Disease Concordance Research Articles

The inheritance of rheumatoid arthritis in Iceland.

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Although there is a large body of evidence suggesting that RA is immune mediated, the etiology remains unresolved. Twin studies have shown disease concordance rates of approximately 15% in monozygotic twins and 4% in dizygotic twins, while the estimated risk ratio for siblings of RA patients ranges from 5 to 8. Our goal was to use genealogic data from Iceland to further investigate the genetic component of RA. Data were obtained from a population-based, computerized genealogy database that was developed to examine multigenerational relationships among individuals in the relatively homogeneous population of Iceland. Using an algorithm, the minimum founder test, we calculated the least number of founders required to account for a list of RA patients, and compared it with 1,000 sets of same-sized matched control groups. In addition, we estimated the kinship coefficient and risk ratios for relatives of the RA patients. Several familial clustering tests demonstrated that the RA patients were more related to each other than were the average control set of Icelanders. A significantly fewer number of founders was necessary to account for our patient list than for the random sets of matched controls (P < 0.001), and the average pairwise identity-by-descent sharing was greater among the patients than among the control sets (P < 0.001). In addition, there was an increased risk of RA in first- and second-degree relatives of the patients; e.g., for siblings, the risk ratio was 4.38 (95% confidence interval 3.26-5.67), and for uncles/aunts, the risk ratio was 1.95 (95% confidence interval 1.52-2.43). The familial component of RA is shown to extend beyond the nuclear family, thus providing stronger evidence for a significant genetic component to RA.

Representativeness of a roster of volunteer North American twins with chronic disease

AbstractTo identify large numbers of twins affected by chronic disease as potential subjects for studies of environmental and genetic chronic disease determinants, we advertised for affected twins over the period 1980–91 in newspapers across North America. Responses were received from 17 245 twin pairs in which cases of cancer or other chronic disease had occurred. To assess the representativeness of affected twins identified by advertising, we evaluated the pattern of reporting, compared the cases identified to the number of cases estimated to be prevalent among all North American twins, compared the cases to population-based singleton case series, compared the healthy co-twins to population-based samples of healthy persons, assessed the impact on ascertainment of opinions about disease causation, compared the pattern of prospective to retrospective ascertainment of disease in the originally unaffected co-twins of cases, and compared the results of the prospective ascertainment of disease in co-twins to comparable published estimates. Youth, gender, zygosity, education, and disease concordance were found to be overall determinants of ascertainment. Disease-discordant DZ twins appeared to be modestly underascertained. While somewhat better educated, both concordant and discordant pairs were judged to be reasonably representative of affected non-Hispanic white North American twin pairs of comparable status, ie of comparable age, sex, race, and zygosity. If interpreted with caution, the concordance patterns of such twins can be used to generate genetic hypotheses, but should not be the basis of definitive heritability analyses. We conclude that advertising offers a method of identifying pairs of twins that can serve as subjects for studies designed to identify disease determinants. Twin Research (2000) 3, 33–42.

Two identical triplet sisters carrying a germline BRCA1 gene mutation acquire very similar breast cancer somatic mutations at multiple other sites throughout the genome.

Monozygotic twins, each of whom has breast cancer, offer a natural study population for gene-environmental interactions as causation of cancer, because they are genetically identical. If heritable factors play a large role in the origin of a neoplasm, disease concordance should be significant in monozygotic twins. Two monozygotic triplet sisters carrying a germline BRCA1 gene mutation (5382insC) who both developed breast cancer at early ages were studied for loss of heterozygosity (LOH) in their microdissected, paraffin-embedded tumors along with control blood and stromal breast tissue at 19 chromosomal arms using 161 microsatellite markers. Microdissected areas of normal lobular and ductal epithelium and ductal in situ carcinoma were also studied for LOH using a subset of microsatellite markers. The mother's DNA (extracted from peripheral blood lymphocytes) was analyzed to determine the parental allele under LOH in each case. Both tumors demonstrated similar histologic features suggestive of a secretory variant of ductal carcinoma. The tumors from both sisters had similar overall LOH frequency expressed by the fractional allelic loss (FAL) indices (0.56 vs. 0.60) and demonstrated concordance for loss or retention at 82 of 97 informative markers (85% correlation). In addition, detailed mapping analysis of several chromosomal arms revealed that identical breakpoints were detected in both tumors at several chromosome regions. Finally, in both sisters' tumors, when a chromosome exhibited allelic loss, all of the markers exhibited LOH of the same parental allele even when there were intervening regions of retention of heterozygosity. In contrast, 17 archival sporadic breast carcinomas demonstrated a wide range of FAL indexes and highly individual patterns of LOH. Our findings support the hypothesis that inherited factors play a role in the development of the multiple somatic deletions occurring in breast carcinomas. Whether one of these factors is the mutant BRCA1 allele or some other gene(s) remains to be determined. Genes Chromosomes Cancer 28:359-369, 2000.

