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Sarcoidosis is a granulomatous disorder of unknown etiology, associated with an accumulation of CD4+ T cells and a TH1 immune response. Since previous studies of HLA associations with sarcoidosis were limited by serologic or low-resolution molecular identification, we performed high-resolution typing for the HLA-DPB1, HLA-DQB1, HLA-DRB1, and HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled biopsy-confirmed cases (736 total) from 10 centers in the United States. Seven hundred six (706) controls were case matched for age, race, sex, and geographic area. We studied the first 474 ACCESS patients and case-matched controls. The HLA-DRB1 alleles were differentially distributed between cases and controls (P<.0001). The HLA-DRB1*1101 allele was associated (P<.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. HLA-DRB1-F(47) was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility for sarcoidosis and, in contrast to chronic beryllium disease, a non-E(69)-containing allele, HLA-DPB1*0101, conveyed most of the risk. Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB1*1501 was differentially associated with sarcoidosis (P<.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB1*0401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites). These studies confirm a genetic predisposition for sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.

A cohort of 215 sarcoidosis patients from the ACCESS study underwent a clinical evaluation at study enrollment and two years later. Approximately 80% of subjects had an improved or stable FVC, FEV1, chest radiograph determined by Scadding stage, and dyspnea scale. African-Americans had less improvement in FVC than Caucasians (p = 0.04). Patients with erythema nodosum at presentation were more likely to have improvement in the chest radiograph at two-year follow-up (p = 0.007). Patients with a lower annual family income were more likely to worsen with respect to dyspnea (p = 0.01) and more likely to have new organ involvement at two-year follow-up (p = 0.045). The development of new organ involvement over the two year follow-up period was more common in African-Americans compared to Caucasians (p = 0.002) and more likely in those with extrapulmonary involvement at study entry (p = 0.003). There was an excellent concordance between changes in FVC and FEV1 over the two-year period. However, changes in FVC alone were inadequate to describe the change in pulmonary status of the patients, as changes in chest radiographic findings or the level of dyspnea did often but not always move in the same direction as FVC. In conclusion, data from this heterogeneous United States sarcoidosis population indicate that sarcoidosis tends to improve or remain stable over two years in the majority of patients. Several factors associated with improved or worse outcome over two years were identified.

Allelic loss is a common occurrence in head and neck tumors and has been shown to be an independent predictor of prognosis; however, the relationship between allelic loss and tumor pathology is not well-known. We studied 139 patients who were newly diagnosed with squamous cell cancer of the head and neck to determine whether tumor pathology was correlated with allelic loss at one or more of eight different regions on chromosomes 3p, 5q, 8p, 9p, 10p, 18q, and 21q. At each chromosomal region, loss of heterozygosity at any one of three or four highly polymorphic microsatellite markers that spanned the region in question was considered evidence for allelic loss. A pathologist scored all tumors for seven tumor pathology and host interface parameters. Mean allelic loss across all eight regions was associated with mitotic index (P =.034) and inflammatory response (P =.005). For allelic loss at specific chromosomal regions, the most statistically significant trends were between overall tumor grade and 3p14.2-p13 (P =.014), mitotic index and 3p24.3-p14.3 (P =.026), 9p24.2-p21 (P =.004) and 18q12.3-q23 (P =.009), inflammatory response and 3p14.2-p13 (P =.008) and 9p24.2-p21 (P =.001), desmoplastic response and 9p24.2-p21 (P =.009), and pattern of invasion and 21q21-q22.2 (P =.015). Our results suggest that genes involved in tumor suppression and oncogenesis can potentially be classified based on specific pathologic events in head and neck squamous cell carcinogenesis that they modify.

Sarcoidosis, in the United States, more commonly and severely affects African Americans. HLA associations with sarcoidosis have been reported, but most studies used case-control designs, which may produce biased results because of population stratification. We examined transmission of HLA-DQB1 alleles in 225 African American families with at least one offspring with sarcoidosis. Of five low-resolution HLA-DQB1 alleles, *02 and *06 showed significant deviation in transmission patterns to affected offspring. High-resolution typing of these allelic subsets revealed that HLA-DQB1*0201 was transmitted to affected offspring half as often as expected (p = 0.001), whereas DQB1*0602 was transmitted to affected offspring about 20% more often than expected (p = 0.029). Examining interactions between *0201 and *0602 alleles and environmental exposures showed that *0602 varied little with respect to exposure, but sarcoidosis risk associated with *0201 often depended on exposure status. Alternatively, the *0602 allele in affected probands was associated with radiographic disease progression, but the *0201 allele showed no significant correlation with phenotype. Major differences in the amino acid sequences encoded by *0201 and *0602 alleles exist, which may explain the differential effects these alleles have on sarcoidosis susceptibility and progression in African Americans.

Objectives: To determine whether certain occupations and occupationally related exposures were associated with a history of sarcoidosis in African-American siblings., Methods: We collected occupational data from 921 African Americans in 273 sibships that had been identified through a sarcoidosis case. Among the 648 siblings of sarcoidosis index cases enrolled, 30 (4.6%) also had a history of sarcoidosis. A detailed job history was obtained for any job held for > or = 6 months throughout the subject's life., Results: Having a usual occupation in education (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.07 to 4.44), in metal machining (OR, 7.47; 95% CI, 1.19 to 47.06), and ever working in metalworking, not elsewhere classified (OR, 2.05; 95% CI, 1.14 to 3.70) were associated with increased sarcoidosis risk. Occupations ever held in the transportation services industry (OR, 12.71; 95% CI, 1.32 to 122.56) and usual occupations in the retail trade industry (OR, 0.49; 95% CI, 0.27 to 0.88) also were associated with sarcoidosis risk. Specific occupational exposures that were associated with sarcoidosis included titanium (OR, 3.15; 95% CI, 1.02 to 9.68) and vegetable dust (OR, 1.82; 95% CI, 1.01 to 3.27), and indoor exposure to high humidity (OR, 1.51; 95% CI, 1.13 to 2.02), water damage (OR, 1.50; 95% CI, 1.11 to 2.03), or musty odors (OR, 1.78; 95% CI, 1.32 to 2.40) for > 1 year., Conclusion: Individuals who work in occupations with potential metal exposures or in workplaces with high humidity may be at an increased risk for sarcoidosis, but the complexity of occupationally related exposures makes it difficult to identify specific agents by using job titles as a surrogate for exposure. A more detailed exposure assessment of such jobs, along with the incorporation of genetic risk factors, should help to uncover the complex etiology of sarcoidosis.

