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.

     

Substance use and other psychiatric disorders in first-degree relatives of opioid-dependent males: a case-controlled study from India

To assess the prevalence of substance use and other psychiatric disorders in first-degree relatives of males with opioid dependence compared to normal controls. DESIGN: Observational, case-control study using family history method. SETTING: A drug addiction treatment centre in northern India. PARTICIPANTS: First-degree relatives of 100 male probands with opioid dependence and no comorbidity (n=493) and those of 50 matched probands from normal population (n=254). Measurement Family interview of probands and family members, using the Family Interview for Genetic Studies. The main outcome measure was relative risk (expressed as odds ratio after controlling for confounding variables using logistic regression) of familial aggregation of psychiatric and substance use disorders. FINDINGS: First-degree relatives of opioid-dependent males were more likely to have a psychiatric disorder than those of normal controls [adjusted odds ratio (OR) 4.47; 95% confidence interval (CI) 1.97-10.11; P<0.001], especially for opioid use disorders in the brothers (adjusted OR 6.55; 95% CI 1.44-29.88; P=0.015) and for alcohol use disorders in the fathers of the probands (adjusted OR 5.64; 95% CI 2.39-13.24; P<0.001). Other disorders (major depression, chronic psychosis and obsessive compulsive disorder) did not have significant aggregation in the first-degree relatives of opioid-dependent subjects. CONCLUSIONS: This study provides further evidence for the higher rates of alcohol and opioid dependence in first-degree relatives of opioid-dependent patients. The exact pattern of this familial aggregation may be influenced by the gender of the relatives and their relation to the proband.     

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.     

The familial aggregation of cannabis use disorders

Aims   The aim of this paper is to examine the familial aggregation of cannabis use disorders and other psychiatric conditions among first-degree relatives and spouses of probands with a cannabis use disorder.
Design   Controlled family study methods.
Setting   Out-patient psychiatric clinics and the local community (same geographic area).
Participants   Two hundred and sixty-two probands with a life-time history of cannabis use disorder, alcohol dependence, anxiety disorders or no history of any disorder, and their first-degree relatives and spouses.
Measurements   Cannabis use disorders and other DSM-III-R disorders in the relatives and spouses using the Schedule for Affective Disorders and Schizophrenia.
Findings   Results reveal an elevated risk of life-time history of cannabis use disorders among siblings [odds ratio (OR: 3.6), adult offspring (OR): 6.9], and spouses (OR: 4.4) of probands with cannabis use disorders. There is a latent familial factor underlying cannabis use disorders that was shared partially with alcohol abuse/dependence. Comorbid mood and anxiety disorders aggregated independently from cannabis use disorders in families. Equal elevation in the magnitude of the association among the first-degree adult relatives and spouses of probands with a cannabis use disorder suggests the probable contribution of both environmental and genetic factors.
Conclusions   These findings support a family-based approach to drug abuse intervention and the importance of future research concerning environmental mediators of familial transmission of drug abuse.     

Prevalence of familial hyper- and hypolipoproteinemias: The Princeton School District Family Study

Using the Princeton School Family Study cohort, our specific aim was to estimate the prevalence of suspected familial hyper- and hypolipoproteinemias, and to provide empirical coronary heart disease (CHD) risk estimates for the proportion of probands' first-degree relatives who were similarly affected. Two hundred and seventy two white probands, 125 randomly recalled, 147 from a hyperlipidemic recall group, and their relatives were assessed. Suspected familial hyper- and hypolipoproteinemias were arbitrarily identified in those kindreds having at least 2 first-degree relatives in the same decile as the proband, top or bottom respectively, for low or high density lipoprotein cholesterol (LDLC, HDLC). Of the 125 randomly recalled probands, 3 had suspected familial hypercholesterolemia (FH), the probands and 3 additional first-degree relatives having top decile LDLC. Of 53 top decile LDLC probands from the hyperlipidemic recall group, 6 (11%), and 7 (13%) came from kindreds where the proband and at least 2 and 3 additional first-degree relatives respectively had top decile LDLC; 3 (6%) had tendon xanthomas. In the 16 top decile LDLC probands with at least 2 similarly affected relatives, overt diseases, drugs, and dietary excess did not appear to cause elevated LDLC. Of the 272 kindreds, there was one (random recall) kindred with familial hypobetalipoproteinemia, and there were 4 (2 random recall, 2 hyperlipidemic recall) with familial hyperalphalipoproteinemia. An average of 32% and 22% of the first-degree relatives of top decile LDLC and HDLC probands respectively also had top decile LDLC and HDLC; 27% and 16% of first-degree relatives of bottom decile LDLC and HDLC probands respectively also had bottom decile LDLC and HDLC. Given our current state of knowledge, we cannot yet provide a definitive conclusion regarding the relative and absolute contributions of single genes, multiple genes, environment, and environment: genetic interactions to familial aggregation of hyper- and hypolipoproteinemias. Whatever definition of FH is used, the high prevalence of FH in the Family Study underlines the importance of sampling all first-degree relatives of top decile LDLC probands; clustering of CHD in families may be related in part to familial aggregation of LDLC and/or HDLC.     

