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PubMed1996

Children's methods of coping with stress: a twin study of genetic and environmental influences.

The relative importance of environmental and hereditary factors in how children cope with stress was examined. Emotion-focused, problem-focused, and additional coping variables were assessed in 44 monozygotic (MZ) and 30 dizygotic (DZ) twin pairs, aged 9-16 years. The effects of heritability, shared environment, and unshared environment were examined in structural modelling analyses. Genetic factors accounted for a majority of the reliable variance in four of seven coping variables, while effects of twins' shared environment were negligible for all but one coping variable. Environmental factors important to individual differences in coping strategies were primarily unique to each child (unshared between the twins), highlighting the importance of individual experiences in shaping coping behaviors.

Adaptation, Psychological↗

PubMed1994

Repertoire of rat MBP-reactive T cells: DNA sequencing analysis further demonstrates the clonal heterogeneity of rat T cells reactive against encephalitogenic epitopes.

Reports of the expression of very similar TCR structures by disparate rodent encephalitogenic T cells reactive with regions of MBP have aroused much interest for both theoretical and practical reasons. To ascertain the extent to which structural requirements of epitope recognition constrain TCR expression by MBP-reactive T cells, we set out to estimate the size of the overall repertoire of TCR beta-chain V beta-D beta-J beta (VDJ) assemblies in T cells of Lewis rats specific for MBP(68-88) as well as those specific for MBP(87-99). We previously reported that such T cells can express a diversity of V beta genes as revealed by PCR analysis. In this study, we have used direct sequencing of PCR products amplified from encephalitogenic T-cell clones and pauciclonal T-cell lines to demonstrate that VDJ structures of the rat T cells specific for either residues 68 to 88 or 87 to 99 of MBP are highly heterogeneous. Our results showed that (1) no pattern is evident in the utilization of germline J gene segments by individual T-cell clones; from a total of over 100 successfully sequenced clones displaying in-frame rearrangements, all the J beta segments have been demonstrated. (2) Even among the T-cell clones which share the V beta expression, J beta is variable. (3) Due to joining variations between the V beta, D beta, and J beta gene segments, no two of the T-cell clones examined share entire VDJ structures. Our study is the first report of nucleotide and amino acid sequences of TCR beta-chains from rat encephalitogenic T cells expressing V beta genes other than V beta 8.2. It demonstrates that the TCR repertoire of the MBP-reactive as well as encephalitogenic T cells is heterogeneous, even though a certain T-cell subset frequently dominated by the mechanism needs to be clarified.

Amino Acid Sequence↗

PubMed2001

LAP2 binds to BAF.DNA complexes: requirement for the LEM domain and modulation by variable regions.

LAP2 belongs to a family of nuclear membrane proteins sharing a 43 residue LEM domain. All LAP2 isoforms have the same N-terminal 'constant' region (LAP2-c), which includes the LEM domain, plus a C-terminal 'variable' region. LAP2-c polypeptide inhibits nuclear assembly in Xenopus extracts, and binds in vitro to barrier-to-autointegration factor (BAF), a DNA-bridging protein. We tested 17 Xenopus LAP2-c mutants for nuclear assembly inhibition, and binding to BAF and BAF small middle dotDNA complexes. LEM domain mutations disrupted all activities tested. Some mutations outside the LEM domain had no effect on binding to BAF, but disrupted activity in Xenopus extracts, suggesting that LAP2-c has an additional unknown function required to inhibit nuclear assembly. Mutagenesis results suggest that BAF changes conformation when complexed with DNA. The binding affinity of LAP2 was higher for BAF small middle dotDNA complexes than for BAF, suggesting that these interactions are physiologically relevant. Nucleoplasmic domains of Xenopus LAP2 isoforms varied 9-fold in their affinities for BAF, but all isoforms supershifted BAF small middle dotDNA complexes. We propose that the LEM domain is a core BAF-binding domain that can be modulated by the variable regions of LAP2 isoforms.

Amino Acid Sequence↗

PubMed1990

Power-sharing in lesbian partnerships.

This study of 70 lesbian couples explored whether partners who characterized certain aspects of their relationships as equal in power-sharing were similar in age, income, education, and financial assets, while those who viewed their power-sharing as unequal would be dissimilar on these social status variables, and, second, whether or not most lesbian couples considered their relationships as egalitarian. Power-sharing was assessed through a number of questionnaire items, and snowball sampling was utilized. Three types of couples emerged: (a) equal, (b) unequal but in agreement about who had more power, and (c) couples with differing perceptions about power-sharing. The findings indicated that power-sharing arrangements could not be explained by age, income, education, and asset differences between partners. Egalitarianism was the ideal in most relationships, but had not been achieved to the same degree in each of the areas investigated.