The DNA sequence data provided by the Human Genome Project offer great promise in the prevention and treatment of lung disease in the new millennium. Making sense of these data with regard to how they relate to disease susceptibility and progression will require new and innovative genetic epidemiological approaches. Although tried and true methodologies such as case-control comparisons are still useful, a better understanding of genotype-phenotype relationships in lung disease can be gained by comparisons across similar diseases, such as the HLA-DPB1 associations observed in both berylliosis and sarcoidosis. Study of gene-environment and gene-gene interactions in lung disease is critical to the understanding of pathogenic processes in the lung such as localized inflammation and malignant transformation. Oligonucleotide microarray studies of gene expression in the lung are well under way and promise to uncover numerous previously unknown genetic factors involved in lung pathogenesis. One of the greatest challenges facing genetic epidemiologists studying lung disease in the new millennium will be how to translate the myriad results from microarray and similar data-driven technologies into information useful to the medicine practiced in pulmonary clinics.

Increasing morbidity due to asthma in children and antimicrobial resistance among human pathogens are both major public-health concerns. Frequent use of antibiotics during childhood might be a factor underlying the rising severity and prevalence of asthma and other allergic disorders. The objective of the study was to determine if pediatric patients with asthma or allergic rhinitis have an altered rate of group A beta hemolytic streptococcal (GABHS) tonsillopharyngeal infection which might support any change in guidelines for antibiotic prescription. A prospective analysis of all patients presenting a clinical feature of GABHS pharyngitis with a sore throat in two pediatric clinics located in Detroit, MI, USA and San Antonio de Areco, Buenos Aires, Argentina. Eligible patients aged between 2 and 18 years were screened for the presence of asthma and/or allergic rhinitis and administered a test (rapid strep test) and throat culture to determine GABHS infection. At the Redford Medical Center, Detroit, 500 patients met the eligibility criteria, with 168 (33.6%) having a positive strep test. At the San Antonio de Areco's Hospital, in a rural area 100 km away from Buenos Aires, 188 patients met the eligibility criteria, with 41 (21.8%) having a positive strep test or GABHS throat cultures. In both the Detroit [odds ratio (OR) = 1.36; 95% confidence interval (CI) 0.72-2.57] and Buenos Aires clinics (OR = 0.50; 95% CI 0.23-1.07), patients with asthma or allergic rhinitis were not at an increased risk for true GABHS tonsillopharyngeal infections when compared with the general pediatric population. These results suggest that children with asthma do not differ from the normal population in their risk of developing GABHS tonsillopharyngeal infection and should not be liberally prescribed antibiotics.

Investigators have intensively evaluated the major histocompatibility (MHC) complex for sarcoidosis susceptibility genes with the majority of reports implicating the human leukocyte antigen (HLA)-DRB1 gene. Because most studies have been performed in white and Asian populations, we sought to determine which MHC genes might be risk factors for sarcoidosis in African Americans. We genotyped six microsatellite markers spanning 11.6 megabases that overlapped the MHC region on chromosome 6p21-22 in 225 nuclear families ascertained by African American probands with a history of sarcoidosis. Using a family-based association methods approach, we performed multiallelic tests of association between each marker and sarcoidosis. A statistically significant association was detected between sarcoidosis and the DQCAR marker (p = 0.002) less than two kilobases telomeric from the HLA-DQB1 gene. Typing two additional markers in this region revealed that DQCAR-G51152 haplotypes, spanning a 38-kilobase region across the HLA-DQB1 gene, were associated with sarcoidosis on a global level (p = 0.022). Analysis of individual DQCAR and G51152 alleles showed that the DQCAR 178 (expected = 21.0; observed = 10; p = 0.0005) and G51152 217 (expected = 25.6; observed = 14; p = 0.0009) alleles were transmitted to affected offspring less often than expected; whereas the DQCAR 182 allele was transmitted more often than expected (expected = 52.6; observed = 66; p = 0.002). Our results indicate that HLA-DQB1 and not HLA-DRB1 plays an important role in sarcoidosis susceptibility in African Americans. Identification of the specific HLA-DQB1 alleles that influence sarcoidosis susceptibility in African Americans and the study of their antigenic-binding properties may reveal why African Americans suffer disproportionately from this disease.

Objective: We aimed to determine if gender differences exist in the selection and training of female and male gastroenterology fellows., Methods: One hundred seventy-six of 218 training program directors returned an 18-question survey about their programs, including leave policies, training, and prevalence of female faculty. Two cohorts of graduating trainees from 1993 and 1995 (N = 393) returned anonymous surveys regarding their training program experiences, demographics, and business training., Results: Female gastroenterology trainees are more likely to choose programs according to parental leave policies (p < 0.05), female faculty (0.2990 correlation coefficient), and "family reasons" (p < 0.04) than the male trainees. Female trainees were more likely to remain childless (p < 0.001) or have fewer children at the end of training despite marital status not unlike their male colleagues. Female trainees altered their family planning because of training program restrictions (20% vs 7%, p < 0.001). They perceived gender discrimination (39%) and sexual harassment (19%) during gastroenterology training. Trainees of both sexes had mentorship during training (65% vs 71%, ns); female trainees were more likely to have an opposite sex mentor (71% vs 3.4%) despite an almost 50% prevalence of female full-time and clinical faculty. Female trainees were apt to be less trained in advanced endoscopy (p < 0.005). Trainees of both sexes were influenced by the changing health care environment in career choice (49% vs 42%, ns); neither gender felt adequately prepared for the business aspects of gastroenterology., Conclusion: Alterations in gastroenterology training are needed to attract qualified female applicants. New graduates of both sexes lack practice management education.