Cancer Risk among the Relatives of Patients with Pancreatic Ductal Adenocarcinoma

Background/Aims: Pancreatic cancer is a leading cause of cancer-related death; the most consistently identified risk factors are smoking and family history. Our aims were to examine familial aggregations of pancreas and other cancers, and to determine the relative risk of the family members. Methods: We prospectively collected data on the families of patients presenting with pancreatic ductal adenocarcinoma. Smoking habits and alcohol consumption of the probands were compared with the available statistics on the Italian population. Mortality from cancer was investigated in first-degree relatives, and age-dependent risks of dying from pancreatic cancer and other tumors were compared with background population levels. Results: Data for 570 families were collected, including 9,204 relatives. Probands were 3- to 5-fold more often heavy smokers than the general population, and 9.3% of them reported a positive family history of pancreatic cancer. In first-degree relatives, only mortality from pancreatic cancer was significantly increased (relative risk at age 85 years = 2.7). Lifetime risk of dying of pancreas cancer was 4.1% for the relatives of all probands, and was 7.2% for the relatives of probands who developed disease before 60 years of age. Conclusions: The data suggest that genetic susceptibility to pancreatic cancer may be attributable, in addition to BRCA2,to moderate-to low-penetrance gene(s).     

A genetic analysis of smoking behavior in family members of older adult males

Aims. To conduct a genetic study of smoking behavior in 493 three-generation families. Design. Complex segregation analysis and maximum likelihood statistics were used to describe the familial clustering of ever-smoking under several transmission models. Setting. The Western Collaborative Group Study, an ageing and health study currently in its 39th year of follow-up. Participants. Probands were male participants who were of mean age 71.6 years at the time of the family history interview in 1986-88. Measurements. Data were collected via an interview that focused on the family smoking history of participants. Smoking histories of all first-degree relatives were obtained from probands. Findings. Evidence for genetic transmission was indicated by rejection of both the environmental and sporadic models in favor of a Mendelian genetic model with residual familial effects from spouses and both parents. Conclusions. The best-fitting model was that of a dominant major gene with low estimated frequency and residual familial correlations. This is the first study to date to model the familial transmission of ever-smoking in three-generation families.     

Familial seropositive rheumatoid arthritis in North American Native families: effects of shared epitope and cytokine genotypes

