Does genetic anticipation occur in familial rheumatoid arthritis?

OBJECTIVE--To determine if there is evidence for genetic anticipation in rheumatoid arthritis (RA) by analysing the possibility that parental disease status and age at proband conception influence the age of onset and disease severity of the proband. METHOD--RA outpatients were identified and data were also taken from Newcastle multicase RA pedigrees. Comparisons of age of onset and parental age at proband conception were made for pedigrees grouped according to the disease status of the parents. Correlation coefficients and linear regression models were calculated for the age of RA onset in the probands. Measures of disease severity were compared in RA mother-proband pairs. RESULTS--The results were similar in both the outpatient (n = 153) and multicase pedigree (n = 15) samples. Significant results were confined to pedigrees in which the mother had RA (20 of the outpatient probands and seven of the multicase group). Probands in these sibships had a younger age of RA onset than their affected mothers (38.3 years (95% confidence interval (CI) 33.8 to 42.8) versus 53.7 (47.3 to 60.0) (p = 0.002) in the outpatient sample; 32.4 years (25.3 to 39.6) versus 43.4 years (29.0 to 57.9) (p = 0.1) in the multicase pedigrees). In the maternal RA group, both the maternal and paternal age at proband conception showed significant negative correlations (r = -0.65, p = 0.002 and r = -0.60, p = 0.005, respectively in the outpatient sample) and linear regression coefficients with age of proband disease onset. In seven affected mother-proband pairs, the probands had a tendency to more severe disease, despite shorter disease duration and younger age. CONCLUSIONS--This preliminary analysis has suggested that within pedigrees in which the mother has RA, the features of genetic anticipation and observations consistent with premutation models may prevail.     

Ages of onset suggestive of genetic anticipation in rheumatoid arthritis multicase sibships can be explained by observational bias

OBJECTIVES: Previous work has suggested that features of genetic anticipation might be present in familial rheumatoid arthritis (RA), but bias is difficult to exclude when looking at disease in two consecutive generations. We used data from the North American Rheumatoid Arthritis Consortium (NARAC) and the Arthritis Research Campaign National repository for RA multicase pedigrees to determine whether differences in age of onset within multicase sibships were supportive of genetic anticipation. METHOD: RA sibling pairs were identified from both data sets. The period of observation was defined as the time between the first sibling developing RA and the time that the sibship was ascertained for the study. A paired t-test for the difference in ages of RA onset within the pairs was calculated. Ages of conception of the parent were correlated with the age of RA onset. RESULTS: Information was available for 743 sibships in the NARAC data set and 396 sibships in the Arthritis Research Campaign (ARC) data set. In both data sets, the older siblings had an older age of onset than their younger siblings (39.3 vs 36.9 in the NARAC, and 43.8 vs 40.1 in the ARC data set, both P < 0.001). The two data sets were then stratified into tertiles by a period of observation. In both data sets, there was a progressive decline in the sibling age of onset differences. For the first tertile (shortest observation period), the older sibling had a significantly older age of onset than the younger. This difference decreased in the second tertile, and was not significant in the third tertile (longest observation period). There was no significant correlation between the age of RA onset and the maternal or paternal ages of conception in either data set. CONCLUSION: Features compatible with genetic anticipation in RA multicase sibships are subject to observational bias. This does not support a role for genetic anticipation in familial RA.     

