Biomedical subjects

B A Rybicki

Publications and source records attributed to B A Rybicki.

At least 19 recordsLinked to original sources

PubMed2005

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Black or African American↗

PubMed2004

Sarcoidosis and granuloma genes: a family-based study in African-Americans.

The evidence for a genetic component in the aetiology of sarcoidosis includes familial aggregation, associations with genetic polymorphisms, and linkage to the major histocompatibility complex class region on chromosome 6p. Unfortunately, the majority of genetic associations with sarcoidosis have not been consistently replicated. In the present study, using a family-based study design, which controls for population stratification, the authors attempted to replicate previously reported associations between sarcoidosis and three attractive candidate genes studied primarily in case-control samples. In 225 nuclear families, ascertained through African Americans with a history of sarcoidosis, no evidence was found for an association between sarcoidosis susceptibility and polymorphisms in the angiotensin converting enzyme, vitamin D receptor and tumour necrosis factor-alpha genes. Further analyses of chronic and acute disease phenotypes failed to reveal any notable associations. Assuming an underlying inheritance model with an additive allelic effect on disease risk, the current study had approximately 80-90% statistical power to detect a 3-fold increased risk associated with the putative risk allele of the polymorphisms under study. The present authors conclude that in African-Americans, the angiotensin converting enzyme, vitamin D receptor, and tumour necrosis factor-alpha genes are not significant risk factors for sarcoidosis susceptibility.

Black or African American↗

PubMed2001

Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).

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.

Adolescent↗

PubMed2001

Familial risk ratio of sarcoidosis in African-American sibs and parents.

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.

Adult↗

PubMed2001

Occupational categories at risk for Parkinson's disease.

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.

Aged↗

PubMed2000

Electrocardiographic presentation of blacks with first myocardial infarction does not explain race differences in thrombolysis administration.

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.

Adult↗

PubMed2000

Effect of delay on racial differences in thrombolysis for acute myocardial infarction.

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.

Adult↗

PubMed2000

The relationship between the sibling recurrence-risk ratio and genotype relative risk.

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.

Alleles↗

PubMed2000

The natural resistance-associated macrophage protein gene in African Americans with sarcoidosis.

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.

Adult↗

PubMed2000

Clinical significance of Y chromosome loss in hematologic disease.

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.

Aged↗

PubMed1999

Smoking and Parkinson's disease: a dose-response relationship.

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.

Aged↗

PubMed1999

Assessment of estimation procedures for risk and onset hazard with dependent data.

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.

Age of Onset↗

PubMed1999

Clinical predictors of heart failure in patients with first acute myocardial infarction.

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.

Aged↗

PubMed1999

The influence of T cell receptor and cytokine genes on sarcoidosis susceptibility in African Americans.

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.

Adult↗

PubMed1999

Adult nutrient intake as a risk factor for Parkinson's disease.

BACKGROUND: This population-based case-control study evaluated nutrient intake as a risk factor for Parkinson's disease (PD) among people aged > or =50 years in metropolitan Detroit. METHODS: Cases (n = 126) were diagnosed between 1991 and 1995 and neurologist-confirmed. Controls (n = 432) were frequency-matched for sex, age (+/-5 years) and race. Using a standardized food frequency questionnaire, subjects reported the foods they ate within the past year. RESULTS: Estimating the association between PD and risk of being in the highest versus the lowest intake quartile, there were elevated odds ratios for total fat (OR 1.94, 95% confidence interval [CI] : 1.05-3.58), cholesterol (OR 2.11, 95% CI: 1.14-3.90), lutein (OR 2.52, 95% CI: 1.32-4.84) and iron (OR 1.88, 95% CI: 1.05-3.38). CONCLUSIONS: These results suggest an association of PD with high intake of total fat, saturated fats, cholesterol, lutein and iron.

Aged↗

PubMed1999

A family history of Parkinson's disease and its effect on other PD risk factors.

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.

Adult↗

PubMed1999

Occupational metal exposures and the risk of Parkinson's disease.

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.

Humans↗

PubMed1999

The Blau syndrome gene is not a major risk factor for sarcoidosis.

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.

Adult↗