OBJECTIVE: A number of North American native (NAN) populations have high prevalence rates of both rheumatoid arthritis (RA) and the shared epitope (SE). We examined the phenotype and familial incidence of RA in a NAN population, and investigated how the SE and cytokine genes may affect disease risk within affected families. METHODS: NAN patients with seropositive RA or polyarthritis rheumatoid factor (RF) positive juvenile idiopathic arthritis (JIA) were identified from clinical databases. Patients were recruited consecutively as they presented for clinic visits. Family pedigrees were constructed and consenting relatives were interviewed and examined. The risk of RA within families was calculated by multiple logistic regression. Input variables were the SE and cytokine genotypes. Probands and affected relatives were entered as the affected group, and unaffected relatives within families as the unaffected group. Results were confirmed among unrelated subjects, i.e., unrelated patients and unaffected relatives of other probands. RESULTS: The familial prevalence of RA was 0.50 (95% confidence intervals 0.30, 0.70) among 28 families studied. The interleukin 10 (IL-10) promoter -1082 G/A genotype decreased the odds of RA relative to the A/A genotype in affected families (OR 0.247, 95% CI 0.081, 0.751; p = 0.014) and among unrelated subjects (OR 0.203, 95% CI 0.064, 0.640; p = 0.006). The G/G genotype yielded an OR of 0.093 (95% 0.013, 0.676; p = 0.019) among unrelated subjects. The SE had no effect in these calculations. CONCLUSION: There was a high familial prevalence of RA in this NAN cohort. In susceptible NAN families, the risk of RA was reduced by IL-10 genotypes, whereas the SE did not affect risk. Study of healthy NAN controls is required to determine if these conclusions apply to this NAN population as a whole.     

Familial aggregation of ankylosing spondylitis in Southern China

OBJECTIVE: To study the familial aggregation of ankylosing spondylitis (AS) in southern China and to compare the clinical and laboratory characteristics between the probands and their first-degree relatives with AS. METHODS: On the basis of questionnaires to 473 patients with AS, 402 responded and 36 self-reported having first-degree relatives with symptoms related to spondyloarthropathies. All together, 144 of 150 first-degree relatives of these 36 probands were examined for clinical and radiographic characteristics. HLA typing for HLA-B27 was performed by standard microlymphocytotoxicity method. RESULTS: The disease duration of the 36 probands was 5.03 +/- 3.76 years (0.5-14 yrs). Forty seven first-degree relatives of the 36 probands were diagnosed as having AS. The prevalence of AS among the first-degree relatives of these 36 aggregated families was 31.3%. The overall prevalence of AS among the first-degree relatives in these 402 families was estimated to be 2.8%. The recurrence risk of the first-degree relatives within these aggregated families was 31.3%, suggesting an excess risk to them of 120.4, while it was 10.8 to the general families. The probands more often had peripheral arthritis and enthesopathies (p < 0.001 and p = 0.01, respectively) than the AS patients among the first-degree relatives. HLA-B27 was associated with development of AS in the probands and the patients among the first-degree relatives. CONCLUSION: Although familial aggregation of AS in southern China is uncommon in general, the recurrence risk of the first-degree relatives of AS probands within the aggregated families is extremely high, according to our study among hospital based patients. As the disease of the first-degree relatives is often mild and atypical, familial background analysis should be encouraged to assist early diagnosis.     

Familial obesity and leanness

Using the Princeton School District Family Study cohort, our specific aim was to estimate the prevalence of suspected familial ponderosity and leanness, to provide empirical risk estimates for the proportion of probands' first-degree relatives who were similarly affected, and to estimate the contributions of diseases, drugs and caloric intake to relative obesity and leanness. We studied 379 probands, 125 whites and 52 blacks from a random recall group, 147 whites and 55 blacks from a hyperlipidemic recall group. Suspected familial obesity and leanness were arbitrarily identified in those kindreds with at least two first-degree relatives in the same Quetelet index decile as the proband, top or bottom respectively. Suspected familial obesity was observed in 2.4 percent and 6 percent respectively of random and hyperlipidemic recall group whites. Suspected familial leanness was identified in 2.4 percent and 1.4 percent of random and hyperlipidemic recall whites and in 3.8 percent of randomly recalled blacks. Approximately twice as many as expected white first-degree relatives of top Quetelet index decile probands themselves had top decile Quetelet indices; approximately three times as many as expected first-degree relatives of bottom decile Quetelet index probands themselves had bottom decile Quetelet indices. Nineteen percent and 31 percent of top decile Quetelet index white probands from random and hyperlipidemic recall groups came from families where at least two other first-degree relatives were similarly obese; 18 percent and 20 percent of white random and hyperlipidemic recall group probands with bottom decile Quetelet indices had suspected familial leanness. Nearly all subjects with familial obesity or leanness had no overt metabolic or pharmacological explanations for their body habitus. Within-family clustering of hypertension was common in kindreds with suspected familial obesity and was absent in kindreds with suspected familial leanness. Marked within-family clustering of both obesity and leanness is useful diagnostically; therapeutic intervention to reduce obesity, to be most effective, should be family-wide in the many kindreds which share familial obesity.     