Concordance of Inflammatory Bowel Disease among Danish Twins: Results of a Nationwide Study

Background: Previous studies have shown an increased risk of inflammatory bowel disease (IBD) among relatives of patients with Crohn disease and ulcerative colitis. In the present study the probandwise concordance rates for ulcerative colitis and Crohn disease among mono- and dizygotic twins were estimated. Further we aimed to evaluate whether smoking habits might influence the concordance, and to look for clinical characteristics of concordant versus discordant twin pairs. Methods: Among the 38,507 identified twins born in Denmark from 1953 to 1982, a questionnaire was sent to the 34,076 who previously had accepted to participate in studies. For twins reporting IBD, the diagnosis was verified by applying standard criteria to records requested from hospitals or practitioners. Results: Among the 29,421 (86.3%) twins answering the questionnaire, 103 pairs had at least one twin who suffered from IBD. In the Crohn disease group five of 10 monozygotic pairs, but none of 27 dizygotic pairs were concordant. In the ulcerative colitis group three of 21 monozygotic, and two of 44 dizygotic pairs were concordant. The probandwise concordance rate among monozygotic pairs was 58.3% for Crohn disease and 18.2% for ulcerative colitis; among the dizygotic pairs the rates were 0 and 4.5%, respectively. The frequency of smokers was higher among twins with Crohn disease and lower among twins with ulcerative colitis compared to the frequency in the twin register. Furthermore, smoking habits were found to be of significance for discordance for disease. Regarding the clinical characteristics no homogenous pattern was observed within the concordant pairs and the differences between concordant and discordant pairs were not significant. Conclusion: The observation of a significantly higher concordance rate among monozygotic than among dizygotic twin pairs strongly points to a genetic influence on occurrence of IBD, which seems to be more pronounced with regard to Crohn disease than to ulcerative colitis. Differences in smoking habits among the members of the discordant twin pairs may influence the discordance.

Concordance among monozygotic and dizygotic twins from a population-based sample for self-reported atopic triad, syndrome x, and psychiatric conditions

A population-based sample of 806 monozygotic (MZ) twin pairs and 553 dizygotic (DZ) twin pairs in the Mid-Atlantic Twin Registry has been analyzed. Since MZ twins are genetically identical (assuming no somatic mutations occur) and DZ twins, like non-twin siblings, share an average of half of their genes, the comparison of disease concordance between MZ and DZ twins can be used to test the degree of genetic involvement in the development of a particular trait. We observed a greater proband concordance rate among MZ twins relative to DZ twins for a number of diseases ([difference (95% confidence interval)] for self-reported asthma [0.33 (0.22-0.44)], hay fever [0.20(0.14-0.26)], eczema [0.13 (0.04-0.22)], diabetes [0.18 (0.01-0.35)], hypertension [0.13 (0.04-0.22)], obesity [0.10 (0.0-0.20)], depression [0.30 (0.21-0.39)], and anxiety [0.16 (0.06-0.26)]). The concordance rates among twin/non-twin sibling pairs were similar to those among DZ twins across all the diseases under investigation ([differences (95% confidence intervals] ranging from [0.01 (-0.07-0.09)] to [0.09 (0.0-0.18)]) in 410 families with data available for both twin members and at least one of the non-twin siblings. The atopic triad (asthma, hay fever, eczema), and anxiety and depression had study population prevalence rates similar to the proband concordance rates in DZ twins; whereas all the syndrome X diseases (diabetes, hypertension, obesity) had higher proband concordance rates among DZ twins relative to their study population prevalences. The present study demonstrates the utility of self-report data in a large population-based sample and is the first to simultaneously study the genetic influences on multiple disease clusters using a twin registry. It confirms previous findings from single disease studies of a significant genetic influence on the risk of each disease in question, and supports the hypothesis that common genetic mechanisms may underlie each disease cluster.