Family study of fibromyalgia

OBJECTIVE: To assess for familial aggregation of fibromyalgia (FM) and measures of tenderness and pain, and for familial coaggregation of FM and major mood disorder (major depressive disorder or bipolar disorder). METHODS: Probands meeting the American College of Rheumatology criteria for FM and control probands with rheumatoid arthritis (RA) and no lifetime diagnosis of FM were recruited from consecutive referrals to 2 community-based rheumatology practices. Probands were ages 40-55 years and had at least 1 first-degree relative age 18 years or older who was available for interview and examination. All probands and interviewed relatives underwent a dolorimeter tender point examination and a structured clinical interview. Interviewed relatives were asked about first-degree relatives who were not available for interview, using a structured family interview. Logistic and linear regression models, adjusting for the correlation of observation within families, were applied to study the aggregation and coaggregation effects. RESULTS: Information was collected for 533 relatives of 78 probands with FM and 272 relatives of 40 probands with RA. FM aggregated strongly in families: the odds ratio (OR) measuring the odds of FM in a relative of a proband with FM versus the odds of FM in a relative of a proband with RA was 8.5 (95% confidence interval [95% CI] 2.8-26, P = 0.0002). The number of tender points was significantly higher, and the total myalgic score was significantly lower in the relatives of probands with FM compared with the relatives of probands with RA. FM coaggregated significantly with major mood disorder: the OR measuring the odds of major mood disorder in a relative of a proband with FM versus the odds of major mood disorder in a relative of a proband with RA was 1.8 (95% CI 1.1-2.9, P = 0.013). CONCLUSION: FM and reduced pressure pain thresholds aggregate in families, and FM coaggregates with major mood disorder in families. These findings have important clinical and theoretical implications, including the possibility that genetic factors are involved in the etiology of FM and in pain sensitivity. In addition, mood disorders and FM may share some of these inherited factors.     

Genetic anticipation in rheumatoid arthritis in Europe. European Consortium on Rheumatoid Arthritis Families

OBJECTIVE: To investigate whether there is evidence for genetic anticipation in rheumatoid arthritis (RA) in Europe. METHODS: Cross sectional comparison of data from all affected parent-offspring pairs identified among (1) the RA population attending our department and (2) a large cohort of families from RA probands with both parents alive recruited by the European Consortium on RA families (ECRAF) for association studies. Longitudinal comparison between probands with and without parental RA. We used prospectively collected data on disease activity, therapies, and radiological outcomes from our Dutch inception cohort of patients with early RA during the first 6 years of followup. RESULTS: From a total of 683 Dutch and 170 European patients we identified 28 Dutch and 21 European parent-offspring pairs with RA. Probands with parental RA had an earlier disease onset compared with affected parents (Dutch p < 0.002, European p < 0.0001). In Dutch patients, the prevalence of HLA-DR4, DR4 double dose, and shared epitope (SE) double dose was slightly higher in probands with parental RA than in those without [odds ratios (95% CI) 2.0 (0.7-5.8), 2.79 (0.8-9.4), and 2.12 (0.6-8.7), respectively]. The same was true for European probands concerning SE double dose [OR (95% CI) 1.76 (0.6-8.7)]. No other relevant differences in demographic or clinical indices were found between probands with affected parents and those without. Disease course (Disease Activity Score) and therapies used during the first 6 years of followup were similar in Dutch patients with and without parental RA. Radiological damage at baseline was lower in the former group and this difference persisted after 3 and 6 years. CONCLUSION: Our data suggest that genetic anticipation in RA does occur in terms of an earlier disease onset in the offspring. Despite a slightly higher prevalence of HLA alleles encoding for the SE, probands with confirmed parental RA had no worse outcome than those without.     

Dutch patients with familial and sporadic ankylosing spondylitis do not differ in disease phenotype

OBJECTIVE: To assess potential differences in the phenotypic expression between familial and sporadic ankylosing spondylitis (AS). METHODS: Clinical data from the patient record forms were compared between 55 patients with AS from multicase families (i.e., families in which > or = 2 first-degree relatives have the disease) (familial AS) and 110 sex and age matched patients with AS who did not have a first-degree relative with the disease (sporadic AS). RESULTS: Between familial and sporadic AS no differences were found in age at disease onset, age at diagnosis, or prevalences of peripheral arthritis and acute anterior uveitis. CONCLUSION: Potential differences in genetic makeup are not reflected in differences in the phenotypic expression of familial and sporadic AS.     

Preliminary evidence of genetic anticipation in Graves' disease.