Familial hyper- and hypouricemias in random and hyperlipidemic recall cohorts: the Princeton School District Family Study

Using the Princeton School Family Study, our specific aim was to estimate the prevalence of familial hyper- and hypouricemia, to estimate the proportion of probands' first-degree relatives who were similarly affected, and to evaluate the contribution of diseases, drugs, and alcohol intake (if any) to uric acid levels. We studied 379 probands and a total of 1928 subjects, 125 and 52 black probands from a randomly recalled group, 147 white and 55 black probands from a hyperlipidemic recall (top decile cholesterol and/or triglyceride) group. Familial hyper- and hypouricemias were arbitrarily identified in those kindreds having at least two first-degree relatives in the same decile as the proband, top or bottom respectively, for serum uric acid. No probands had symptomatic gout. Diseases, drugs, and alcohol intake were not consistently associated with aggregations of high and/or low uric acid levels in families, and had little relationship to uric acid levels in individuals. Of the 177 randomly recalled probands, and of the 55 black probands in hyperlipidemic recall familial hyperuricemia, with concurrent primary hyperlipoproteinemia and hypertension. Familial hypouricemia was present in 1 of 125 white and in 1 of 52 randomly recalled black kindreds, and in 3 of 147 white and 3 of 55 hyperlipidemic recall black kindreds. While familial clustering of hyperuricemia was limited, clustering of hypouricemia was much more marked. Seventy-four and 84% respectively of first-degree relatives of hypouricemic white and black probands had uric acid less than the 50th percentile. In randomly recalled probands and their first-degree relatives there were significant inverse partial correlations between uric acid and high density lipoprotein cholesterol. Inverse associations of uric acid with high density lipoprotein cholesterol and the concurrence of hyperlipoproteinemia and hypertension in hyperuricemic families points to the importance of lipoprotein and blood pressure screening in families with asymptomatic hyperuricemia. The potential ramifications of within-family clustering of hypouricemia need to be further assessed in populations, particularly in regards to uric acid nephrolithiasis.     

Familial occurrence of inflammatory bowel disease in Korea

BACKGROUND: Little information is available about the familial aggregation of inflammatory bowel disease (IBD) in Asian populations. We therefore determined the risk of familial aggregation of IBD among first-degree relatives of patients with ulcerative colitis (UC) or Crohn's disease (CD) in an ethnically distinct Korean population. METHODS: Familial aggregation of IBD was evaluated in terms of family history, prevalence, lifetime risk, and population relative risk in first-degree relatives of 1440 unrelated patients with UC (n = 1043) or CD (n = 397). RESULTS: A positive first-degree family history of IBD was observed in 27 probands (1.88%): 21 of 1043 (2.01%) with UC and 6 of 397 (1.51%) with CD. The crude prevalence of IBD in first-degree relatives of probands with IBD was 0.31%. The lifetime risk of IBD was 0.54% in all first-degree relatives of IBD probands, 0.52% in UC probands, and 0.67% in CD probands, with overall lifetime relative risks of 0.12% in parents, 0.79% in siblings, and 1.43% in offspring. The age- and sex-adjusted population relative risk of IBD was 13.8 in first-degree relatives of probands with IBD. CONCLUSIONS: Although a positive family history, prevalence, and lifetime risk of IBD among first-degree relatives of Korean IBD patients are much lower than among relatives of Western patients, the population relative risk in first-degree relatives is about equal in Koreans and Westerners. This finding indicates that a positive family history is an important risk factor for IBD in Koreans and in Westerners.     

Clinico-genealogical characteristics of patients with ischemic heart disease and different disorders of lipid metabolism]

The paper presents a clinical and genealogical characterization of 50 probands suffering from coronary heart disease concurrent with various lipid metabolic disturbances and 211 first-degree relatives whose data have been obtained from the probands' histories while making up their pedigrees. The prevalence of atherosclerosis among the first-degree relatives has been demonstrated to be related to the nature of lipid metabolic disturbances in a proband. Some dyslipoproteinemias in the proband have been characterized by early onset of coronary heart disease, stroke, and their grave course in close relatives.     