Objectives: To better understand the effect of admixture on long range linkage disequilibrium (LD), we characterized extended LD in gene-rich regions of an African-American population., Methods: Approximately 290 cM of chromosomes 1, 3, 6, 11-17, 20 and 22 were scanned using 109 polymorphic microsatellite markers spaced an average of 3 cM apart. Disequilibrium between loci (D') was based on maximum-likelihood estimates of haplotype frequencies computed for 200 unrelated African Americans., Results: Mean D' values were highest on chromosomes 6p23-p21.3 (D' = 0.33) and 15p22.2-p25.3 (D' = 0.34), and lowest on chromosome 12p11.2-q14 (D' = 0.21). Overall, the variance in LD among chromosomes accounted for approximately two-thirds of the total LD variance. Of the 434 locus pairs spaced between 0.3 and 38.7 cM apart, there was no detectable correlation between LD and recombination distance and a weak negative correlation between LD and physical distance (r(s) = -0.12; p = 0.031). For the 192 intrachromosomal locus pairs where allele frequency data were available from the Centre d'Etude du Polymorphisme humain (CEPH), we found a statistically significant positive correlation between LD and the allelic frequency differences (delta) between the African-American study population and Caucasian reference CEPH population (r(s) = 0.53; p < 0.0001). The correlation between LD and both recombination and physical distance was markedly increased for locus pairs with high delta levels., Conclusions: Our results suggest that recent Caucasian admixture maintains a high level of long range LD in African Americans on a genomic scale, and selected markers with large African American/Caucasian delta levels may be useful in association studies., (Copyright 2002 S. Karger AG, Basel)

Despite reports of familial clustering of sarcoidosis, little empirical evidence exists that disease risk in family members of sarcoidosis cases is greater than that in the general population. To address this question, we estimated sarcoidosis familial relative risk using data on disease occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age, sex, race, and geographically matched cases and controls who participated in the multicenter ACCESS (A Case-Control Etiology Study of Sarcoidosis) study from 1996 to 1999. Familial relative risk estimates were calculated using a logistic regression technique that accounted for the dependence between relatives. Sibs had the highest relative risk (odds ratio [OR] = 5.8; 95% confidence interval [CI] = 2.1-15.9), followed by avuncular relationships (OR = 5.7; 95% CI = 1.6-20.7), grandparents (OR = 5.2; 95% CI = 1.5-18.0), and then parents (OR = 3.8; 95% CI = 1.2-11.3). In a multivariate model fit to the parents and sibs data, the familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI = 2.3-9.7). White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p = 0.098). In summary, a significant elevated risk of sarcoidosis was observed among first- and second-degree relatives of sarcoidosis cases compared with relatives of matched control subjects.

Background: The etiology of Parkinson's disease (PD) is considered to have a strong environmental component, but relatively few studies have investigated the potential association between occupation and the disease., Methods: In a population-based case-control study, we collected comprehensive occupational histories from all study participants, 144 case and 464 control subjects., Results: Chi-square analysis revealed that working in an agricultural occupation increased estimated PD risk (OR = 1.74; 95% CI = 0.85, 3.60). In contrast, a history of ever working in a service occupation was negatively associated with PD risk (OR = 0.69; 95% CI = 0.47, 1.00). Risk estimates were close to one for specific service occupations. Adjusted odds ratios for all non-service occupational and industrial categories were similar, and working in a service occupation was the only significant inverse predictor of PD risk., Conclusions: Future investigations focusing on lifestyle factors and environmental exposures within the agricultural and service occupational categories are warranted., (Copyright 2001 Wiley-Liss, Inc.)

While sarcoidosis is thought to aggregate in families, little is known about the risk to relatives of sarcoidosis patients. To estimate the familial risk ratio (lambda) of sarcoidosis in sibs and parents of cases, the authors studied 179 African-American families ascertained through an index sarcoidosis case diagnosed at Henry Ford Hospital in Detroit, Michigan. Among those relatives enrolled between 1997 and 1999, 12 of 327 (3.7%) sibs and 11 of 161 (6.8%) parents reported a history of sarcoidosis. The lambda in this sample of relatives, estimated by computing an age, sex, and race standardized incidence ratio, was 2.24 (95% confidence interval: 1.16, 3.92) for sibs and 2.82 (95% confidence interval: 1.41, 5.05) for parents. For sibs and parents combined, lambda was 2.49 (95% confidence interval: 1.58, 3.73). Results stratified by proband characteristics indicated that lambda was greater for relatives of younger (lambda = 2.93, 95% confidence interval: 1.52, 5.12) and male (lambda = 3.98, 95% confidence interval: 1.99, 7.12) probands. A higher lambda was also found for male family members and sibs born later in the birth order. A Monte Carlo method was also used to estimate lambda, with similar results obtained. Overall, these results indicate that, in African Americans, sibs and parents of sarcoidosis cases have about a 2.5-fold increased risk for sarcoidosis and that heterogeneity in disease risk may exist among family members.

Objective: To analyze the effect of delay times on racial differences in thrombolysis for acute myocardial infarction., Background: Lower rates of thrombolytic therapy in blacks with acute myocardial infarction have recently been reported, but the reasons for this disparity are unknown. We hypothesized that lower rates of thrombolysis are caused by delay in presentation after symptom onset., Methods: From November 1992 through November 1996, consecutive patients with a first acute myocardial infarction presenting to a large, urban teaching hospital were prospectively enrolled. Delay times were determined retrospectively from review of medical records. Patients were prospectively followed up for in-hospital cardiac events and death. A multivariable regression model was built to relate presentation times and other variables to thrombolysis administration., Results: A total of 395 patients were included in the study, of which 33% were black. Symptom onset to emergency department presentation and door-to-needle times were significantly longer in blacks. Thrombolysis was administered significantly less often in blacks compared with whites (47% vs 68%, P =.001). Black race and age above 60 years were independently associated with delayed presentation and prolonged door-to-needle times. Black race, time to presentation, and non-Q-wave myocardial infarction were independently associated with not receiving thrombolysis. In-hospital mortality rates were similar in both groups., Conclusions: Blacks presented later than whites for first acute myocardial infarction. Late arrival strongly influenced the rate of thrombolysis administration. Lower rates of thrombolysis and prolonged door-to-needle times were apparent in blacks after adjustment for delay times and other clinical factors, a finding that merits further investigation.

Background: Previous studies have suggested that thrombolysis is used less often in blacks than in whites. However, whether the greater prevalence of contraindications or less specific electrocardiographic manifestations of myocardial infarction (MI) account for this difference is unclear., Methods and Results: We studied 498 consecutive patients (32% blacks) with first MI. Initial electrocardiograms were analyzed, blinded to race and outcome, for ST-segment deviation and bundle branch block to determine eligibility for thrombolysis. The relation of electrocardiographic eligibility for thrombolysis and actual use of thrombolysis in both races was explored. Among blacks, 45% received thrombolysis compared with 66% of whites (P <.001). A similar proportion of blacks and whites were eligible for thrombolysis (59% and 66% respectively, P =. 116), but 62% of electrocardiography-eligible blacks were treated with thrombolysis compared with 75% of whites (P =.016). After accounting for eligibility for electrocardiography and other clinical variables likely to affect the decision to administer thrombolysis by means of conditional logistic regression, blacks were still less likely to receive thrombolysis (relative risk 0.73; 95% confidence interval 0.55 to 0.97)., Conclusions: We conclude that the differences in thrombolysis administration to blacks and whites are not accounted for by differences in electrocardiographic presentation or other measured variables. Unmeasured differences in clinical presentation of MI may explain racial differences in thrombolysis and merits further study.

