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PubMed2000

The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Groupe Français d'Etude Génétique des Spondylarthropathies.

OBJECTIVE: To investigate the interrelationships among different phenotypes, and their relationship to the HLA-Blocus, in multiplex families with spondylarthropathy (SpA). METHODS: We recruited 115 white French families, each of which had at least 2 members with SpA. Pedigrees were established. Clinical data and pelvic radiographs were collected. The HLA-B27 status of all patients was determined. Analysis was performed to determine the prevalence of SpA manifestations according to sex, disease duration, and HLA-B status, and to examine clustering of specific manifestations in subsets of families. RESULTS: We identified 329 SpA patients. Mean +/-SD age at onset was 24+/-9.4 years. The male:female ratio was 186:143, or 1.3, with few sex differences in disease expression. Axial manifestations and HLA-B27 were each present in 97% of the patients. Inflammatory bowel disease and HLA-B35 were overrepresented in the 7 families containing HLA-B27-negative patients. The frequency of radiographic sacroiliitis increased in parallel with disease duration. Peripheral enthesitis, radiographic sacroiliitis, and psoriasis were evenly distributed in the families. Clustering independent of age was only observed for peripheral arthritis, suggesting that specific factors may predispose individuals to this manifestation. CONCLUSION: Familial SpA appears to be homogeneous, based on the high frequencies of axial skeletal involvement and HLA-B27. The lack of clustering of most manifestations in families suggests that a predominant shared component, including HLA-B27, predisposes individuals to all forms of familial SpA, and that ubiquitous genetic or environmental factors contribute to phenotype diversity.

Adult↗
PubMed2002

CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy.

OBJECTIVE: To analyze the CARD15 gene in families with heritable multi-organ granulomatoses, including the original Blau syndrome kindred as well as other families with related granulomatous conditions. METHODS: Linkage mapping was performed in 10 families. Observed recombination events were used to exclude regions centromeric or telomeric to 16q12.1, and the Blau gene critical region was refined to <3 cM, corresponding to a physical distance of 3.5 megabasepairs. Based on its known biochemical function, CARD15 was analyzed as a positional candidate for the Blau syndrome susceptibility gene, by direct DNA sequencing. RESULTS: These studies resulted in the identification, in 5 of the families, of 2 sequence variants at position 334 of the gene product (R334W and R334Q). Affected family members from the original Blau syndrome kindred were heterozygous for the R334W missense mutation; mutations at the same position were also observed in several unrelated Blau syndrome families, some of whose phenotypes included large-vessel arteritis and cranial neuropathy. The missense mutations segregated with the disease phenotype in the families, and were not seen in 208 control alleles. CONCLUSION: These findings demonstrate that CARD15 is an important susceptibility gene for Blau syndrome and for other familial granulomatoses that display phenotypic traits beyond those of classic Blau syndrome.

Arteritis↗
PubMed1994

Exon eight APC mutations account for a disproportionate number of familial adenomatous polyposis families.

The familial adenomatous polyposis gene, APC, has recently been identified. Detection of APC mutations will facilitate genetic screening in family members at risk for this disease. The length of APC makes it impractical to examine the entire coding sequence in each new family encountered. Identification of mutation cluster regions within the gene has therefore become a priority. Initial reports suggested that exon eight might contain a disproportionate number of mutations. This study describes direct sequencing of exon eight in 21 unrelated Australians with familial adenomatous polyposis. Mutations were detected in three of the 21 subjects (14%). Two were previously described point mutations changing an arginine to a stop codon. The third was a novel two base-pair deletion producing a frameshift and downstream stop codon. All three mutations segregated with the disease gene in their respective families. Three at risk children from two of these families were studied and shown not to have inherited the disease producing mutation. These results confirm that exon eight is a frequent site of mutation in familial adenomatous polyposis and should be examined routinely in families requesting genetic screening.

Adenomatous Polyposis Coli↗
PubMed2003

Scaling law in sizes of protein sequence families: from super-families to orphan genes.