Familial aggregation of non-insulin dependent diabetes and coronary heart disease are accompanied by different effects on serum lipids, lipoproteins and apolipoproteins

This study was designed to investigate whether the presence of non-insulin-dependent diabetes mellitus (NIDDM) or coronary heart disease (CHD) in probands have different effects on serum lipid, lipoprotein and apolipoprotein concentrations in the first-degree relatives. Altogether 161 probands (114 men, 47 women) and 788 first-degree relatives of these probands (174 brothers, 246 sisters, 180 sons, 188 daughters) were included in the analyses. The presence of NIDDM in the proband was associated with lowered total, LDL and HDL cholesterol and apolipoprotein A1 and elevated total triglyceride levels in the brothers (P less than 0.05) and elevated total and LDL cholesterol levels in the sisters (P less than 0.05). Total LDL and VLDL cholesterol and apolipoprotein B were higher (P less than 0.05) and HDL/total cholesterol ratio and apolipoprotein A1/B ratio lower (P less than 0.05) in the daughters of the nondiabetic and diabetic probands were pooled, CHD in the proband was associated particularly with low apolipoprotein A1/B ratio. In conclusion, (1) the presence of NIDDM in the proband appears to be associated in siblings with more profound lipid and lipoprotein changes (especially low HDL cholesterol and high total triglycerides) than a history of CHD in the proband, (2) a history of CHD in the proband is associated in children with apolipoprotein changes favouring atherosclerosis (low apolipoprotein A1, high apolipoprotein B, low apolipoprotein A1/B ratio). Different effects of a history of NIDDM and CHD in the proband on lipid, lipoprotein and apolipoprotein levels in the first-degree relatives warrants more population-based studies.     

Familial aggregation of rheumatoid arthritis in The Netherlands: a cross-sectional hospital-based survey. European Consortium on Rheumatoid Arthritis families (ECRAF).

OBJECTIVES: To study the familial aggregation of rheumatoid arthritis (RA) in The Netherlands and to analyse the effect of proband characteristics on the concordance rates for RA. Secondary aims were to compare the characteristics of patients in an early RA inception cohort with those of regular patients and to select Dutch families for the genome-wide scan carried out by the European Consortium on RA families (ECRAF). METHODS: A cross-sectional, hospital-based survey aimed to identify affected sibpair (ASP) families among our whole RA population. Familial RA, or an ASP family, was defined by the presence of at least two siblings fulfilling the 1987 ACR criteria for RA. RESULTS: The estimated prevalence for familial RA was 9.8% and similar to that found in previous hospital series. The true-positive reporting rate for RA in sibs was 60%. Sibship size in ASP families (mean +/- S.D. = 7.8+/-3.3) was significantly larger than in the Dutch population. Probands with familial RA were more often rheumatoid factor positive and had a longer follow-up. Male gender and history of joint replacements were associated with higher concordance rates for RA. However, regression analysis showed that, correcting for sibship size, the concordance rate for RA was largely not explained by proband characteristics. Compared to regular RA patients, our inception cohort encompassed more male and/or rheumatoid factor-negative patients, but had similar performance in the study and rate of familial aggregation. CONCLUSIONS: The familial aggregation of RA in The Netherlands is not increased and occurs preferentially in large sibships. Among proband characteristics, sibship size is most clearly related to the recurrence of RA in particular families. Patients' recognition of RA manifestations in relatives is not optimal.     