The histologic and clinical similarities between tuberculosis and sarcoidosis suggest a shared underlying pathophysiology. Human natural resistance-associated macrophage protein (NRAMP1), which is closely related to the mouse gene, has been associated with susceptibility to tuberculosis in some human populations. Given the importance of the Nramp1 gene in animal models of granulomatous disorders, the association with human tuberculosis, and the possible role of NRAMP1 in macrophage activation and function, we hypothesized that human NRAMP1 plays a role in susceptibility to sarcoidosis. We analyzed several NRAMP1 gene polymorphisms in a case-control study of 157 African American patients with sarcoidosis and 111 African American control subjects. Our results, in contrast to those in tuberculosis patients, showed that the less common genotypes were found more often in control subjects than in case patients (odds ratio, 0.48; 95% confidence interval, 0.28-0.81). In particular, one polymorphism, a (CA)(n) repeat in the immediate 5' region of the gene, was found to have a protective effect (P = 0. 014). Whereas NRAMP1 polymorphisms have been associated with increased susceptibility to tuberculosis, our results suggest that at least one NRAMP1 polymorphism may decrease susceptibility in sarcoidosis.

The recurrence-risk ratio of disease in siblings, lambdaS, is a standard parameter used in genetic analysis to estimate the statistical power for detection of a disease locus. However, the relationship between the underlying risk conferred by a disease-susceptibility allele and lambdaS has not been well described. The former is generally quantified as a genotype relative risk, gamma, and measures the ratio of disease risks between those with and those without the susceptibility genotype(s). We demonstrate that lambdaS varies significantly more with respect to gamma and the disease-allele frequency for two-locus multiplicative models than for other two-locus and for single-locus models. For the single- and two-locus dominant-inheritance models that we studied, when a disease-susceptibility allele had a frequency >/=.2, lambdaS had an upper limit of <10. In general, lambdaS values >10 are possible only under recessive inheritance, dominant inheritance with relatively rare (<5%) disease-susceptibility alleles, or when two or more disease loci have alleles acting either epistatically or multiplicatively. We introduce the idea of a restricted sib recurrence-risk ratio (lambda*S) estimated by restriction of sibships to those ascertained through a proband who already has a putative high-risk allele. A lambda*S larger than the lambdaS value estimated from randomly selected probands can serve as an indirect way of testing whether the posited susceptibility allele increases disease risk. Our results demonstrate that a lambdaS of 2-3 may portend successful mapping for a variety of genetic models but that, for some two-locus models, a lambdaS as high as 10 does not guarantee underlying genes easily mapped by linkage.

We have studied 215 male patients (aged 45-97 years) whose sole cytogenetic abnormality was clonal loss of the Y chromosome in metaphase cells from unstimulated cultures. The patients comprised a control group with no evidence of hematologic disease and four disease case groups: 1) myelodysplastic syndrome (MDS), refractory anemia, refractory anemia with excess blasts (RAEB), RAEB in transformation, and chronic myelomonocytic leukemia; 2) acute myelogenous leukemia; 3) myeloproliferative disorder (MPD), chronic granulocytic leukemia, and polycythemia vera; and 4) B-cell lymphoma/leukemia. The frequency of cells with Y loss increased with age and was significantly greater in cases than in controls, but it was not correlated with survival or with prior therapy. The frequency of cases with a -Y clone was 6.3% of male karyotypes and represented 16.4% of all abnormal male cytogenetic reports. Much of the difference between cases and controls appears to be accounted for by a greater frequency of cases with > 75% Y loss. A value of 81% chromosome Y loss maximized the combined sensitivity (28%) and specificity (100%) for predicting disease status, but a 75% cutoff provided the best estimate of disease risk. Even in older males, if > 75% of metaphase cells are 45,X,-Y, they probably represent a disease-associated clonal population, and it is possible that the critical genetic change is not visible through the microscope. This observation is true for MDS, MPD, B-cell disease, and especially acute myelogenous leukemia. The prognostic association of Y chromosome loss for survival appears to be neutral or favorable. Genes Chromosomes Cancer 27:11-16, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Background: The occurrence of heart failure associated with an acute myocardial infarction has a strong adverse effect on long-term morbidity and mortality. The prediction and prevention of heart failure could influence these adverse events., Methods and Results: We studied 483 consecutive patients who had their first acute myocardial infarction and who were admitted within 24 hours of the onset of symptoms. Heart failure was defined as the presence of pulmonary rales or an S3 gallop, or the presence of alveolar or interstitial edema by radiograph. Baseline demographic data, determination of peak creatine phosphokinase level, echocardiographic left ventricular ejection fraction, blood pressure, and pulse were obtained. Heart failure occurred in 41.6% (201 of 483) of the patients. We observed a bimodal occurrence of heart failure with an early occurrence at admission in 4% (20 of 483) followed by a second increase beginning after the fourth day of admission in 39% of the remaining patients (181 of 463). Predictors of early heart failure were older age, diabetes mellitus, or previous cardiac symptoms, whereas the predictors of heart failure after the fourth day included the same demographic predictors in addition to a history of hypertension, male sex, increased peak creatine phosphokinase level and heart rate, and decrease in left ventricular ejection fraction. In-hospital death occurred in 5.3% compared with 1.4% (P =.012) in patients who did and did not have heart failure, respectively. The occurrence of heart failure during hospital admission also adversely affected the 18-month follow-up, with 14.9% deaths in the patients with heart failure and 6.4% in those without heart failure (P =.002)., Conclusion: Heart failure is frequently associated with acute myocardial infarction and occurs with a bimodal distribution and is associated with increased risk of death during hospitalization and during 18 months of follow-up. Predictors of early heart failure include previous medical conditions and age. The second peak occurrence can be predicted by similar characteristics in addition to increased peak creatine phosphokinase level, decreased left ventricular ejection fraction, and increased heart rate.