It has been observed that the size of protein sequence families is unevenly distributed, with few super families with a large number of members and many "orphan" proteins that do not belong to any family. Here it is shown that the distribution of sizes of protein families in different databases and classifications (Protomap, Prodom, Cog) follows a power-law behavior with similar scaling exponents, which is characteristic of self-organizing systems. Since large databases are used in this study, a more detailed analysis of the data than in previous studies was possible. Hence, it is shown that the size distribution is governed by two exponents, different for the super families and the orphan proteins. A simple model of protein evolution is proposed, in which proteins are dynamically generated and clustered into families. The model yields a scaling behavior very similar to the distribution observed in the actual sequence databases, including the two distinct regimes for the large and small families, and thus suggests that the existence of "super families" of proteins and "orphan" proteins are two manifestations of the same evolutionary process.

Algorithms↗
PubMed1999

Work and Family Stress and Well-Being: An Examination of Person-Environment Fit in the Work and Family Domains.

Research indicates that work and family are significant sources of stress. However, this research has underemphasized the cognitive appraisal process by which work and family generate stress. This study used person-environment fit theory to examine how the comparison of work and family experiences to the person's values relates to stress and well-being. Using data from 1758 employees, we assessed fit regarding autonomy, relationships, security, and segmentation for both work and family, and examined the relationship of fit with work and family satisfaction, anxiety, depression, irritation, and somatic symptoms. In general, well-being improved as experiences increased toward values and improved to a lesser extent as experiences exceeded values. Well-being was also higher when experiences and values were both high than when both were low. These relationships were generally strongest for within-domain fit and well-being (i.e., work fit and work satisfaction, family fit and family satisfaction), and several relationships were moderated by work and family centrality. Copyright 1999 Academic Press.

Journal Article↗
PubMed2003

Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics.

If the risk of disease is not the same for all germline mutations in a given gene, or if there are other familial modifiers of risk in carriers, then family-history-based estimates of average risk for detected mutations in that gene will depend on how carriers are sampled. Risk may also depend on the site or type of mutation. We studied 51 families with strong histories of breast cancer who attended Australian family cancer clinics and in which a germline mutation in BRCA1 or BRCA2 had been identified (28 and 23 families, respectively). Breast cancer risk in carriers was estimated under maximum likelihood theory, using information from all family members including those not tested, with adjustment for ascertainment by conditioning on genotype of the proband and family phenotype. The average cumulative risk of breast cancer for mutations in either BRCA1 or BRCA2 was 27% (95% confidence interval 16-43%) to age 50 and 64% (44-83%) to age 70. When grouped, the incidence in carriers was on average 17 (10-30) times that in non-carriers, independent of gene or mutation type (hazard ratios: 11 (4-29) for BRCA1, 23 (12-43) for BRCA2 (P for difference = 0.23); 13 (6-29) for protein-truncating mutations, 30 (9-104) for missense mutations and 30 (10-90) for splice-site mutations). For missense mutations, this was equivalent to a cumulative risk to age 70 of 83% (40-100%) and was due in part, but not totally, to the missense mutations 300 T>G in BRCA1 and 4486 G>T in BRCA2, which were individually found to be associated with high risk (P<0.001). Mutations in the central region of BRCA1 may be associated with a lower risk. The issue of the pathogenicity of specific variants may be addressed analytically providing there are one or more suitably informative families with that mutation.

Age Factors↗
PubMed1984

Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia).

