performance consistent with their heavy physical activity in daily life. None complained of chest pain at near maximal exertion, and the previous diagnosis of angina pectoris