The pathogenesis of sarcoidosis, a multisystem granulomatous disorder, is mediated through immunoregulatory pathways. While sarcoidosis clusters in families, inherited risk factors remain undefined. In search of possible sarcoidosis susceptibility genes, we examined anonymous polymorphic genetic markers tightly linked to six different candidate gene regions on chromosomes 2q13, 5q31, 6p23-25, 7p14-15, 14q11 and 22q11. These candidate regions contain T cell receptor, interleukin (IL) and interferon regulatory factor (IRF) genes. Our study population consisted of 105 African-American sarcoidosis cases and 95 unrelated healthy controls. The allelic frequency distribution of two out of the six markers, IL-1 alpha marker (p = 0.010) on 2q13 and the F13A marker (p = 0.0006) on 6p23-25, was statistically significantly different in cases compared with controls. The two alleles most strongly associated with sarcoidosis were IL-1 alpha*137 (Odds Ratio (OR) = 2.60; 95% confidence interval (CI) = 1.36-4.98) and F13A*188 (OR = 2.42; 95% CI = 1.37-4.30). Individuals that had both of these alleles were at a six-fold increased risk for sarcoidosis (OR = 6.19; 95% CI = 2.54-15.10). Restricting the analysis to cases with at least one first or second-degree relative affected with sarcoidosis increased the OR to 15.38. IL-1 levels are elevated in sarcoidosis and the F13A marker is tightly linked to a gene that codes for a newly identified interferon regulatory factor protein (IRF-4), which is thought to play a role in T cell effector functions. Our results suggest genetic susceptibility to sarcoidosis may be conferred by more than one immune-related gene that act synergistically on disease risk.

Background: A genetic predisposition to sarcoidosis has long been postulated, although no specific susceptibility genes are known. Candidate genes for the two granulomatous inflammatory disorders with clinical similarities to sarcoidosis, Blau syndrome and Crohn's disease, have been localized to a 40 centimorgan region spanning the chromosome 16 centromere., Patients and Methods: Using a sample of 35 African-American sibling pairs, who both had clinically confirmed sarcoidosis, we tested for genetic linkage between the 16p12-q21 interval (the likely location of the Blau syndrome gene) and sarcoidosis., Results: We found no evidence for linkage to any of the eight markers we tested in the 16p12-q21 interval. Ninety percent of the 16p12-q21 region had a LOD score < -2 for a dominant gene conferring a relative risk of 3 or greater for sarcoidosis. One hundred percent of the region had a LOD score < -2 for a dominant gene with a relative risk of 3.5 or greater or recessive gene with relative risk of 2.5 or greater. Based on simulation results we could not exclude a dominant gene with relative risk < 5 at the 0.05 significance level, nor a recessive gene with relative risk < 3, over the entire 16p12-q21 interval., Conclusions: While the clinical similarities between Blau Syndrome and sarcoidosis suggest genetic homogeneity between the disorders, we found no evidence for linkage of sarcoidosis to the Blau syndrome locus. Our exclusion results suggest that the Blau Syndrome gene does not have a major effect on sarcoidosis susceptibility.

A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PD. However, more than 20 years exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83) or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD. Occupational exposure for > 20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 1.40,9.71) was also associated with the disease. No association of occupational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD.

Parkinson's disease (PD) is likely a result of both inherited and exogenous factors. In a study of 144 PD cases and 464 controls, we used PD family history as a surrogate for inherited PD susceptibility. Cases were more likely to report a first- or second-degree relative with PD: 16.0 vs. 4.3%; odds ratio (OR) = 4. 2; 95% confidence interval (CI) = 2.3-7.6. A PD family history was a greater risk factor for PD in subjects under age 70 (OR = 8.8; 95% CI = 3.4-22.8) compared with those over 70 (OR = 2.8; 95% CI = 1.3-6. 1) and in men (OR = 8.1; 95% CI = 3.4-19.2) compared with women (OR = 2.6; 95% CI = 1.1-6.0). We also tested whether a PD family history modified the effects of other PD risk factors. In subjects with a PD family history, occupational exposure to copper, lead or iron increased the risk for PD (OR = 3.0; 95% CI = 0.7-13.3), but this was not the case for those without a family history (OR = 1.1; 95% CI = 0.7-1.6). Ever smoking cigarettes was inversely associated with PD in those without a PD family history (OR = 0.6; 95% CI = 0.4-0.9), but was positively associated with PD in those with a PD family history (OR = 1.7; 95% CI = 0.5-5.9). In summary, our results suggest that a PD family history, and perhaps, therefore, an inherited susceptibility, confers a greater risk for PD in men and individuals under 70 years of age and may modify the effects of environmental risk factors for PD.

Objective: To determine whether an inverse dose-response relationship exists between cigarette smoking and PD among ever-smokers and ex-smokers., Methods: Smoking and alcohol consumption were analyzed in 144 PD patients and 464 control subjects, who were frequency matched for sex, race, and age (+/-5 years), in a population-based case-control study of men and women > or =50 years old in the Henry Ford Health System., Results: With never-smokers as the reference category, there was an inverse association between current light smokers (>0 to 30 pack-years) and PD patients (odds ratio [OR], 0.59; 95% CI, 0.23 to 1.53), and a stronger inverse association of PD with current heavy smokers (>30 pack-years; OR, 0.08; 95% CI, 0.01 to 0.62). When former >30-pack-year smokers were stratified by the interval since quitting, there was an inverse association between those who stopped >20 years ago and PD (OR, 0.86; 95% CI, 0.42 to 1.75), and a greater inverse relationship with those who stopped 1 to 20 years ago (OR, 0.37; 95% CI, 0.19 to 0.72). Alcohol consumption had no independent, significant association with PD, but heavy drinking (>10 drink-years) had a greater effect than light-moderate drinking in reducing but not eliminating the inverse association between smoking and PD., Conclusions: The inverse dose-response relationship between PD and smoking and its cessation is unlikely to be due to bias or confounding, as discussed, providing indirect evidence that smoking is biologically protective.

Occupational exposure to specific metals (manganese, copper, lead, iron, mercury, zinc, aluminum and others) appears to be a risk factor for Parkinson's disease (PD) in some, but not all, case-control studies. These epidemiological studies are reviewed. Several methodological issues that may account for the lack of unanimity of findings are discussed, and suggestions for improved case-control methodology are offered. The study of the neurological disease outcome of workers who have had long-term, well-defined occupational exposure to one or more metals is also urged, with collaborative work including industrial hygienists, occupational toxicologists, neurologists, epidemiologists and biostatisticians. Such efforts, employing state-of-the-art case and control ascertainment and enrollment from suitable population bases, neurological diagnostic rigor and exposure assessment, will help to further define the potentially important roles played by metals in PD and other neurodegenerative disorders.

