Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands

OBJECTIVE: To estimate in a Chinese population the prevalence of undifferentiated spondyloarthropathy (USpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) probands, and to compare the clinical features of familial USpA with those of sporadic USpA. METHODS: The FDRs of two separate cohorts of consecutive AS probands were evaluated for the prevalence of USpA, using the Modified New York criteria and the European Spondylitis Study Group criteria for AS and SpA, respectively. Sporadic USpA and FDRs of non-SpA rheumatic patient probands served as separate controls. RESULTS: Among the 301 FDRs of 102 AS probands, 7.0% were USpA. This was 1000 times higher than the 147 FDRs of 40 non-SpA probands (P = 0.00230). Within the AS families, USpA was less male-dominated than AS (33.3 vs 72.5%) (P = 0.006). The only feature distinguishing familial from sporadic USpA was that the percentages of HLA B27 were 100 and 50%, respectively (P<0.001). CONCLUSION: USpA and AS coexist in the same Chinese families, both being predisposed by HLA B27. In these families, a female gender favours the development of USpA rather than AS. A significant subset of sporadic USpA (HLA B27-negative group) has a different genetic predisposition compared with familial USpA.     

Familial dilated cardiomyopathy in patients transplanted for idiopathic dilated cardiomyopathy

OBJECTIVE: To evaluate the prevalence, clinical features, and pattern of inheritance of familial dilated cardiomyopathy (DCM) in heart transplant patients. PATIENTS AND METHOD: Patients with idiopathic DCM who had undergone heart transplantation were invited to participate. Patients with alcohol abuse were excluded. A clinical evaluation, 12-lead ECG, echocardiogram, blood tests, and DNA extraction were performed in patients and relatives. Familial DCM was defined as the presence of at least one relative with idiopathic DCM. Possible familial DCM was considered when at least one relative had left ventricular enlargement (LVE) (> 112% predicted LVEDD). RESULTS: One hundred and ninety-nine relatives of 43 families were studied. DCM was familial in 11 probands (25.6%) and possibly familial in 11 (25.6%). Fifteen relatives had DCM (7.5%), 26 (13.1%) LVE, and 5 (2.5%) hypertrophic cardiomyopathy. The pattern of inheritance was autosomal dominant in most families. Five probands (3 with familial DCM) had antecedents of consanguinity and possible recessive inheritance. Six probands (14%, 1 with familial DCM) had relatives with conduction system defects. Creatine kinase was moderately increased in 9 relatives (4.5%), 3 of them with LVE. Fifteen patients had at least moderate alcohol intake. Three of them had familial DCM (relatives without alcohol abuse) and 6 had possible familial DCM. CONCLUSIONS: The prevalence of familial DCM is high in patients who undergo heart transplant. Left ventricular enlargement, conduction system abnormalities, and elevated creatine kinase may be early markers of familial disease. Hypertrophic cardiomyopathy is present in some relatives of patients with idiopathic DCM. Familial DCM is present in patients with a previous diagnosis of alcoholic DCM.     

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.     

Frequency of NOD2/CARD15 variants in both sporadic and familial cases of Crohn''s disease across Italy. An Italian Group for Inflammatory Bowel Disease study

BACKGROUND: Three variants of the NOD2/CARD15 gene are strongly associated with susceptibility to Crohn's disease; however, striking racial and geographic differences of their frequency have been described. AIMS: We have compared the allele frequencies of familial cases of Crohn's disease recruited in a multicentre study across Italy, in order to disclose possible geographic heterogeneity. Moreover, we also compared the allele frequencies in sporadic cases of Crohn's disease and healthy controls from Southern Italy with those reported in other two populations from Central and Northern Italy. SUBJECTS AND METHODS: A total of 731 subjects were genotyped for the polymorphism of three main variants (R702W, G908R and 1007 fs): 152 patients were familial cases of Crohn's disease, 183 were healthy first-degree relatives, 180 were sporadic cases of Crohn's disease, and 216 were unrelated healthy subjects. RESULTS: The frequency of the frameshift mutation (1007 fs) was significantly higher in both familial and sporadic cases of Crohn's disease (P = 0.000001), and healthy first-degree relatives (P = 0.0001) compared to controls. At least one risk allele was found in 44% of familial Crohn's disease patients, compared to 7% of healthy controls (OR = 4; CI = 2-6.5). Two risk alleles were found in 14% of familial Crohn's disease, compared to less than 1% of controls (OR = 26: CI = 4-129). CONCLUSIONS: Our data confirm the strong correlation between the 1007 fs variant and Crohn's disease, in both familial and sporadic cases. Moreover, no significant difference of allele frequencies was detected in familial cases, sporadic cases and healthy controls among different geographic areas of Italy.     