Adult↗

PubMed2001

Form species Nostoc commune (Cyanobacteria).

The form species concept for the Cyanobacteria was evaluated using a comprehensive set of Nostoc samples that were collected during the past two centuries, from all continents, including regions from the Tropics to the Poles. Phylogenies were constructed based upon the conserved regions of tRNALeu (UAA) group I intron DNA sequences. Thirty-four forms contained a tRNALeu (UAA) intron of 284 nt. These 284-nt introns contained 200 nt of conserved sequence that, in most cases, shared 100% sequence identity, they had three variable regions (I, II and III) amounting to 84 nt, contained no hypervariable region and formed a discrete cluster in phylogenetic analysis. These forms represented 31 independent populations in both hemispheres and constitute examples of form species Nostoc commune. Multiple introns were obtained from several of the populations. Ten populations contained introns of 287-340 nt with a hypervariable region, 8 to 59 nt in length, located between variable regions I and II. Alignments identified 15 examples where 5'-AAAAUCC-3' occurred at the hypervariable region-variable region II boundary; this sequence is identical to the conserved sequence at the 3' intron-exon boundary (splice site) within the tRNALeu (UAA) gene. The possibility that hypervariable regions were removed from the primary intron through secondary splicing was tested in vitro but proved to be negative under the experimental conditions used. Shared morphologies of genetically different strains, dissimilar morphologies in strains that share identical genetic markers, incorrect naming of culture collection strains and genetic drift in cultured strains emphasize that the successful delineation of cyanobacterial species requires the application of multiple taxonomic criteria.

Base Sequence↗

PubMed2001

Diagnosis as a covariate in sib-pair linkage analysis.

A novel technique to detect significant covariates in linkage analysis using a logistic regression approach is illustrated. An overall test of linkage is first performed to determine whether there is significant perturbation from the expected 50% sharing in sib pairs. Covariates may include variables defined on the sib pair (multiple levels of diagnosis), covariates defined on the parents (parental diagnosis or gender of the transmitting parent), or indicators of study when analyzing multiple datasets to examine heterogeneity. A detailed example using a hierarchical diagnosis of severe, intermediate, mild, and unaffected is provided. This permits testing whether sib allele sharing differs by level of diagnosis and allows the use of discordant pairs to protect against marker allele misspecification.

Genetic Linkage↗

PubMed2005

F-81 skeleton from Wadi Mataha, Jordan, and its bearing on human variability in the Epipaleolithic of the Levant.

The discovery of a Middle Epipaleolithic adult skeleton (F-81) at the site of Wadi Mataha in southern Jordan provides new insights into human variability in the Epipaleolithic of the Levant. This paper analyzes the skeletal morphology of Wadi Mataha F-81 in the context of other Epipaleolithic remains from Jordan and Israel to assess the current evidence for morphological variability throughout this period. The F-81 skeleton shares morphological features with earlier Epipaleolithic skeletons from Ohalo and Nahal Ein Gev, and later Natufian populations. Despite the morphological similarities, F-81 extends the range of known variability prior to the Natufian with its unusually small stature and unique combination of morphological characteristics. High levels of cranial and postcranial robusticity suggest that the F-81 individual was physically active and terrestrially mobile. Pronounced bilateral asymmetry in the upper limb suggests significant lateralization of habitual activity. In the context of Epipaleolithic remains, the F-81 skeleton provides preliminary evidence for greater morphological variability, terrestrial mobility, and lateralized habitual behavior prior to the Natufian, and skeletal gracilization between the Middle and Late Epipaleolithic in the Levant.

Adult↗

PubMed1999

Sharing cross-reactive groups of MHC class I improves long-term graft survival.

BACKGROUND: Renal transplant loss from chronic rejection remains substantial. To increase our understanding of this syndrome, we identified risk factors predicting late graft loss, with a special emphasis on the impact of human lymphocyte antigen (HLA) matching. METHODS: We studied all 654 cadaveric kidney transplants performed in our center between 1983 and 1996 that had survived for more than six months. Eighty-two transplants, lost because of chronic rejection, were used as the outcome variable. The influence of HLA mismatches and shares on long-term graft survival was evaluated at the level of private antigens and cross-reactive groups (CREG) of multiple histocompatibility complex (MHC) class I. HLA and other recipient, donors and transplant parameters were studied using univariate and multivariate Cox regression analysis. RESULTS: The cohort had a mean number of 1.9 HLA mismatches. Because of the homozygosity of HLA antigens, HLA mismatches were not reciprocal to shares. CREG and HLA-A-B mismatches had a relative risk for graft loss of 1.19 (95% CI, 0.97 to 1.45) and 1.05 (0.84 to 1.32) per mismatch. In contrast, the relative risk per shared CREG and broad HLA-A-B antigen was 0.76 (0.63 to 0.92) and 0.79 (0.61 to 1.03). Multivariate analysis revealed that individuals sharing less than four CREGs had a relative risk of 2.13 (1.29 to 3.75) for late graft loss. Other independent predictors were a recipient age of less than 50 years, relative risk 1.95 (1.02 to 3.71); a donor age of more than 50 years, relative risk 1.68 (1.01 to 2.80); acute rejection (vascular vs. no rejection), relative risk 3.52 (1.72 to 7.18); proteinuria (dipstick > 1+ vs. negative), relative risk 2.86 (1.29 to 6.35); and a serum creatinine concentration of more than 150 micromol/liter at six months, relative risk 3.41 (1.96 to 5.94). CONCLUSION: We identified several coexisting recipient-, donor-, and transplant-related risk factors for graft loss from chronic rejection. In this well-matched group of renal transplants, HLA mismatches and shares had a nonreciprocal relationship. Sharing of HLA antigens, especially CREG of MHC class I, was associated with improved long-term survival.