The role of genetic factors in autoimmune disease: implications for environmental research.

Studies in both humans and in animal models of specific disorders suggest that polymorphisms of multiple genes are involved in conferring either a predisposition to or protection from autoimmune diseases. Genes encoding polymorphic proteins that regulate immune responses or the rates and extent of metabolism of certain chemical structures have been the focus of much of the research regarding genetic susceptibility. We examine the type and strength of evidence concerning genetic factors and disease etiology, drawing examples from a number of autoimmune diseases. Twin studies of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes, and multiple sclerosis (MS) indicate that disease concordance in monozygotic twins is 4 or more times higher than in dizygotic twins. Strong familial associations (odds ratio ranging from 5-10) are seen in studies of MS, type I diabetes, Graves disease, discoid lupus, and SLE. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Recent genomewide searches in RA, SLE, and MS provide evidence for multiple susceptibility genes involving major histocompatibility complex (MHC) and non-MHC loci; there is also evidence that many autoimmune diseases share a common set of susceptibility genes. The multifactorial nature of the genetic risk factors and the low penetrance of disease underscore the potential influence of environmental factors and gene-environment interactions on the etiology of autoimmune diseases.

Evidence for the role of environmental agents in the initiation or progression of autoimmune conditions.

The concordance of autoimmune disease among identical twins is virtually always less than 50% and often in the 25-40% range. This observation, as well as epidemic clustering of some autoimmune diseases following xenobiotic exposure, reinforces the thesis that autoimmune disease is secondary to both genetic and environmental factors. Because nonliving agents do not have genomes, disease characteristics involving nonliving xenobiotics are primarily secondary to host phenotype and function. In addition, because of individual genetic susceptibilities based not only on major histocompatibility complex differences but also on differences in toxin metabolism, lifestyles, and exposure rates, individuals will react differently to the same chemicals. With these comments in mind it is important to note that there have been associations of a number of xenobiotics with human autoimmune disease, including mercury, iodine, vinyl chloride, canavanine, organic solvents, silica, l-tryptophan, particulates, ultraviolet radiation, and ozone. In addition, there is discussion in the literature that raises the possibility that xenobiotics may also exacerbate an existing autoimmune disease. In this article we discuss these issues and, in particular, the evidence for the role of environmental agents in the initiation or progression of autoimmune conditions. With the worldwide deterioration of the environment, this is a particularly important subject for human health.

The impact of antimicrobial resistance and Streptococcus pneumoniae serotype distribution on the mortality of children under 5 years of age with invasive disease

Severe pneumonia and meningitis caused by Streptococcus pneumoniae have been persistently associated with high mortality rates, despite advances in antimicrobial therapy and the development of vaccines. Resistance to penicillin and other antimicrobial agents is increasing and spreading worldwide. Even though risk factors for development of antimicrobial resistance have been identified, their influence on mortality has not been clarified. With regard to virulence, differences among serotypes have been determined, but their impact on mortality is unknown. The aim of this study was to determine the risk factors associated with mortality in children with invasive pneumococcal disease. Clinical records for 245 children under 5 years of age with invasive disease due to S.pneumoniae were reviewed. Children were diagnosed between 1994 and 1996 in Colombia, during the study of S.pneumoniae capsular types conducted by the Pan American Health Organization's Regional System for Vaccines. Of the 245 patients whose charts were examined, 29 (11%) died. No significant differences in age, gender, underlying disease, nor antimicrobial treatment concordance were found. Variables associated with mortality in the univariate analysis were a diagnosis of meningitis; antimicrobial resistance to penicillin, trimethoprim-sulfamethoxazole (TMS), or erythromycin; multiresistance, and serotypes 6, 23F, 7F, 8, and 35B. In the logistic regression, serotypes 7F (OR = 7.13; P = 0.04) and 8 (OR = 13.8; P = 0.07), polipnea (OR = 2.74; P = 0.03), meningitis (OR = 5.02; P = 0.0001) and TMS resistance (OR = 2.62; P = 0.02) continued to be associated with mortality. In patients with pneumonia, serotype was the factor most consistently associated with mortality; in meningitis patients, it was antimicrobial resistance. Differences in mortality according to serotype must be taken into account in developing a vaccine if a substantial impact on pneumococcal disease morbidity and mortality is to be achieved.