The histologic characteristics of the parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia) are disputed, some finding parathyroid hyperplasia and others finding no abnormalities. To further investigate this issue, the histologic appearance of 82 parathyroid glands from 47 control patients (surgical and autopsy) were compared with those of 28 glands from 23 patients with familial hypocalciuric hypercalcemia who had undergone surgery for suspected primary hyperparathyroidism. Median and mean weights of 23 parathyroid glands from 12 patients with familial hypocalciuric hypercalcemia were 50 mg and 60 mg, respectively, with a range from 5 to 181 mg. Eighty-three percent of individual glands were within extreme normal limits for weight (less than 75 mg). Percent parenchymal area in familial hypocalciuric hypercalcemia was slightly but significantly less than control values (62 +/- 2 versus 71 +/- 2 percent, respectively; (p = 0.009). Conversely, percent fat was higher in familial hypocalciuric hypercalcemia than control values (30 +/- 3 versus 21 +/- 2 percent, respectively; p = 0.015). Stromal area was 8 +/- 1 percent in each group. Although 15 to 20 percent of parathyroid glands in familial hypocalciuric hypercalcemia exceeded normal size, most were indistinguishable from normal by size, weight, and microscopic appearance. The significantly reduced percent parenchyma in glands from patients with familial hypocalciuric hypercalcemia further suggests that the condition is not uniformly accompanied by typical parathyroid hyperplasia and should not be thought of as merely a variant of the latter.

Adenoma↗
PubMed2003

Evaluation of familial clustering of breast and prostate cancer in the Minnesota Breast Cancer Family Study.

Few studies examining familial clustering of breast and prostate cancer (PC) have focused on a clearly defined high-risk population with epidemiologic risk factors. We conducted a cohort study of prostate cancer among a subset of 426 families ascertained through female breast cancer probands. Three groups of males were included: 804 relatives in 60 families with four or more breast or ovarian cancers, 536 marry-ins in these high-risk families, and 484 relatives in 81 families where only the proband had breast cancer. A total of 118 prostate cancers were reported. The rate of prostate cancer among blood relatives in high-risk families was significantly lower than among marry-ins (RR = 0.6, 95% C.I.: 0.4-0.9). The rate of prostate cancer among blood relatives in low-risk families was not significantly different from the rate among marry-ins (RR = 0.8, 95% C.I.: 0.5-1.2). These results provide little evidence that male relatives in high-risk breast cancer families are at increased risk of prostate cancer.

Adult↗
PubMed2003

Expression of serum human leukocyte antigen and growth factor levels in a Greek family with familial endometriosis.

OBJECTIVE: An increased incidence of endometriosis in the first-degree relatives of patients with endometriosis has been reported, suggesting a familial predisposition and possible genetic influence. In this study, we present a family with four members who have histologically proven endometriosis (mother and three daughters) in two generations and one member with suspected endometriosis in the third generation. The aim of this study was to investigate the presence of serum-soluble class I and class II human leukocyte antigen (sHLA) levels, because they have been shown to be reduced in women with endometriosis. We also studied the levels of vascular endothelial growth factor (VEGF) and epidermal growth factor-receptor (EGF-Rc) whose function in angiogenesis implies an active role in endometriosis. METHODS: Apart from the family members under study, the control groups consisted of 38 women with endometriosis and 30 without any pelvic disease. All the soluble factors under investigation were measured by an enzyme-linked immunosorbent assay technique using a specific immunoassay. RESULTS: All the affected family members and the 38 women with endometriosis had very low levels of serum-soluble class I and class II HLA levels compared with healthy subjects. The circulating levels of VEGF were higher in the endometriosis group than the healthy control group, a pattern in accordance with the family members. On the contrary, EGF-Rc was negative in controls and women with endometriosis, with the exception of certain family members in specific stages of endometriosis. CONCLUSION: We studied the association of endometriosis with circulating levels of human leukocyte antigens and VEGF in two generations of a single family (mother and three daughters). These markers were expressed distinctly in women with familial endometriosis.

Adolescent↗
PubMed1998

Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases.