Despite strong epidemiologic evidence in favor of a genetic component in the etiology of Graves' disease, few hereditary risk factors have been consistently identified. The term genetic anticipation denotes a decrease in the age of onset as disease is passed through generations. In the past 5 years, genetic anticipation has been described in immune-mediated diseases such as rheumatoid arthritis and chronic inflammatory bowel disease, and recently this phenomenon has been linked to unstable expanded trinucleotide repeat sequences in several diseases. If present in Graves' disease, anticipation could provide clues to its genetic etiology. The aim of the present study was to investigate whether genetic anticipation may occur in Graves' disease. Age at diagnosis and age at ascertainment were registered and compared in 33 same-gender parent-offspring pairs with Graves' disease from multiply affected families primarily ascertained for a genetic linkage study. The mean age at diagnosis was 46.6 years (range, 16-77) in the parents and 34.1 years (range, 16-44) in the children. The difference in the mean age at diagnosis between parents and their children was 12.5 years (95% confidence interval 3.0-21.9), p = 0.010. Children were younger than their parents at diagnosis in 25 of 33 pairs (76%). In 7 pairs (21%), the parent was diagnosed after the child according to the calendar years. Essentially similar results were obtained after controlling for gender and smoking habits. In conclusion, our data suggest that patients in the second affected generation seem to acquire their disease at an earlier time in life in familial cases of Graves' disease, indicating that genetic anticipation might occur.     

Anticipation in familial plasma cell dyscrasias

Familial myeloma was described as early as 1925; however, the causative factors are unknown. Studies of families with other familial haematological malignancies demonstrate anticipation. Five new families are described in which plasma cell dyscrasias occurred in parent and child generations (six such pairs), and data were pooled with those of 16 other families (with 20 parent–child pairs affected) recorded in the literature. Disease-free survival for parent and child generations were each estimated and differences in the disease-free survival between generations were tested by the log-rank and signed rank methods. In all six previously unreported parent–child pairs with plasma cell dyscrasia and in 18/20 such pairs found in the literature, the disease occurred at an earlier age in the child generation. The median age of onset of myeloma in the parent and child generations of all 26 pairs was 71 years (95% CI 67–78 years) and 50 years (95% CI 45–55 years), respectively ( P  < 0.0001). The ages of onset of malignant plasma cell dyscrasias in the parent and child generations of these families compared with patients in the general population were significantly different for the child generation ( P  < 0.005) but not for the parent generation. It would appear that anticipation occurs in familial myeloma.     

Juvenile idiopathic arthritis in multicase families

OBJECTIVE: To characterize juvenile idiopathic arthritis (JIA) patients from multicase families. METHODS: The study series comprised 80 affected siblings belonging to 37 families. Comparisons were made with a population-based series of JIA patients from Finland and with a sibling series from the United States. RESULTS: The distribution of cases according to onset type was similar in the sibling and population-based series. The age at diagnosis was significantly lower in the sibling series (4.8 years vs 7.4 years; p < 0.001). There was more intra-pair similarity in onset and course types in the United States series compared to the Finnish series and the proportion of girls was higher in the former. CONCLUSION: The only significant difference between familial and sporadic cases with JIA is an earlier onset of disease in familial cases. There is no essential difference in clinical features of the disease between patients in the multicase and sporadic groups. Differences between the Finnish and US series may be due to selection bias in the latter.     

Clustering of disease features within 512 multicase rheumatoid arthritis families

OBJECTIVE: To determine whether specific rheumatoid arthritis (RA) disease features demonstrate the presence of significant familial clustering. METHODS: We studied 1,097 individuals with RA from 512 multicase families enrolled in the North American Rheumatoid Arthritis Consortium. All patients were interviewed and examined to collect standardized information about demographic and clinical characteristics. Affected individuals also underwent radiography of the hands and wrists and were genotyped for the HLA-DRB1 shared epitope. Familial clustering of disease features was assessed using contingency table analysis and Pearson correlation coefficients. Multivariate logistic and linear regression analyses were used to account for other characteristics that might influence familial clustering, such as disease duration, sex, and age at diagnosis. RESULTS: Several disease characteristics exhibited significant familial clustering, including seropositivity (multivariate odds ratio [OR] 4.3, P < 0.0001), nodules (OR 2.3, P < 0.0001), and age at RA diagnosis (multivariate regression coefficient [beta] 0.44, P < 0.0001). Other characteristics demonstrated statistically significant but modest degrees of familial clustering (Joint Alignment and Motion score, Health Assessment Questionnaire score, and year of RA diagnosis) or modest but nonsignificant familial clustering (other extraarticular manifestations, other autoimmune diseases). CONCLUSION: The clustering of certain disease characteristics implicates specific genetic or nongenetic causes. These results highlight the importance of considering disease phenotype in future genetic and epidemiologic studies of RA.     

Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds

BACKGROUND & AIMS: Approximately 10% of pancreatic cancers are inherited, but the factors that affect tumorigenesis in familial pancreatic cancer are unknown. We sought to determine whether smoking or other factors could predict cancer risk in familial pancreatic cancer kindreds. METHODS: We conducted a nested case-control study including 251 members of 28 families. All families included 2 or more members with pancreatic cancer. We determined the effects of smoking, young age of onset within the family, diabetes mellitus, sex, and number/standing of affected relatives on the risk of pancreatic cancer. RESULTS: Smoking was an independent risk factor for familial pancreatic cancer (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.8-7.6), and the risk was greatest in males and subjects younger than 50 (OR, 5.2 and OR, 7.6, respectively). Smokers developed cancer 1 decade earlier than nonsmokers (59.6 vs. 69.1 years; P = 0.01), and the number of affected first-degree relatives also increased risk (OR, 1.4; 95% CI, 1.1-1.9 for each additional family member). Diabetes was not a risk factor for pancreatic cancer, although diabetes was associated with pancreatic dysplasia. One third of families demonstrated genetic anticipation, as the mean age of onset decreased by 2 decades between generations. CONCLUSIONS: Smoking is a strong risk factor in familial pancreatic cancer kindreds, particularly among males and those under age 50. Persons with multiple affected first-degree relatives are also at increased risk. These factors may be useful in selecting candidates for pancreatic cancer screening. Members of families with multiple pancreatic cancers should be counseled not to smoke.     

Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins

OBJECTIVE: Twin concordance data for rheumatoid arthritis (RA) on their own provide only limited insight into the relative genetic and environmental contribution to the disease. We applied quantitative genetic methods to assess the heritability of RA and to examine for evidence of differences in the genetic contribution according to sex, age, and clinical disease characteristics. METHODS: Data were analyzed from 2 previously published nationwide studies of twins with RA conducted in Finland and the United Kingdom. Heritability was assessed by variance components analysis. Differences in the genetic contribution by sex, age, age at disease onset, and clinical characteristics were examined by stratification. The power of the twin study design to detect these differences was examined through simulation. RESULTS: The heritability of RA was 65% (95% confidence interval [95% CI] 50-77) in the Finnish data and 53% (95% CI 40-65) in the UK data. There was no significant difference in the strength of the genetic contribution according to sex, age, age at onset, or disease severity subgroup. Both study designs had power to detect a contribution of at least 40% from the common family environment, and a difference in the genetic contribution of at least 50% between subgroups. CONCLUSION: Genetic factors have a substantial contribution to RA in the population, accounting for approximately 60% of the variation in liability to disease. Although tempered by power considerations, there is no evidence in these twin data that the overall genetic contribution to RA differs by sex, age, age at disease onset, and disease severity.     

Evidence for genetic anticipation in nodal osteoarthritis

OBJECTIVE—Evidence was sought for genetic anticipation (disease occurring at an earlier age in subsequent generations, with increasing severity) in nodal osteoarthritis (NOA).
METHODS—Age at symptom onset and disease severity was compared within 30 parent/offspring pairs with NOA. Correlation between the offspring age of disease onset and the parental age at conception was also assessed.
RESULTS—The age at onset of nodal symptoms was earlier in the offspring (43 years (95% confidence intervals (CI) 38 to 47) v 61 (CI 58 to 65); mean difference 18 years (CI 13 to 22): p< 0.001) as was large joint symptom onset (48 years (CI 41 to 55) v 67 (CI 61 to 73); mean difference 20 years (CI 13 to 27): p< 0.01). A negative correlation existed between age of offspring symptom onset and parental age at conception. Fifteen (50%) offspring had similar or more extensive disease than their parents.
CONCLUSIONS—These results suggest genetic anticipation occurs in NOA and if confirmed a search for trinucleotide repeats is warranted.