Parkinson disease in twins: an etiologic study.

The cause of Parkinson disease (PD) is unknown. Genetic linkages have been identified in families with PD, but whether most PD is inherited has not been determined. To assess genetic inheritance of PD by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. Twin study comparing concordance rates of PD in MZ and DZ twin pairs. A total of 19842 white male twins enrolled in the National Academy of Sciences/National Research Council World War II Veteran Twins Registry were screened for PD and standard diagnostic criteria for PD were applied. Zygosity was determined by polymerase chain reaction or questionnaire. Parkinson disease concordance in twin pairs, stratified by zygosity and age at diagnosis. Of 268 twins with suspected parkinsonism and 250 presumed unaffected twin brothers, 193 twins with PD were identified (concordance-adjusted prevalence, 8.67/1000). In 71 MZ and 90 DZ pairs with complete diagnoses, pairwise concordance was similar (0.129 overall, 0.155 MZ, 0.111 DZ; relative risk, 1.39; 95% confidence interval, 0.63-3.1). In 16 pairs with diagnosis at or before age 50 years in at least 1 twin, MZ concordance was 1.0 (4 pairs), and DZ was 0.167 (relative risk, 6.0; 95% confidence interval, 1.69-21.26). The similarity in concordance overall indicates that genetic factors do not play a major role in causing typical PD. No genetic component is evident when the disease begins after age 50 years. However, genetic factors appear to be important when disease begins at or before age 50 years.

Lifestyle, stress, and genes in peptic ulcer disease: a nationwide twin cohort study.

The familial accumulation of peptic ulcer disease observed in several studies may be attributable to genetic effects, aggregation of environmental exposure (shared environment), or both. The intrafamilial spread of Helicobacter pylori infection has raised the question whether shared environment could explain the familial aggregation of peptic ulcer disease rather than genetic similarity of family members. To examine the contribution of genetic and environmental factors to the pathogenesis of peptic ulcer disease in a nationwide population-based cohort of adult twins. The Finnish Twin Cohort consists of all same-sexed twin pairs born before 1958 with both twins alive in 1975. The total number of twin pairs is 13888, of whom 4307 are monozygotic (MZ) and 9581 are dizygotic (DZ) twins. Questionnaire surveys of twins were carried out in 1975, 1981, and 1990, including medical and psychosocial questions. One question asked whether a physician had ever made a diagnosis of gastric or duodenal ulcer. In addition, hospital discharge data from 1972 to 1991 were linked with the twin cohort to obtain those twin individuals who had been treated for gastric or duodenal ulcer. The prevalence of and concordance for peptic ulcer disease were examined in MZ and DZ twins. Model-fitting analysis was used to specify the relative roles of genetic and environmental factors. The contribution of lifestyle factors and stress was examined prospectively in an incidence study and by comparison of discordant pairs. The prevalence of peptic ulcer disease was 6.2% in men and 2.8% in women in 1975. There were 63 MZ and 86 DZ pairs concordant for peptic ulcer disease. Concordance for disease was significantly higher in MZ than in DZ twin pairs; the probandwise concordance rate was 23.6% (95% confidence interval [CI], 20.9%-26.3%) in MZ twins and 14.8% (95% CI, 13.3%-16.3%) in DZ twins. In the model-fitting analysis, a model with both additive genetic and unshared environmental effects had the best goodness-of-fit. Thirty-nine percent (95% CI, 32%-47%) of the liability to peptic ulcer disease was explained by genetic factors and 61% (95% CI, 53%-68%) by individual environmental factors. In the incidence study (logistic regression analysis of the entire cohort initially free of peptic ulcer disease, with subjects diagnosed as having peptic ulcer after 1975 as cases), current smoking (relative risk, 2.2; 95% CI, 1.5-3.2) and high stress levels (relative risk, 3.2; 95% CI, 1.4-7.6) in men and regular use of analgesics (relative risk, 3.3; 95% CI, 1.3-8.1) in women predicted peptic ulcer disease during the follow-up from 1976 to 1991. In the analysis of discordant pairs, smoking in men and regular use of analgesics in both sexes were predictors of peptic ulcer disease. The questionnaire and hospital usage data on peptic ulcer disease in the population-based twin cohort suggest that the familial aggregation of the disease is modest, and attributable almost solely to genetic factors. Environmental effects not shared by family members were significant predictors of disease, and they were attributable to smoking and stress in men and the use of analgesics in women. The minor effects of shared environment to disease liability do not support the concept that the clustering of risk factors, such as H pylori infection, would explain the familial accumulation of peptic ulcer disease.