Adult↗

PubMed1999

Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition.

Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called "common variable immunodeficiency" (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated "IGAD1," in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of parents transmitting the defect: affected mothers were more likely to produce offspring with IgAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by higher frequency of anti-IgA-positive females transmitting the disorder to children, in comparison with female IgAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype.

Alleles↗

PubMed2005

Circumstances surrounding the first injection experience and their association with future syringe sharing behaviors in young urban injection drug users.

Young injection drug users are at heightened risk for acquisition of blood-borne infections because of their high rates of unsafe injection behaviors, yet there has been little research examining the circumstances surrounding injection drug users' first injection experience ('hit'). We examined the relationship between factors associated with young drug users' first hit and their future syringe sharing behaviors among 420 new initiates to injection drug use (less than 5 years), aged 15-30 years old in urban Baltimore, Maryland. Contingency table analysis and logistic regression were used to determine the association between circumstances surrounding the first hit and recent receptive syringe sharing. Participants were primarily male (58.8%), White (71.2%), and were a median age of 24 years (interquartile range [IQR]: 21-27 years). Adjusting for race, gender, and homelessness, the following variables were independently associated with recent receptive syringe sharing: age at first hit (adjusted odds ratio [AOR] = 0.92 per year increase; 95% confidence interval [CI]: 0.87-0.98), self-injection at initiation (AOR = 0.55; 95% CI: 0.32-0.97) and using a syringe that had previously been used by someone else at first hit (AOR = 2.81; 95% CI: 1.70-4.64). These data suggest that injection-related risk behaviors may be established as early as the onset of injection initiation, supporting the need to educate non-injectors of the harms associated with unsafe injection practices.

Adolescent↗

PubMed1990

Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma.

We analyzed the relevance of HLA incompatibility to acute graft-versus-host disease, relapse, and survival in 281 patients with hematologic neoplasms who underwent bone marrow transplantation. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, -B, and -D antigens of the haplotype not shared; 29 were phenotypically identical, 119 were incompatible for one locus, 104 for two loci, and 29 for three loci. These 281 patients were compared with 967 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. Occurrence of severe acute graft-versus-host disease was evaluated in patients who achieved sustained engraftment. In recipients of haploidentical grafts occurrence of severe acute graft-versus-host disease was associated with (1) graft-versus-host disease prophylaxis containing the combination of methotrexate plus cyclosporine versus standard methotrexate, relative risk = 0.35; 95% confidence interval, 0.21-0.57, p less than 0.0001; and (2) the degree of recipient HLA incompatibility, relative risk = 1.95 for each locus incompatible; 95% confidence interval, 1.52-2.50, p less than 0.0001; (3) patient age, relative risk = 1.23 per decade; 95% confidence interval, 1.05-1.44, p = 0.0094. Acute graft-versus-host disease was associated with lower leukemic relapse after transplant in patients with acute lymphocytic leukemia, and chronic graft-versus-host disease was associated with lower relapse after transplant for acute nonlymphocytic leukemia in relapse or chronic myelogenous leukemia in blast crisis. After transplantation for acute nonlymphocytic leukemia in remission, the rate of leukemic relapse was 22% in 61 recipients of "one-locus" (A, B, or D)-incompatible grafts compared to 37% in 561 recipients of HLA-identical sibling grafts. Survival was decreased as the degree of HLA disparity increased. Survival of "one-locus"-incompatible transplant recipients, however, was equivalent to that of HLA-identical sibling transplant recipients.

Bone Marrow Transplantation↗

PubMed1989

Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.

We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.

Adolescent↗

PubMed1996

Influence of genetic variability in the nondeletion LDL-receptor allele on phenotypic variation in French-Canadian familial hypercholesterolemia heterozygotes sharing a 'null' LDL-receptor gene defect.