Keywords: nodal osteoarthritis; genetic anticipation; trinucleotide repeats     

Familial vs sporadic rheumatoid arthritis (RA). A prospective study in an early RA inception cohort

OBJECTIVES: To study potential differences in demographic, process and outcome variables between familial and sporadic rheumatoid arthritis (RA) in an early RA inception cohort. METHODS: In 1998, we ascertained the familial status of all collaborative patients in a large early RA inception cohort at our department. Familial RA was defined by the presence of at least two siblings fulfilling the American College of Rheumatology criteria for RA. Baseline demographic data and prospectively recorded disease activity variables, therapies and radiological damage during the first 6 yr of disease were included in the analysis. A regression analysis was performed to assess whether familial clustering is a prognostic factor. RESULTS: We identified 142 patients with sporadic and 36 with familial RA. The most striking difference between these groups was the larger sibship size in multicase families (8.2 +/- 2.5 vs 5. 5 +/- 2.8; P < 0.0001). Age at onset was similar in both groups, although males with familiar RA were younger at disease onset than those with sporadic RA (median 50 vs 57 yr; P=0.03). No differences were found in gender, presence of rheumatoid factor (RF), antinuclear factor and HLA-DR typing or in disease activity, interventions and outcome over 6 yr of follow-up. Early radiological damage and disease activity, but not familial history of RA were prognostic for X-ray damage. CONCLUSION: We show that sibship size is the only relevant risk factor for familial RA. No differences in genotypic and phenotypic characteristics, disease severity or radiological damage were observed among familial and sporadic RA. Familial history of RA is not a poor prognostic factor. This prospective study confirms previous cross-sectional findings in the Dutch population.     

Influence of male sex on disease phenotype in familial rheumatoid arthritis

OBJECTIVE: To examine sex differences in clinical, demographic, and genetic characteristics among a large cohort of patients with familial rheumatoid arthritis (RA). METHODS: We studied 1,004 affected members of 467 Caucasian multicase RA families recruited from the North American Rheumatoid Arthritis Consortium. Standardized information about demographic and clinical characteristics was collected from all patients. Affected individuals also underwent radiography of the hands and were genotyped for markers in the HLA region. Sex differences were assessed using contingency table analysis (for categorical variables) and Student's t-tests for (continuous variables), and by multivariate logistic and linear regression analysis. RESULTS: Male patients had a significantly later onset of RA, were more likely to be seropositive for RF, and had significantly higher titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies compared with female patients, even after adjustment for covariates in multivariate analyses. Male patients were also significantly more likely to have a history of smoking and to be HLA-DRB1 shared epitope (SE) positive. Interestingly, female patients with an affected male sibling had significantly higher titers of anti-CCP antibodies and were more likely to be SE positive compared with female patients without affected male siblings. Multivariate analyses indicated that the presence of the SE did not fully explain the increased anti-CCP antibody titers observed in these families. CONCLUSION: Sex has an important influence on the disease phenotype in RA, including the age at disease onset and autoantibody production. Furthermore, families with affected male members are characterized by higher titers of autoantibodies, particularly anti-CCP antibodies. Our results indicate that these findings are not fully explained by differences in exposure to tobacco smoke, presence of the HLA-DRB1 SE, or other HLA region genetic variation. Thus, other genetic or nongenetic factors also contribute to sex differences in the RA phenotype.     