Genetics of Parkinson's Disease

Publisher Summary This chapter presents an overview of the genetics of Parkinson's disease (PD). Parkinsonism is clinically characterized by the triad of tremor, rigidity, and bradykinesia. PD is the most common cause of Parkinsonism and the second most prevalent neurodegenerative disorder after Alzheimer's disease. Earlier, PD was thought to have no genetic basis, and epidemiological data appeared to support this view. Cross-sectional studies also suggested that either there is no genetic basis, or that it is only evident in early-onset PD. Differing disease concordance rates between monozygotic and dizygotic twins in longitudinal studies including those using 18F-dopa positron emission tomography support heritability in PD. Studies show that Parkin mutations usually occur either as homozygous or compound heterozygous mutations (with different mutations in both alleles). However, many have been reported in which, despite extensive screening, only one of the alleles appears to be mutated. This chapter starts with a discussion on genetics of familial Parkinson's disease and then explains the term Parkinsonism-plus genes. The chapter concludes with explaining sporadic PD, genetic associations, and familial genes.

Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment.

To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence-specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co-twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

Comparison of arbutamine stress 99mTc-labeled sestamibi single-photon emission computed tomographic imaging and echocardiography for detection of the extent and severity of coronary artery disease and inducible ischemia

Background. Arbutamine is a new synthetic catecholamine developed specifically for pharmacologic stress testing. Methods and Results. We investigated 39 patients undergoing coronary arteriography to compare arbutamine stress 99mTc-labeled sestamibi single-photon emission computed tomographic imaging and echocardiography for detection of the extent and severity of coronary artery disease and inducible ischemia. Rest and stress studies were analyzed blindly according to a 12-segment left ventricular model for both techniques. Each segment was graded according to severity of wall thickening abnormality and perfusion defect (1 = normal to 4 = severe). Total perfusion defect and wall thickening scores were calculated at peak stress and the difference in scores between stress and rest (Δperfusion defect; Δwall thickening) were used as indexes of inducible ischemia. Twenty-one patients had multivessel disease, nine had single-vessel disease, and nine had normal coronary arteries. Diagnostic accuracies for the detection of coronary artery disease for single-photon emission computed tomographic imaging and echocardiography were 95% and 92%, respectively. Extent and severity of coronary artery disease indicated by a peak stress perfusion defect score of 26 ± 6.4 and wall thickening score of 25.1 ± 8.4 were similar, and there was no significant difference in the Δperfusion defect and Δwall thickening scores of 8.7 ± 5.5 and 10.4 ± 7.1, respectively. Segmental concordance rates for the detection of coronary artery disease and inducible ischemia were 74% (κ = 0.47; confidence interval 0.39 to 0.55) and 74% (κ = 0.42; confidence interval 0.34 to 0.51), respectively. Regional concordance for coronary artery disease was 84% (κ = 0.68; confidence interval 0.51 to 0.84). Where discordance was present, there was a greater prevalence of perfusion abnormality compared with wall thickening abnormality. Conclusion. Arbutamine stress single-photon emission computed tomographic imaging and echocardiography provide largely equivalent and accurate pathophysiologic information for the evaluation of coronary artery disease and inducible ischemia.