Analysis of the role of candidate genes as risk factors for age-dependent hereditary conditions often ignores the importance of dependence among sibships or other family clusters for age of onset. We examined the performance of several methods of survival analysis with dependent data using Collaborative Study on the Genetics of Alcoholism families as submitted for GAW11. Additionally, an arbitrary truncation of cluster size was performed to explore the potential impact of heterogeneity of family size on the resulting inferences concerning the role of candidate genes. Our results showed substantial differences in attribution of risk to candidate genes according to whether the method utilized allowed for dependence in onset age and according to whether the sample was truncated or arbitrarily stratified. Further work needs to be done to clarify the importance of properly accounting for dependent data in age-dependent phenotypes and in integrating these methods into widely used genetic analysis computer programs.

The angiotensin-converting enzyme (ACE) has been implicated in the pathophysiology of sarcoidosis. Serum ACE levels in normal and sarcoidosis patients are influenced by an insertion (I)/deletion (D) polymorphism in the ACE gene. To elucidate the role of this ACE gene polymorphism in sarcoidosis, we conducted a case-control study in African Americans and Caucasians. The ACE gene (I/D) polymorphism did not differ between 60 Caucasian cases and 48 control subjects (p = 0.577). In contrast, a comparison of 183 African-American cases and 111 control subjects resulted in a marked difference in genotypic distributions (p = 0.005). In African Americans, the risk for sarcoidosis was 1.30 (95% confidence interval [CI] = 0.72 to 2. 36) for ID heterozygotes, and 3.17 (95% CI = 1.50 to 6.71) for deletion/deletion (DD) homozygotes. The risk associated with the DD homozygotes was even greater in African Americans when cases were restricted to those with a positive family history (odds ratio = 4. 83; 95% CI = 1.86 to 12.59). Further analyses of African-American cases showed that the ACE genotype was not associated with disease severity, extrathoracic involvement, or overall radiographic change 2 to 4 yr after diagnosis. We did find a moderate association between the II genotype and radiographic progression (OR = 2.97; 95% CI = 1.01 to 8.76). Our results suggest the ACE genotype may play a more important role in sarcoidosis susceptibility and progression in African Americans than Caucasians.

Epidemiological knowledge of sarcoidosis is based mainly on studies performed more than 30 years ago. These early case-control studies produced some interesting risk factor-disease associations, but a clear causative mechanism in sarcoidosis remains unknown. Studies in military and veteran populations showed a clear preponderance of sarcoidosis in African Americans compared with Caucasians. Our recent sarcoidosis incidence study in a racially heterogeneous population found African Americans at three- to fourfold greater risk, which was less than the 10 to 17 times greater risk previously reported. Females are consistently found at greater risk than males, although the relative risk difference generally does not exceed two. The striking racial differences and numerous reports of familial clustering suggest genetic susceptibility. We have found that familial sarcoidosis is almost three times more common in African-American (17%) than Caucasian cases (6%). Future genetic studies can benefit from the extensive catalog of candidate genes that is emerging from the human genome project. The epidemiological evidence to date strongly suggests that studies seeking causes for sarcoidosis need to consider both environmental and genetic risk factors to be successful because the two likely interact with each other to produce disease.

Several studies have found weak associations between certain human leukocyte antigen (HLA) alleles and sarcoidosis, but none have been conclusive. Glutamic acid at position 69 in HLA-DPB1 has been reported to be strongly associated with chronic beryllium disease. The immunopathologic and clinical similarities between chronic beryllium disease (CBD) and sarcoidosis suggest that similar immune-response genes may be involved in susceptibility in both diseases. We analyzed the DNA sequence of HLA-DPB1 exon 2, which contains the hypervariable regions involved in binding antigens, in blood samples from African-American sarcoidosis patients and healthy controls. Results indicate that Val36 (odds ratio [OR] = 2.30) and Asp55 (OR = 2.03) are associated with increased risk for sarcoidosis, but no association with Glu69 was found. These results suggest that although HLA-DPB1 Glu69 is not associated with sarcoidosis, other alleles may make some contribution to susceptibility to sarcoidosis in African-Americans.

Homozygosity for the mutation Cys282Tyr in the HFE gene has recently been identified as a cause of hereditary hemochromatosis, a disorder resulting in the inappropriate absorption of iron. Approximately 10% of Caucasians are heterozygous for this mutation; however, the gene frequency in African Americans is unknown. A study of a control population of African Americans was performed to determine the frequency of the Cys282Tyr and His63Asp alleles in this ethnic group. The carrier frequency for each mutant allele in our African American population was 3.0%. DNA studies of four African-American hemochromatosis patients did not identify any individuals with the Cys282Tyr allele. These findings suggest that if the Cys282Tyr mutation confers susceptibility to hemochromatosis in Caucasians (as suggested by recent studies) there is an alternative mechanism for hemochromatosis in the American black population.

We assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinson's disease (PD) in a population-based case-control study consisting of men and women > or = 50 years of age who had primary medical care at Henry Ford Health System in metropolitan Detroit. Enrolled PD patients (n = 144) and control subjects (n = 464) were frequency-matched for age, race, and sex. When adjusted for these variables and smoking status, there was a significant association of occupational exposure to herbicides (odds ratio [OR], 4.10; 95% CI, 1.37, 12.24) and insecticides (OR, 3.55; 95% CI, 1.75, 7.18) with PD, but no relation was found with fungicide exposure. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55), but there was no increased risk of the disease with rural or farm residence or well water use. The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.