Differences between female and male patients with familial rheumatoid arthritis

OBJECTIVE: To determine whether there are genetic differences between female and male patients with familial rheumatoid arthritis (RA). METHODS: 45 men and 119 women from 78 families with RA who all had at least one first degree relative with RA were compared. HLA-DRB1 alleles were analysed, including DRB1*04 subtypes and associations of DRB1*04 haplotypes with DQB1*0301 or DQB1*0302 alleles, the age of the patients at disease onset, the presence of rheumatoid factor (RF), joint erosions, and rheumatoid nodules. RESULTS: HLA-DRB1*13 allele (the subtype allele of DR6, reported to be protective against the development of RA) was found in 14/119 (12%) of female but in none of the male patients (p=0.036). The HLA-DR4 allele was found slightly more often in men than women patients with familial RA (31/45 (69%) v 75/119 (63%), NS). Men were also more often RF positive than women (44/45 (98%) v 98/117 (84%); p=0.031). On the other hand, the mean age at onset of RA was significantly lower in the female group (40.4 years) than in men (46.6 years, p=0.0044). CONCLUSION: The results indicate that there is stronger genetic background in familial male than female patients with RA in the genetic susceptibility defined by the studied HLA antigens. However, the earlier age of onset of the disease in female group and the increased proportion of women with RA indicate that there are additional sex related predisposing factors enhanced in familial cases.     

Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma

Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain neurological and haematological disorders. This study was conducted to determine whether anticipation occurs in familial non-Hodgkin's lymphoma (NHL). Eleven published reports of multigenerational familial NHL were analysed for evidence of anticipation, together with 18 previously unreported families with familial NHL. Differences in disease-free survival between generations were determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. These analyses were also performed separately using only parent-child pairs with age of onset > 25 years to avoid ascertainment bias. In addition, the age at onset distribution of the studied cases was compared with that of the Surveillance Epidemiology and End Results (SEER) Program using data for 1973-98. The median ages at onset in the child and parent generations of all families (48.5 and 71.3 years respectively) and in the selected pairs (52.5 and 71.5 years respectively) were significantly different (P < 0.000002 and P < 0.000001 respectively). The null hypothesis was rejected for all (P < 0.000001) as well as selected pairs (P < 0.000003). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.009), but not between the parent generation and the SEER population. Anticipation occurs in familial NHL, which suggests a genetic basis for it.     

Prevalence and distribution of autoimmune diseases in 368 rheumatoid arthritis families

OBJECTIVE: To investigate whether frequency of rheumatoid arthritis (RA) and/or other autoimmune (AI) disorders was increased in RA French Caucasian families among the first- (FDR) and second-degree relatives (SDR), and to test whether the presence of AI disease family history identified a specific RA subset. METHODS: We conducted telephone interviews to obtain histories of AI diseases among the FDR and SDR of 368 RA probands, belonging either to trio or affected sib-pair (ASP) families. All the AI diagnoses were confirmed by the physician of the affected relative. RESULTS: Probands of the ASP families were characterized by older age at RA onset, longer disease duration, and larger family size versus trio families. In the trio families, the prevalence of AI diseases was 6.05% (4.76%-7.57%) in FDR and 2.40% (1.85%-3.06%) in SDR. In ASP families, the prevalence of AI diseases was, respectively, 10.24% (8.68%-11.97%) and 1.79% (1.41%-2.25%). The most frequent AI diseases among relatives were RA, thyroid AI diseases, and vitiligo. In trio families, a proband with a mean age of RA onset < 30 years was associated with AI disease prevalence in the relatives, and male gender was associated with prevalence of RA among the FDR. CONCLUSION: The prevalence of AI diseases is increased, particularly among FDR, in French RA families, and some characteristics of the RA proband seem to be associated with prevalence of AI diseases in families.     

Family study of fibromyalgia

Objective

To assess for familial aggregation of fibromyalgia (FM) and measures of tenderness and pain, and for familial coaggregation of FM and major mood disorder (major depressive disorder or bipolar disorder).