Familial Occurrence of Coronary Heart Disease According to Clinical Manifestation

ABSTRACT. Occurrence of different clinical manifestations of coronary heart disease (CHD) was assessed among the parents and siblings of 309 men with CHD (case probands), including 103 men with fatal and 100 with nonfatal myocardial infarction (MI), and 106 men with angina pectoris (AP) and among the relatives of 106 reference men. CHD was equally common among relatives of all case probands. It was four times as common in case brothers and twice as common in case sisters as in the respective reference siblings. There were differences between the various case groups as to the predominant clinical manifestation of CHD. Cardiac deaths were commonest in the sibs of men with fatal MI, and uncomplicated angina in the men with AP. The familial resemblance in the clinical manifestations of CHD suggests familial influence in the mechanisms determining the clinical expression of the disease.     

Equivocal and borderline myocardial hypertrophy in relatives of patients with hypertrophic cardiomyopathy: possible implications in genetics of the disease

To determine the occurrence of familial and sporadic forms of hypertrophic cardiomyopathy (HC) 74 first-degree relatives of 21 patients with proven HC were studied by M-mode and two-dimensional echocardiography. A diagnosis of HC was made in 11 relatives (15%) while it was excluded in 61 of them (82%); 2 subjects (3%) were considered neither affected nor unaffected (borderline left ventricular hypertrophy suggestive of HC). Inspection of pedigrees revealed 38% of familial forms of HC with an autosomal dominant pattern of inheritance in 5/8 families (62%). Furthermore, among those relatives judged unaffected by means of full echocardiographic criteria for HC, an attempt was made to find out whether minor changes of left ventricular geometry were present for their possible implications in genetics of HC (latent or potential forms, low phenotypic expression of the disease). Eleven out of 61 unaffected relatives had a left ventricular wall thickness radius ratio greater than 0.50 (equivocal hypertrophy), a value that was higher than two standard deviations of the control group. Assessment of clinical significance of borderline and equivocal hypertrophy in relatives of patients with HC is required for a better understanding of genetic transmission of this disease. In this view the occurrence of sporadic and familial forms of HC might be revisited.     

Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.     

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.     

Abnormalities of pulmonary venous flow in patients with lone atrial fibrillation.

AIMS: Mechanisms underlying lone atrial fibrillation (LAF) are poorly defined. We sought to investigate indices of left atrial (LA) function in patients with recurrent LAF, in comparison with that in healthy subjects. METHODS AND RESULTS: Investigations were performed in 42 patients aged 51.8 +/- 8.7 at least 30 days after the last episode of LAF and in 38 healthy controls. Each subject underwent echocardiographic evaluation including left ventricular parameters and LA function indices. LA ejection fraction served as a measure of LA systolic performance, and acceleration (SAT) and deceleration time (SDT) of systolic phase of pulmonary venous flow (PVF) corresponded to LA relaxation and compliance, respectively. Patients with LAF showed significantly lower values of SAT (179.1 +/- 63.2 vs. 199.2 +/- 45.1 ms, P < 0.02) and higher values of SDT (250.8 +/- 81.6 vs. 211.7 +/- 57.3 ms, P < 0.01) when compared with controls. No significant differences were found with respect to other measured parameters. The combination of SAT < 185 ms and SDT > 239 ms showed a positive predictive value of 92% in the identification of patients prone to LAF. CONCLUSION: This study suggests that (i) patients with LAF have abnormalities of the systolic phase of PVF and (ii) Doppler estimation of PVF seems to be very valuable in the evaluation of patients with LAF.     

Alcohol-related Symptoms in Heterogeneous Families of Hospitalized Alcoholics

Heterogeneity in the clinical symptoms of alcohol abuse was examined in 243 men and 305 women from families of hospitalized alcoholics, who had demonstrated different patterns of inheritance of susceptibility to alcoholism. Discriminant analysis was utilized to identify nine alcoholic symptoms that distinguished male relatives of alcoholic men from those of alcoholic women. Inability to abstain from alcohol, fighting and reckless driving while intoxicated, and alcohol treatment other than Alcoholics Anonymous were more prevalent in families of male probands. Male relatives of female probands experienced later onset of loss of control over drinking associated with benders, and cirrhosis and feelings of guilt. Female relatives of alcoholic men and women showed a marked predominance of the latter (Type 1) features, whereas male relatives had different clinical features, depending on the associated mode of inheritance.     

Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care

CONTEXT AND OBJECTIVE: Constitutional delay of growth and puberty (CDGP), more commonly observed in boys than girls, often has a familial background. We characterized the occurrence of CDGP in relatives of CDGP patients to elucidate the mechanisms influencing timing of puberty. PARTICIPANTS AND DESIGN: We identified 492 subjects with CDGP from hospital records of two pediatric clinics in Finland; 95 male and 29 female subjects and their first-degree relatives participated. In family members, CDGP was defined by use of growth charts (growth spurt taking place 2 sd beyond the mean). One third of the families was expanded to include also second-degree relatives with an interview-based assessment of pubertal timing. RESULTS: Of males, 80%, and of female probands, 75% had first-degree relatives with CDGP. Of all probands, 45% had one parent (unilineal families) and 32% had two parents affected. In 2% of the families, only siblings were affected. The prevalence of CDGP in male first-degree relatives was only slightly higher than in female relatives: 79 of 148 (53%) vs. 64 of 164 (39%), respectively (P=0.01); male to female ratio was 1.2:1. In 74% of extended unilineal pedigrees (17 of 23), the inheritance pattern of CDGP was consistent with autosomal dominant inheritance. CONCLUSIONS: CDGP clusters in families. Although its inheritance likely is complex, some predisposing genetic factors may have a dominant effect. CDGP was almost as common in male and female relatives of the CDGP subjects seen at specialist care, challenging the view of a marked overall male preponderance of CDGP.     

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.     

CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies

OBJECTIVES: The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. METHODS: Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. RESULTS: In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P>or=0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). CONCLUSION: In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.     

血浆抵抗素水平与心房颤动关系的临床研究

目的：通过测定血浆抵抗素的水平,研究其在孤立性心房颤动（房颤）的发生与维持中的作用;同时分析影响其水平的相关因素及房颤的风险因素。方法研究对象为2014年6月至12月因心悸等不适就诊我院心内科的患者140例,其中试验组为房颤人群,分为孤立性房颤（60例）和房颤合并高血压（55例）;根据发病时间不同,孤立性房颤又分为阵发性与持续性房颤,各30例。正常对照组为正常人群,共25例。使用单因素方差分析比较房颤人群与正常人群血浆抵抗素水平的差异。用 Pearson 及多重线性回归法分析影响房颤患者抵抗素水平的相关因素。用 Logistic 回归分析影响房颤的风险因素。结果①超敏 C 反应蛋白（hs-CRP）及血浆抵抗素水平：所有房颤组的水平均高于对照组,其中孤立性房颤组低于房颤合并高血压组;阵发性房颤组低于持续性房颤组。② Pearson 相关分析：血浆抵抗素水平与hs-CRP 水平、左房内径大小及收缩压均呈正相关（分别为 r ＝0．530,P ＝0．000;r ＝0．265,P ＝0．004;r ＝0．364,P ＝0．000）。多重线性回归分析进一步显示收缩压（SBP）、hs-CRP 水平与血浆抵抗素的水平存在线性关系：Y ＝－2．172＋0．089 SBP ＋1．347 hs-CRP（R2＝0．307,P ＜0．05）。③ Logistic 回归分析表明血浆抵抗素水平、hs-CRP 水平均被纳入回归方程,且 OR 值均＞1。结论①血浆抵抗素水平孤立性房颤组明显高于对照组,其中又以持续性房颤组增高为著,表明抵抗素与房颤的发生、节律的维持相关。②血浆抵抗素水平与 hs-CRP 的水平呈正相关,间接表明房颤的发生可能与抵抗素具有某种炎性特质相关,提示抵抗素可引起炎症反应并和炎症介质一起参与了房颤发生、维持。③血浆抵抗素水平在房颤合并高血压患者中升高明显,且具有协同效应,提示抵抗素也许具有独立表达高血压与房颤疾病的潜质。同时本研究也证实了高血压为房颤的风险因素,可推测抵抗素通过高血压影响房颤。     

Clinical characteristics of familial versus sporadic Crohn's disease using the Vienna Classification

BACKGROUND: The etiology of Crohn's disease, an illness protean in its manifestations, may be better resolved through studies involving more homogenous subgroups of patients. Because a strong genetic influence exists, family history of inflammatory bowel disease may be a useful variable for patient classification if patients with familial and sporadic Crohn's disease are clinically different. Our study attempted to define any possible differences. METHODS: The medical records of 552 patients were reviewed, and patients were classified according to guidelines of the Vienna Classification. Patients were then divided based on family history of inflammatory bowel disease, and the familial and sporadic groups were compared. RESULTS: Overall, 422 (78.9%) patients were diagnosed before age 40 years (A1) and 114 (21.1%) at age 40 years or older (A2). There were 141 (26.3%) patients with disease involving the terminal ileum only (L1), 211 (39.4%) in the colon only (L2), 117 (21.9%) in the terminal ileum and colon (L3), and 66 (12.3%) in the upper gastrointestinal tract (L4). Disease behavior, as determined at the time of last visit or telephone contact, was nonstricturing, nonpenetrating (B1) in 149 (27.9%) patients, stricturing (B2) in 50 (9.3%) patients, and penetrating (B3) in 336 (62.8%) patients. Comparisons among the groups of 53 patients with first-degree relatives only, the 96 patients with either first-, second-, or third-degree relatives (familial CD group), and the 439 patients with sporadic disease demonstrated no differences in sex, age at diagnosis, or disease location. There was a difference in disease behavior between the familial and sporadic groups (p = 0.048) that failed to exist when nonstricturing, nonpenetrating cases were excluded. No such difference was observed between the first-degree relatives only group and the sporadic group (p > 0.10). CONCLUSIONS: Using the Vienna Classification, familial and sporadic Crohn's disease differed only in disease behavior. However, this difference failed to exist after patients with nonstricturing, nonpenetrating disease were excluded. Therefore, familial and sporadic groups appear to be quite similar clinically, and family history does not appear to be a variable useful for disease subclassification.     