Model-free age-of-onset methods applied to the linkage of bipolar disorder.

We performed Haseman-Elston regression on a set of bipolar pedigrees using each of three dependent variables: a binary trait indicating disease concordance or discordance, a binary trait adjusted for age-of-onset, and the residuals from a survival analysis. The latter two methods, which both adjust for age-of-onset, gave smaller p-values when previous analyses suggested linkage between disease and marker, but not when previous analyses were not suggestive of linkage.

Familial aggregation in Crohn's disease: Increased age-adjusted risk and concordance in clinical characteristics

BACKGROUND & AIMS: Because the mode of Crohn's disease inheritance is unknown, age-adjusted risk estimates and knowledge of disease characteristics will aid genetic counseling and modeling. The aim of this study is to determine the prevalence of familial occurrence of inflammatory bowel disease in first-degree relatives of patients with Crohn's disease and estimate their age-adjusted risks. It also evaluates agreement in disease characteristics between generations within families with a history of Crohn's disease. METHODS: Six hundred forty patients with Crohn's disease and 800 control subjects were questioned about the occurrence of inflammatory bowel disease in their first-degree relatives. Agreement for age at diagnosis, initial disease location, disease behavior, and number of bowel resections was determined in 68 families with two or more members affected and compared with data in 100 unrelated patients with Crohn's disease. RESULTS: Probands with Crohn's disease had a more frequent positive family history than controls. The age at diagnosis between probands with and without a positive family history was insignificant. Crude and age-adjusted risk elements were higher in relatives of patients, especially daughters, compared with those of controls. The age at diagnosis was older for parents than offspring but similar between siblings. Initial disease location was especially striking between siblings. CONCLUSIONS: This study confirms familial aggregation and a high degree of disease concordance in Crohn's disease. The age at diagnosis and initial disease location was especially strong within generations. (Gastroenterology 1996 Sep;111(3):597-603)

Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease

The incidence of treated end-stage renal disease (ESRD) in the United States is four times more frequent in African-Americans (AAs) than in whites. This is explained neither by a greater prevalence of hypertension and diabetes mellitus nor by socioeconomic issues. To investigate familial risk of renal disease in AAs, we examined the records of 472 AA dialysis patients in Jefferson County, Alabama. Applying strict criteria, we identified 85 index cases of ESRD associated only with hypertension (H-ESRD). We examined the records of 75 index cases and studied the first-degree relatives of 40 patients. The numbers of men and women with H-ESRD were similar (38 and 37, respectively). There was no statistical difference in age at the onset of dialysis (women 53.7 ± 13.5 years [±SD] and men 49.2 ± 12.2 years; P = 0.0863). We found evidence for renal disease in 26 of 40 (65%) index cases with participating families. Hypertension was present in all 40 families (100%) and diabetes mellitus was present in 24 families (60%). Eighteen of the 75 H-ESRD index patients had a first-degree relative with ESRD. In total, we found evidence for renal disease in 35 of 75 (47%) families. We conclude that there is a strong concordance of renal disease in the families of AAs with H-ESRD.

Genetics versus environment in inflammatory bowel disease: results of a British twin study

A genetic component to the cause of inflammatory bowel disease has been inferred from the increased risk among first degree relatives (5-20% cumulative incidence).1 The only previous study of inflammatory bowel disease in twins used the Swedish twin registry and a register of hospital inpatients to identify 80 twin pairs.2 The aim of our study was to determine the levels of concordance for inflammatory bowel disease in British twin pairs. The National Association for Colitis and Crohn's Disease is a patient support group with about 16000 members with inflammatory bowel disease. All members were asked to complete and return a prepaid postcard if they had inflammatory bowel disease and were born as one of a twin pair. Those replying were sent a follow up questionnaire to obtain details of the member's diagnosis and twin. Zygosity was determined with a validated questionnaire.3 A report of inflammatory bowel disease in a proband's twin was confirmed …

Occupational factors in multiple sclerosis: an analysis of occupational mortality statistics for men and married women in Great Britain.