Germline mutations in the BRCA1 gene predispose to breast and ovarian cancer. An estimated 45% of families with multiple breast cancer cases and more than 80% of breast-ovarian cancer families are linked to BRCA1. Mutation analyses by collaborative laboratories have revealed around 460 distinct BRCA1 sequence alterations, mostly germline mutations from familial cases. The majority of these alterations were nonsense and frame-shift mutations. In the present study, breast tumors of both sporadic and familial origin were investigated for allelic imbalance (AI) at the BRCA1 locus. AI was observed in 52% of the sporadic cases and in 17% of the familial cases. Furthermore, 104 breast carcinomas from patients with sporadic disease and 77 patients with positive family histories of breast and/or ovarian cancer were examined for translation-terminating mutations in exon 11 of the BRCA1 gene using the protein truncation test (PTT). No somatic mutations were detected in any of the tumors analysed, and only one BRCA1 mutation carrier was found among the familial cases. The result of this study gives no indication that truncating somatic mutations in exon 11 of BRCA1 play a major role in the tumorigenesis of the breast. Furthermore, the frequency of such mutation carriers in breast cancer populations with weak family histories of breast and/or ovarian cancer seems to be low.

Breast Neoplasms↗
PubMed2000

Familial aggregation of amount and distribution of subcutaneous fat and their responses to exercise training in the HERITAGE family study.

OBJECTIVE: Investigate the familial aggregation of amount and distribution of subcutaneous fat and their changes in response to endurance training. RESEARCH METHODS AND PROCEDURES: A total of 483 sedentary subjects from 99 nuclear families were recruited, trained for 20 weeks of exercising on cycle ergometers, and measured before and after training for the following indicators of subcutaneous fat and fat distribution: trunk fat (TRUNK = sum of abdominal, subscapular, suprailiac, and midaxillary skinfolds), extremity fat (EXTREM = sum of biceps, triceps, thigh, and calf skinfolds), subcutaneous fat (SF8 = sum of the eight skinfolds), the trunk to extremity skinfolds ratio adjusted for SF8 (TER) and waist girth adjusted for body mass index (WAIST). The familial aggregation of the age- and sex-adjusted baseline phenotypes and their responses to training (delta) after adjustment for the baseline values was investigated using a familial correlation model. RESULTS: Significant familial aggregation was observed for all the phenotypes measured at baseline and for deltaTRUNK and deltaWAIST. Transmissibility estimates reached about 30% to 35% for TRUNK, EXTREM, and SF8 and 50% for TER and WAIST. The transmissibilities of the response phenotypes were lower, ranging from 0% for deltaWAIST to 21% for deltaTRUNK and the pattern of familial correlations suggested a greater within- than between-generation resemblance in the response. DISCUSSION: This study suggests that the amount and distribution of subcutaneous fat strongly aggregates in families, whereas the response to exercise training is characterized by a moderate and more complex pattern of familial resemblance. We conclude that familial/genetic factors are more important in determining the amount and distribution of subcutaneous fat than their responses to exercise training.

Adipose Tissue↗
PubMed2001

Family dynamics of child-bearing families in Athens, Greece: a pilot study.

The purpose of this pilot study was to describe family dynamics in Greek families during the third trimester of a low-risk pregnancy with a first or second child. The description is based on Barnhill's framework for healthy family systems. The sample consisted of families expecting their first or second child. Both mothers (n = 160) and fathers (n = 47) participated in the study. The Family Dynamics Measure and a sociodemographic questionnaire were used in data collection. Data on 160 mothers and 47 couples were analyzed. Fathers perceived their families as having greater stability and role reciprocity than mothers. Fathers also reported clearer communication than mothers. There were no statistically significant relationships among family dynamics dimensions, maternal age and parity. Delayed first-time expectant mothers reported greater flexibility than normative first-time expectant mothers. The results provide some useful clues for prenatal care and also for further family dynamics research in Greece.

Adolescent↗
PubMed2000

Familial aggregation of stroke volume and cardiac output during submaximal exercise: the HERITAGE Family Study.