Tumor suppressor genes play an important role in normal growth regulation. Loss or inactivation of these genes has been implicated in the development of squamous cell cancer and progression of neoplasia. Previous studies in our laboratories have implicated chromosome 18 long-arm deletions as a possible marker of progression in head and neck squamous cell cancer (HNSCC). To test this hypothesis, we evaluated DNA from 67 HNSCC patients for loss of heterozygosity (LOH) at 18q loci, and for association of LOH with survival. Tumor and normal DNA were extracted from fresh tissue and paraffin blocks and were amplified by PCR using primers for three microsatellite repeat polymorphisms in 18q (D18S336, D18S34, and MBP). A total of 27 (40%) patients had LOH of 18q, and these patients had a statistically significantly poorer two-year survival compared to those without 18q LOH (30% vs. 63%; P = 0.008). In a Cox proportional hazards model in which time from diagnosis to death was the outcome variable, patients with 18q LOH had an unadjusted relative risk (RR) of death of 2.46 (P = 0.005). When 18q LOH was placed in a multivariate model controlling for possible confounders in the study, the RR for death was still elevated (RR = 2.10; P = 0.025). The observation of a prognostic association between 18q LOH and poor patient survival suggests that loss of an 18q tumor suppressor gene or genes is important in the progression of HNSCC.

Hereditary susceptibility to sarcoidosis is suggested by ethnic preponderance, familial clustering, and multigenerational involvement. The genetics of sarcoidosis cannot be adequately addressed in small samples of patients; a large-scale study with stratification for patient phenotypic differences is necessary. A study that uses both genetic marker and environmental data would be able to control for and examine different causative mechanisms. Until such a well-designed, comprehensive study is carried out, we are left with interesting patterns of disease in families and uncertain allelic associations.

In a population-based case-control study, we investigated the potential role of occupational exposure to iron, copper, manganese, mercury, zinc, and lead as risk factors for Parkinson's disease (PD). Concurrently recruited, nondemented patients (n = 144) with idiopathic PD and controls (n = 464) consisting of men and women > or =50 years of age, frequency-matched for age (within 5 years), race, and sex were enrolled. All had primary medical care at Henry Ford Health System in urban/suburban metropolitan Detroit. Subjects were given an extensive risk-factor questionnaire detailing actual worksite conditions of all jobs held for more than 6 months from age 18 onward. An industrial hygienist, blinded to the case-control status of subjects, rated occupational exposure to each of the metals of interest. When adjusted for sex, race, age, and smoking status, we found in those with more than 20 years' exposure a significantly increased association with PD for copper (OR = 2.49, 95% CI = 1.06, 5.89) and manganese (OR = 10.61, 95% CI = 1.06, 105.83). For more than 20 years' exposure to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07, 7.50), and iron-copper (OR = 3.69, 95% CI = 1.40, 9.71), there was a greater association with PD than with any of these metals alone. These findings suggest that chronic exposure to these metals is associated with PD, and that they may act alone or together over time to help produce the disease.

Reports of racial differences in the incidence of sarcoidosis, a granulomatous disorder of unknown etiology, are primarily based on studies of military and veteran populations. To determine racial differences in sarcoidosis incidence in a metropolitan population the authors conducted a study of newly diagnosed cases that occurred between 1990 and 1994 among members of the Health Alliance Plan health maintenance organization in Detroit, Michigan. The study population was racially heterogeneous, was limited to individuals aged 20-69 years, and comprised about 5% of the Detroit metropolitan area population in that age group. Annual age-adjusted incidence, in number of new cases per 100,000, was highest in African-American females (39.1 cases). The next highest incidence was found in African-American males (29.8 cases), followed by Caucasian females (12.1) and Caucasian males (9.6). African-American females aged 30-39 years were at the greatest risk, with an annual incidence of 107/100,000. Overall, African Americans had about a threefold higher age-adjusted annual incidence (35.5/100,000) compared with Caucasians (10.9/100,000). Additional adjustment for sex, area of residence, and year of study resulted in 3.8-fold greater risk for African Americans compared with Caucasians. This study further confirmed the higher incidence of sarcoidosis in African Americans compared with Caucasians, but the racial difference was lower than previously reported. The results should be more generalizable than previous studies done with select populations and should serve as a useful frame of reference for future epidemiologic research of sarcoidosis.

Many occupational case-control studies have relied on either self-report or exposure assessment based on job titles linked to a job exposure matrix (JEM) as opposed to the generally considered more accurate, but labor intensive, method of expert review of job histories. Our study examined the comparability of these different methods in assessing occupational exposure to the metals copper (Cu), lead (Pb), and iron (Fe) in manufacturing industries. Subjects were older people from a case-control study of a neurologic disease, and consisted of 188 individuals (72% male, 85% white) who had worked an average of 22.4 years in the manufacturing industry. An industrial hygienist review (IHR) of occupational history data from a comprehensive questionnaire was used as the reference method. The percent agreement (%A), sensitivity (SE), and specificity (SP) for direct self-report of metal exposures were: Cu, %A = 94.6, SE = 83.6, SP = 96.1; Pb, %A = 91.9, SE = 72.5, SP = 93.5; and Fe, %A = 82.7, SE = 64.5, SP = 88.1. Using the National Institute for Occupational Safety and Health (NIOSH) JEM, we analyzed the jobs of 115 of the 188 study subjects who had all their jobs listed in the JEM. Exposure assessment based on the NIOSH JEM compared with the IHR resulted in greater misclassification relative to direct self-report: Cu, %A = 81.5, SE = 21.2, SP = 89.2; Pb, %A = 86.0, SE = 0.0, SP = 92.6; and Fe, %A = 69.2, SE = 15.5, SP = 86.4. For all three study metals, combining the information from both direct self-report and the JEM did not improve upon the results compared with direct self-report alone. Due to the complex nature of metal exposure assessment, we suggest using an expert review of job histories whenever possible to minimize potential misclassification.

Familial clustering of sarcoidosis and the higher prevalence and clinical severity of sarcoidosis in African Americans suggests etiologic heterogeneity. To test for heterogeneity in familial risk of sarcoidosis, we studied 3,395 siblings and parents of 558 index cases (361 African American, 197 Caucasian) diagnosed at Henry Ford Hospital between 1951 and 1994. Using the age- and sex-specific cumulative incidence of sarcoidosis in our sample, we found a statistically significant heterogeneity in familial risk of disease (P < .001). To determine if this was due to a greater risk of sarcoidosis in African Americans, we recalculated disease probabilities using age-, sex-, and race-specific disease cumulative incidence and found the same amount of heterogeneity in familial risk (P < .001). Index cases (n = 69) from high-risk families were more likely to be African American (odds ratio [OR] = 3.24; 95% confidence interval (CI) = 1.71-6.14) and to have an offspring or second- degree relative affected (OR = 6.21; 95% CI = 2.86-13.45). We conclude that the heterogeneity of familial sarcoidosis risk found in this study is supportive of multiple etiologies. Our results also show that a quantitative assessment of familial risk based on siblings and parents may be a useful screening tool for identifying families with additional affected members. Of the high-risk families, African Americans made up a greater-than-expected percentage even after accounting for differences in disease prevalence. We suggest targeting African Americans for studies of sarcoidosis that focus on Mendelian hypotheses and genetic linkage.