This paper presents an exploratory study based on occupational mortality statistics for Great Britain. It examines disease concordance between marital partners for multiple sclerosis (MS). Previous studies have revealed that a married woman's life expectancy and her specific cause of death is reliably associated with the occupational mortality of her husband. This relationship exists across a wide range of occupations but is particularly marked in the case of MS. The present study examines the mortality rates for MS for a large number of occupations (taking into account possible sources of statistical bias) and considers the relationship of these findings with existing hypotheses about the aetiology of MS. It is suggested that there should be more consideration of occupational and psychological factors in multicausal explanations of the disease.

Genetic epidemiology of rheumatoid disease.

The aetiology of rheumatoid arthritis (RA) has both genetic and environmental origins. However, the relationship of these with each other and with RA disease is complicated as both genes and environment may be protective or render individuals susceptible. Diagnostic certainty and disease heterogeneity have posed serious hurdles for investigating RA. Patients with similar disease phenotypes may have different aetiologies and it may now be more appropriate to investigate genetic susceptibility with respect to disease process or characteristic immunopathology. Disease concordance studies have been a classical approach to estimating the upper threshold of the genetic contribution to RA and recent studies have approximately halved the much quoted figure of 32% reported by Lawrence for RA concordance in monozygotic twins. However, the interpretation of twin data has to be treated with caution as MZ twins can differ in terms of somatic rearrangement/mutation of immunoglobulin and T cell receptor genes, X chromosome inactivation in females, genomic imprinting and in utero immune relationship. Calculations based on heritability put the genetic component in RA much higher. HLA is an important genetic factor in RA and risk is thought to be associated with a consensus sequence of amino acids within the third hypervariable region of certain DRB1 alleles. It is now clear that HLA is not particularly associated with onset of synovitis but is more associated with progression and severity of the disease process. The HLA-DRB1*0401/0404 genotype is particularly associated with severe, erosive and seropositive RA. Clear differences in RA susceptibility exist between males and females and this may be attributed to hormonal status. Males have a higher threshold requirement for developing RA and this may explain why RA in males is more associated with HLA risk alleles. We have now reached a critical time for the investigation of RA aetio-pathology. Recent advances in molecular biology and automated microsatellite gene scanning technology are making it possible to map disease susceptibility genes over the whole genome in common disorders such as RA. This will require large numbers of well characterised multiplex affected families. It is anticipated that some of the genes identified will fit in with our current concepts of which inflammatory and immune processes are pathologically important in RA. However others may be a major surprise.

Concordance for Hodgkin's Disease in Identical Twins Suggesting Genetic Susceptibility to the Young-Adult Form of the Disease

Relatives of young adults with Hodgkin's disease are at increased risk of Hodgkin's disease, and lines of evidence implicate both inheritance and environment. We have identified and followed 432 sets of twins affected by Hodgkin's disease. The number of cases of Hodgkin's disease observed before the age of 50 years in the healthy monozygotic and dizygotic twins of the patients with Hodgkin's disease was compared with the number expected from national age-specific incidence rates. None of the 187 pairs of dizygotic twins became concordant for Hodgkin's disease, whereas 10 of the 179 pairs of monozygotic twins did; in 5 of these pairs, the second case appeared after the original ascertainment. During the observation period, 0.1 (monozygotic) and 0.1 (dizygotic) cases in the unaffected twins were expected. Monozygotic twins of patients with Hodgkin's disease thus had a greatly increased risk (standardized incidence ratio, 99; 95 percent confidence interval, 48 to 182), whereas no increase in the risk for dizygotic twins of patients with Hodgkin's was observed. Genetic susceptibility underlies Hodgkin's disease in young adulthood.