Familial aggregation of stroke volume (SV) and cardiac output (Qc by CO2 rebreathing) at 50 Watts (W) and 60 % of maximal oxygen uptake (VO2max) as well as their changes in response to a 20-week endurance exercise training program was assessed in 99 Caucasian families who participated in the HERITAGE Family Study. In order to interpret familial influences independent of effects of age, sex, and body size (indexed by body surface area here), SV and Qc levels were adjusted for these primary parameters prior to genetic analysis within four sex-by-generation groups (the responses to training were additionally adjusted for their baseline values). Maximal heritabilities for baseline SV, Qc, and their changes in response to training during the two stages of submaximal exercise were estimated using a familial correlation model. At 50W, maximal heritabilities reached 41% and 42% for baseline SV and Qc, respectively, and were 29% and 38% for the respective responses to training. At 60% of VO2max, maximal heritabilities reached 46 % for baseline SV and Qc, and were 24% and 30% for the respective responses to training. Generally there were no meaningful differences between the maximal heritabilities at 50 W and 60% of VO2max. However, the maximal heritabilities for the baseline were slightly higher than the estimates for the changes in response to training. Based upon results arising from these non-obese, non-hypertensive, and sedentary families, we found that SV and Qc at 50 W and 60% of VO2max as well as their changes in response to the 20-week endurance exercise training were moderately heritable. Not only genetic determinants but also familial non-genetic factors might attribute to the observed patterns of familial aggregation of SV and Qc during submaximal exercise in the present study.

Adult↗
PubMed1992

Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val-->Ile.

Following the identification of mutations in the beta-amyloid precursor protein (APP) gene in familial, early onset Alzheimer's disease (AD), we have developed a screening protocol using single strand conformation analysis (SSCA) to screen exon 17 for the known mutations within APP. In addition, we used this protocol to screen the other seventeen exons of APP and a three hundred and thirty base pair regulatory region of the promoter for new mutations in 9 families with early onset AD. Exons 16 and 17, which encode the deposited beta-amyloid peptide, were screened in a further 10 families. Our screening procedure identifies all the reported mutations within APP. While we have identified a further family with APP717 Val-->Ile, we did not find any previously undescribed mutations. Screening of other exons of APP in 2 families in which we have previously reported mutations at APP717, failed to reveal other sequence abnormalities supporting the hypothesis that the mutations at APP717 cause the disease in these families. These data suggest that mutations in APP are a rare cause of familial early onset AD (3/21 families tested) and that within APP most, possibly all, mutations which cause AD are in exon 17.

Adult↗
PubMed2001

Familial multiple myeloma: a family study and review of the literature.

BACKGROUND: The etiology of multiple myeloma (MM) remains obscure, although reports of familial clustering have implicated both a host susceptibility factor and environmental effects. Here we describe the medical histories of members of a family prone to MM. METHODS: We developed a pedigree for an MM-prone family by using information obtained from a questionnaire. Protein immunoelectrophoresis of serum and urine from the proband and from 19 family members was performed to detect monoclonal immunoproteins. Peripheral blood obtained from the proband and from five relatives was subjected to standard cytogenetic studies to detect constitutional chromosomal abnormalities. Multifluor-fluorescence in situ hybridization (M-FISH) and standard FISH studies were performed on peripheral blood from the proband and from two other affected living relatives to determine their karyotypes and to detect clonal chromosomal abnormalities frequently seen in patients with MM. RESULTS: Within this family, a sibship of seven included three individuals (including the proband) with histologically verified MM and two individuals with a monoclonal gammopathy of unknown significance (MGUS), as determined by immunoelectrophoresis of serum and urine. This family also had members with acute lymphocytic leukemia, malignant melanoma, and prostate cancer. In the family members tested, we detected no constitutional chromosomal abnormality. None of the three individuals analyzed by FISH had a deletion of the retinoblastoma (Rb-1) locus, which is frequently deleted in patients with MM, and only one (the proband) had a translocation involving chromosomes 11 and 14, a clonal abnormality commonly seen in MM. CONCLUSION: The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders.

Adenocarcinoma↗
PubMed2004

Parental familial vulnerability, family environment, and their interactions as predictors of depressive symptoms in adolescents.