Allele frequency distributions were determined for seven microsatellite DNA markers spanning the short arm of chromosome 6 in a population of African-Americans. A total of 196 chromosomes were analyzed. African-Americans differed from reported studies on Caucasians in the number of alleles, allele frequency and predominating alleles. These differences resulted in higher heterozygosity and polymorphic information content for these loci in the African-American population than in Caucasians. Each marker appeared to be in Hardy-Weinberg equilibrium within this population. These results demonstrate the need to determine population-specific allele frequency distributions for polymorphic markers when performing genetic linkage studies in racially defined groups. This study provides gene frequency data for this ethnic group in a region of the genome which has attracted attention as contributing genetic susceptibility to a number of diseases.

Although patients with Parkinson's disease (PD) are often treated by neurologists, most are first diagnosed by a primary care physician. Epidemiologic studies which use PD cases from only neurology clinics may be subject to referral bias due to differential case selection in the referral process. To study this methodological issue, a historical cohort study of all outpatients with PD diagnosed by a non-neurologist from January 1, 1988 to June 1, 1992 at the Henry Ford Health System was conducted. This health system has specialty and primary care outpatient clinics located at the main facility in Detroit, Mich. and throughout the metropolitan area. The analysis included those who had at least one outpatient visit during the follow-up period from January 1, 1988 to June 30, 1993 (n = 588), of whom 183 (31.1%) were referred to a neurologist. The univariate analysis resulted in crude risk ratios for referral of 2.14 [95% confidence interval (CI) = 1.56-2.93] for age less than 70, 2.11 (95% CI = 1.57-2.84) for male sex, 1.64 (95% CI = 1.17-2.32) for nonwhite race, 2.48 (95% CI = 1.77-3.47) for private health insurance, 1.79 (95% CI = 1.32-2.43) for being married, 1.44 (95% CI = 1.08-1.92) for 10 or more health care visits per year and 2.27 (95% CI = 1.66-3.11) for having the initial visit for PD at the main Detroit clinic. In a Cox proportional hazards model which included all study variables, race and marital status were no longer statistically significant (p < 0.05), and no risk estimates were greater than 2.0. In summary, patients referred to neurologists in this study were more likely younger, male, to have private health insurance, frequent users of health care and to use hospital-based clinics for their primary health care. We suggest that future case-control studies of PD avoid potential referral bias by not using a study population comprised solely of patients referred to a neurology clinic or design studies which can estimate the potential effect of this bias.

Using data from death certificates, we compared underlying causes of death for two populations of Michigan decedents: (1) persons 40 years of age and older for whom Parkinson's disease (PD) was listed as a contributing cause of death and who died in the years 1970 through 1989, and (2) all persons in Michigan over 40 years of age who died in 1970, 1980, or 1990. PD decedents were approximately 1.5 times more likely to die from cerebrovascular disease and three to four times more likely to die from pneumonia/influenza, but they had just 29% of the expected number of deaths due to cancer. These associations were maintained irrespective of gender or race. PD decedents had diabetes mellitus and heart diseases as frequently as decedents in the general population, but liver diseases were less frequent among PD decedents. These trends held throughout the 21-year study period. When we stratified cancers by whether they are known to be (1) highly related, (2) moderately related, or (3) weakly related or unrelated to smoking, there were still 2.5 times fewer cancers unrelated or weakly related to smoking among PD decedents than among decedents in the general population. We believe that the greater frequency of cerebrovascular disease in PD decedents may be due to a detection bias, since PD patients are more likely to be seen by neurologists, who are more apt to diagnose and document diseases of the nervous system. Pneumonia/influenza is more common among PD patients because of their relative immobility near the end of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Parkinson's disease (PD) mortality rates in Michigan counties for 1986-1988 were calculated with respect to potential heavy metal exposure (iron, zinc, copper, mercury, magnesium, and manganese) from industry based on recent census data. Individuals were counted as a PD death if the diagnosis was listed as an "underlying" or "related" cause of death on the death certificate. Counties with an industry in the paper, chemical, iron, or copper related-industrial categories (ICs) had statistically significantly (p < 0.05) higher PD death rates than counties without these industries. Significant correlations of chemical (rs = 0.22; p = 0.05), paper (rs = 0.22; p = 0.05) and iron (rs = 0.29; p = 0.008) industry densities with PD death rates were also present. Counties were divided into high (> 15/100,000 individuals 45 years old and over) and low (< = 15/100,000) PD death rate counties by cluster analysis. Geographically, counties with high PD mortality were located mainly in the southern half of the lower peninsula and eastern half of the upper peninsula; low PD death rate counties formed two distinct clusters in the western edge of the upper peninsula and the north-central portion of the lower peninsula. Other possible risk factors that may explain the varied distribution of PD death rates in Michigan were examined. Those significantly correlated with PD mortality included population density (rs = 0.31; p = 0.005), farming density (rs = 0.25; p = 0.02), and well water use (rs = -0.24; p = 0.03). These ecologic findings suggest a geographic association between PD mortality and the industrial use of heavy metals.

Regressive models were used to search for possible major gene effects on pulmonary function in two groups of families: one ascertained through patients with chronic obstructive pulmonary disease [COPD defined as forced expiratory volume in one second (FEV1) less than 70% forced vital capacity (FVC)] and the other ascertained through patients with non-pulmonary disorders. There were 85 COPD families with data on 270 individuals and 56 non-pulmonary families with data on 199 individuals. The analysis was done on residuals obtained from a regression of FEV1 on age, sex, race, height, and ascertainment group. Smoking status was incorporated directly as a covariate in the regressive models. Data on probands were excluded in this analysis as a partial correction for ascertainment bias. The best fitting model for the 85 COPD families included a major gene effect with sex specific variances, but no residual familial correlation. The best fitting model for the non-pulmonary families was one with no major gene effect and no residual familial correlation. Cigarette smoking was a significant covariate in both groups of families. Testing for heterogeneity showed a significant difference in the control of pulmonary function among these COPD and non-pulmonary families (X2 = 20.12 on 6 df; p = 0.0026). Major gene effects appear to be limited to these COPD families, while there was no evidence for major gene effects in the non-pulmonary families.