HLA-linked hemochromatosis alleles in sporadic porphyria cutanea tarda

We tested the hypothesis that the hepatic siderosis that characterizes sporadic porphyria cutanea tarda is due to the presence of HLA-linked hemochromatosis alleles. We studied 21 probands with sporadic porphyria cutanea tarda and 135 of their relatives by determining HLA haplotypes and measuring transferrin saturation and serum ferritin concentration. Liver biopsies were performed in all probands and in relatives when appropriate. Seventeen pedigrees were available and were studied by both likelihood analysis and by a gene counting method. We estimated that 10 of the 17 probands with available living relatives possessed at least one hemochromatosis allele. Thirteen of the 21 probands (62%) possessed at least one HLA-A3 alloantigen. Eighteen of 69 relatives who shared an HLA haplotype with a proband (26%) had an elevation of transferrin saturation or serum ferritin concentration. Only one first-degree relative not sharing an HLA haplotype with a proband had an elevated transferrin saturation or serum ferritin concentration. These findings indicate that HLA-linked hemochromatosis alleles are far more common in patients with sporadic porphyria cutanea tarda than in individuals in the general population and may be responsible for the hepatic siderosis associated with most cases of sporadic porphyria cutanea tarda.     

Prevalence of familial malignancy in a prospectively screened cohort of patients with lymphoproliferative disorders

Increasing evidence points to a heritable contribution in the development of lymphoma. The goal of this study was to determine the rate of familial lymphoproliferative malignancy among consecutive lymphoma patients presenting to a tertiary care center and to enroll families with multiple affected first-degree relatives on a data and tissue collection study. Beginning in 2004 all new patients presenting to the Dana-Farber Cancer Institute with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) or chronic lymphocytic leukaemia (CLL) were asked to complete a one-page self-administered family history questionnaire. 55.4% of 1948 evaluable patients reported a first-degree relative with a malignancy, with the highest rate among CLL probands. Lymphoid malignancies were particularly common, with 9.4% of all probands reporting a first-degree relative with a related lymphoproliferative disorder (LPD). This frequency was again highest for CLL, at 13.3% of CLL probands, compared to 8.8% of NHL probands and 5.9% of HL probands (P = 0.002). The prevalence of CLL was significantly increased in parents of CLL probands (P < 0.05), and a greater risk of NHL was seen in fathers of NHL probands than in mothers (P = 0.026). We conclude that familial aggregation of LPDs is common among newly diagnosed patients, varies significantly by diagnosis and contributes meaningfully to the population disease burden.     

Specific familial transmission in substance abuse

In contrast to studies on alcoholism, there is little documentation on familial transmission of drug abuse. This study was designed to determine whether specific familial transmission of substance abuse occurs: a greater incidence of drug abuse in probands with a family history of drug abuse than in those with a family history of alcoholism. Probands were 305 consecutively admitted patients to an inpatient chemical dependency treatment center, whose substance abuse/dependence diagnoses were based on DSM-III criteria and a structured interview. Family history data were obtained from each proband. Log linear analysis investigated the association between family and proband substance abuse. As abuse of nonalcoholic substances was significantly greater in probands with family histories of drug abuse, specific familial transmission is suggested.     

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.     

Linkage of rheumatoid arthritis with HLA.

OBJECTIVE--To determine whether HLA exerts a variable influence on the predisposition of siblings of probands with clinically mild and severe rheumatoid arthritis (RA). METHOD--Calculation of crude and adjusted odds ratios for concordance rates in sibships sharing two, one and no HLA haplotypes with a proband with clinically mild and severe RA, and HLA haplotype sharing in multiply affected sibships in the same clinical groups. RESULTS--Compared with a reference value of 1.0 in siblings sharing no HLA haplotypes with a proband with mild RA, siblings sharing two HLA haplotypes with a severely affected proband had a sibship concordance rate odds ratio of 9.7 (95% confidence interval 2.5 to 38.2). When adjusted for age, sex, and disease duration, the odds ratio was 7.6 (1.8 to 32.4). No other sibships showed concordance rates which were significantly higher than the reference group. HLA haplotype sharing in multiply affected sibships in which the proband had severe RA deviated significantly from random (two, one, and no HLA haplotypes shared: 53.3, 40, and 6.7%, respectively; expected 25, 50, and 25%), whereas in sibships of probands with mild RA they did not (14.6, 70.8, and 14.6%). CONCLUSIONS--In the predisposition of siblings to RA, sharing HLA haplotypes with a proband is only important if the proband has severe RA. Mild RA is not genetically linked to the HLA region.