OBJECTIVE: Familial risk for depression results from both biological and social influences. These may also be associated with other characteristics, including alcohol use, smoking, and body mass index (BMI), and with environmental risks such as social problems, life events, and educational level, all of which may be associated with depression in offspring. The authors examined the links between (1) parental familial vulnerability to depression and (2) the role of associated parental characteristics on severe adolescent depressive symptoms. Third, the authors explored the influence of family environment variables. Fourth, the authors sought interactions between parental familial vulnerability and family environment. METHOD: Questionnaires were obtained from 1,294 parents of 1,818 adolescent offspring. RESULTS: The odds of severe adolescent depressive symptoms increased by a factor of 1.5 per standard deviation increase in parental familial vulnerability to depression (odds ratio [OR] = 1.50). Parental BMI (OR = 1.05) and educational level (OR = 2.60) had significant influences independent of parental vulnerability. Analyses indicated a significant interaction such that those with high parental familial vulnerability, whose parents also had no qualifications, had a threefold risk of severe depressive symptoms. CONCLUSIONS: Adolescents with a family history of depression whose parents also lack qualifications may be a target for intervention.

Adolescent↗
PubMed1990

Familial acromegaly: studies in three families.

Acromegaly is usually regarded as a disease which arises sporadically except on those rare occasions in which it occurs as one component of an inherited pluriglandular syndrome. Familial acromegaly occurring in isolation has been reported only rarely. We have studied three families in each of which two first-degree relatives have developed acromegaly without clinical evidence of other endocrinopathies, in order to clarify the relationship of familial acromegaly to multiple endocrine neoplasia, type 1 (MEN 1). No further subclinical cases of acromegaly have been detected in those first-degree relatives of the index cases who were screened. In two of the families, we have found no evidence of abnormal pancreatic or parathyroid function either in the acromegalic index cases or their asymptomatic relatives: a diagnosis of MEN 1 is therefore effectively excluded. In the third family, the presence of multiple subcutaneous lipomata in several members of the family and elevation of PTH levels in two (normocalcaemic) acromegalic index cases, might indicate a highly atypical presentation of MEN 1. None of the six acromegalic index cases had elevations of circulating growth hormone releasing hormone levels. We conclude that isolated familial acromegaly may be more common than has hitherto been realized and that, in these families at least, ectopic production of growth hormone releasing hormone is not responsible.

Acromegaly↗
PubMed2004

Estimation of the familial relative risk of cancer by site from a French population based family study on colorectal cancer (CCREF study).

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of death from cancer in France. A family history of CRC increases an individual's risk of developing CRC. Family history has been suggested to have a greater impact on proximal than distal tumours. AIM: We estimated the familial risk of CRC and other cancers, and examined how risk varies according to localisation of the tumour in the colorectal tract. SUBJECTS: We recorded all cases of CRC diagnosed between 1993 and 1998 in the region served by the Calvados Cancer Registry. A trained interviewer asked all participants about their family history of cancer. STATISTICAL METHODS: Familial risk was estimated from a cohort analysis of the relatives of the CRC cases. The expected numbers of cancers were calculated from Calvados incidence rates. Familial relative risks were calculated using standardised incidence ratios. RESULTS: Our findings showed that colon cancer had a stronger familial/genetic component (relative risk (RR) 1.47) than rectal cancer (RR 0.98). The familial/genetic component appeared stronger for proximal colon cancer than for distal colon cancer only among women (RR 2.24 v RR 1.45). CRC appeared to be positively associated with leukaemia (RR 1.77), stomach cancer (RR 1.32), and testicular cancer (RR 3.13), and negatively associated with urinary bladder cancer (RR 0.57) within families. The cancer spectrum associated with CRC among younger participants included prostate (RR 1.93), uterus (RR 2.49), and thyroid (RR 3.85) cancers. CONCLUSION: If our results are confirmed, follow up guidelines for patients with a family history of CRC should depend on the sex and tumour site of affected relatives to avoid needless invasive screening.

Adult↗