Methods

Probands meeting the American College of Rheumatology criteria for FM and control probands with rheumatoid arthritis (RA) and no lifetime diagnosis of FM were recruited from consecutive referrals to 2 community‐based rheumatology practices. Probands were ages 40–55 years and had at least 1 first‐degree relative age 18 years or older who was available for interview and examination. All probands and interviewed relatives underwent a dolorimeter tender point examination and a structured clinical interview. Interviewed relatives were asked about first‐degree relatives who were not available for interview, using a structured family interview. Logistic and linear regression models, adjusting for the correlation of observation within families, were applied to study the aggregation and coaggregation effects.

Results

Information was collected for 533 relatives of 78 probands with FM and 272 relatives of 40 probands with RA. FM aggregated strongly in families: the odds ratio (OR) measuring the odds of FM in a relative of a proband with FM versus the odds of FM in a relative of a proband with RA was 8.5 (95% confidence interval [95% CI] 2.8–26, P = 0.0002). The number of tender points was significantly higher, and the total myalgic score was significantly lower in the relatives of probands with FM compared with the relatives of probands with RA. FM coaggregated significantly with major mood disorder: the OR measuring the odds of major mood disorder in a relative of a proband with FM versus the odds of major mood disorder in a relative of a proband with RA was 1.8 (95% CI 1.1–2.9, P = 0.013).

Conclusion

FM and reduced pressure pain thresholds aggregate in families, and FM coaggregates with major mood disorder in families. These findings have important clinical and theoretical implications, including the possibility that genetic factors are involved in the etiology of FM and in pain sensitivity. In addition, mood disorders and FM may share some of these inherited factors.

     

Anticipation phenomenon in familial adenomatous polyposis:an analysis of its origin

AIM:To analyze the origin of the anticipation phenomenon, which means earlier death in successive generation in familial adenomatous polyposis.METHODS:The study subjects were 2161 patients with familial adenomatous polyposis and their 7465 first degree relatives who were members of 750 families registered at our Polyposis Registry. The ages at death and cumulative mortality rates in theparent, the proband, and the child generations were compared for both all subjects and the patients alone.RESULTS:In the patients over 5 years of age, the mean age at death was 50.9 years for the parent, 42.3 years for the proband, and 33.3 years for the child generations, respectively a(c)(P < 0.001). The deceased rates in the three generations were 90.7%, 51.3% and 23.1% of the patients, respectively, and this difference was the main cause of the anticipation measured by parent-child paring method. The cumulative mortality rates for all subjects failed to show anticipation, however the cumulative mortality rates for the patients showed the anticipation. The anticipation phenomenon was shown by any parent-child pairing methods for the deceased patients. Other important causes of the anticipation were different proportion of causes of death between generations a(c)(P <0.001), and a low proportion of detected or deceased patients (P < 0.001) in the child generation.CONCLUSION:Anticipation in familial adenomatous polyposis may be caused by parent child paring methods as well as several intergenerational biases.     

Immunogenetic differences between patients with familial and non-familial rheumatoid arthritis

OBJECTIVE: To search for possible immunogenetic differencies between the patients with familial and non-familial rheumatoid arthritis (RA). METHODS: The study compared 129 familial RA patients with 217 non-familial patients for the frequencies of HLA-DR antigens including DR4 subtypes, DR4-DQB1*0301 and DR4-DQB1*0302 haplotypes and HLA-B27 antigen as well as the age of disease onset and existence of rheumatoid factor or joint erosions. RESULTS: Two major differences between familial and non-familial groups were found: firstly, familial RA patients had increased frequency of HLA-DR4 as compared with the non-familial RA group (68.2 v. 54.8%; p = 0.019). Secondly, the mean age at onset of RA was significantly lower in the familial than in the sporadic RA patients (42.0 v. 46.5 years; p = 0.0020) and the difference still remained when the DR4 positive and negative subgroups were compared separately. CONCLUSION: These results confirm the more prominent association with HLA-DR4 in familial than in the non-familial cases and suggest that accumulation of HLA risk genes may, at least partly, explain the familial occurrence of the disease. Other susceptibility genes may also be concentrated in multiplex case families as suggested by an earlier age at the onset of RA in both HLA-DR4 positive and negative familial patients.