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.     

A comparison of clinical and immunogenetic features in familial and sporadic rheumatoid arthritis

Clinical and immunogenetic factors were compared in 214 patients with sporadic rheumatoid arthritis (RA) and 117 patients from 52 multiplex families. Sex distribution, articular disease severity and seropositivity for rheumatoid and antinuclear factors were similar in familial and sporadic disease. There was a trend for Sj?gren's and Felty's syndromes to be more frequent in familial RA but extraarticular disease features were otherwise similar in the 2 RA disease groups. Mean age of onset was 41.1 years in familial and 46.5 years in sporadic RA (p less than 0.0006); 67% of family probands, 74% of affected relatives and 57% of sporadic patients were HLA-DR4 positive (p less than 0.05 affected relatives vs sporadic). The similarity of clinical features found in familial and sporadic RA justifies the use of families with RA to study aspects of disease pathogenesis.     

Characteristics of patients undergoing atrial fibrillation ablation: trends over a seven-year period 1999-2005

Background: Catheter ablation procedures for treating atrial fibrillation (AF) have dramatically increased since triggers of AF were first described in 1998.
Objective: We explored changes in patient characteristics in patients referred for catheter ablation of AF over a seven-year period from 1999 through 2005.
Methods: Patient characteristics were examined for all patients undergoing AF ablation from 1999 through 2005 at the University of Pennsylvania Health System (UPHS). The gender of patients undergoing ablation was also compared with outpatients seen at UPHS with a primary diagnosis of AF.
Results: From 1999 to 2005 the number of patients undergoing ablation has increased steadily, from 29 patients in 1999 to 265 patients in 2005 (P < 0.01). Patients have become older (47 to 56 years; P < 0.01), with more persistent or permanent AF (17% to 45%; P < 0.01), larger left atrial size (4.0 to 4.4 cm; P < 0.01), and fewer antiarrhythmic drugs used prior to ablation (3.9 to 2.0 drugs; P < 0.01). Patients undergoing ablation have been predominantly male, with a significantly higher male prevalence than patients seen in the UPHS outpatient primary care clinic with AF (77% vs 59% male; P < 0.001).
Conclusions: Patients undergoing AF ablation from 1999 to 2005 are older, with larger left atrial size, more persistent/permanent AF, and fewer prior antiarrhythmic agents used. Compared with the gender-specific rates of AF in the population, the majority of patients referred for ablation are men, suggesting a referral bias against this invasive procedure for women. These findings are important for interpreting the outcome of ablation in the current era, and for designing prospective randomized trials.     

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.     

X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation

Introduction: Atrial fibrillation (AF) is a heritable disorder with male predilection, suggesting a sex chromosome defect in certain patients. Loss-of-function truncation mutations in EMD, encoding the nuclear membrane protein emerin, cause X-linked Emery-Dreifuss muscular dystrophy (EDMD) characterized by localized contractures and skeletal myopathy in adolescence, sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a variably associated trait. This study sought to identify the genetic basis for male-restricted, nonsyndromic sinus node dysfunction and AF in a multigenerational family.
Methods and Results: Genealogical and medical records, and DNA samples, were obtained. Progressive SND and AF occurred in four males related through maternal lineages, consistent with X-linked inheritance. Skeletal myopathy was absent, even at advanced ages. Targeted X chromosome genotyping mapped the disease locus to Xq28, implicating EMD as a positional candidate gene. DNA sequencing revealed hemizygosity for an in-frame 3-bp deletion in EMD (Lys37del) in affected males, disrupting a residue within the LEM binding domain critical for nuclear assembly but leaving the remainder of the protein intact. Buccal epithelial cell staining with emerin antibody demonstrated near-total functional loss of emerin. Female relatives underwent prospective electrocardiographic and genetic testing. Those heterozygous for Lys37del had ∼50–70% emerin-positive nuclei and variable degrees of paroxysmal supraventricular arrhythmia.
Conclusions: Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.