We investigated the associations between low density lipoprotein (LDL)-receptor gene haplotypes and lipid and lipoprotein levels in French-Canadian individuals with familial hypercholesterolemia (FH). The 112 unrelated patients studied shared the same > 10 Kb deletion in the 5' region of the LDL-receptor gene, leading to a null allele. Support for the hypothesis that the deletion is carried on only one LDL-receptor restriction fragment length polymorphism (RFLP) haplotype in this sample has previously been demonstrated [1]. We studied associations of genetic variability in DNA polymorphisms of the nondeletion LDL-receptor allele with variation in plasma lipid levels in these patients heterozygous for the deletion. All analyses were done separately in males and females. The traits were adjusted for variation in the concomitants age, height and weight, and for variation in apolipoprotein (apo) E phenotype, and then the association between variability in haplotypes defined by two RFLP loci and variation in trait levels were tested. The results indicated that in this sample of French-Canadian > 10 Kb deletion FH heterozygotes, variability at the LDL-receptor gene contributes to quantitative variation in measures of lipid metabolism and that the effects are different in males and females. The results indicated that variability at the LDL-receptor gene defined by two RFLP loci contributes to quantitative variation in high density lipoprotein (HDL)-cholesterol and LDL-cholesterol concentrations in French-Canadian FH women heterozygous for the > 10 Kb deletion and not in men.

Alleles↗

PubMed1981

The variable gain element of the vestibulo-ocular reflex is common to the optokinetic system of the cat.

The gain (slow-phase eye velocity/head velocity) of the vestibulo-ocular reflex (VOR) of 6 alert cats was sequentially adapted to values between 0.2 and 1.66 by the chronic wearing of visual reversing or 2 X magnifying spectacles, combined with forced rotation in the light. Gain was measured during sinusoidal oscillation in darkness at 0.05 Hz at a peak velocity of about 30 degrees/s. In each state of VOR gain adaptation, optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN) were measured in a full-field optokinetic drum at velocities of 20-80 degrees/s. Steady-state, slow-phase, optokinetic eye velocity nearly equaled low drum velocities, but saturated at higher velocities and declined when drum velocity further increased. The saturation velocity varied in relation to VOR gain, ranging from 10-20 degrees/s at a VOR gain of 0.2-0.4, to 65 degrees/s at a VOR gain of 1.66. The means that the variable gain element of the VOR is shared by the optokinetic system (OKS). OKAN, measured in darkness, had a roughly exponential decay. The time constant of OKAN (Tokan) also varied with VOR gain, ranging form about 2 s at a VOR gain of 0.2, to 10 s at a VOR gain of 1.66. This is a novel finding which suggests that the velocity-storage mechanism was also affected by gain changes. A model is proposed in which a neural, variable-gain element is located in a positive-feedback, velocity-storage loop common to both the VOR and the OKS. Computer simulation showed that this hypothesis could account for most of the observed changes in OKN saturation and Tokan with changes in VOR gain. The model also predicts that low frequency VOR phase lead in darkness should increase with decreasing VOR gain. Experimental VOR phase lead at 0.05 Hz varied from about 10 degrees for VOR gains above 1.1 to about 50 degrees for VOR gains below 0.3. Such phase-lead data agree with the trend predicted by the model.

Animals↗

PubMed2001

Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD.

Administration of cyclosporine A (CsA) after autologous stem cell transplantation elicits an autoimmune syndrome with pathology similar to graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with the appearance of autoreactive T cells directed at major histocompatibility class (MHC) class II antigens. In the rat model of autologous GVHD, clonal analysis reveals that the effector T cells are highly conserved and recognize a peptide from the invariant chain peptide presented by MHC class II. Although human autologous GVHD effector T cells share a similar phenotypic specificity, clonality of the response in humans has not been determined. To examine the human effector T-cell response, the T-cell repertoire of peripheral blood lymphocytes was assessed by complementarity-determining region 3 (CDR3) size distribution analysis and T-cell clonotype analysis in 26 patients treated with CsA after transplantation. Autologous GVHD developed in 3 of 4 patients with human leukocyte antigen (HLA)-DRB1*0701, and clonal expansions of beta-chain variable region (BV)16(+) T cells were shared. Clonal expansions within BV15(+) and BV22(+) T cells were also detected in 4 of 6 patients with HLA-DRB1*1501 and in 3 of 4 patients with HLA-DRB1*0401, respectively. Sequencing of BV16 cDNA for which the CDR3 size pattern exhibited apparent clone predominance revealed an identical CDR3 peptide sequence in 2 different patients, one with HLA-DRB1*0701 and the other with HLA-DRB1*1502. These findings indicate that the discrete antigen-driven expansion of T cells is involved in autologous GVHD. (Blood. 2001;98:868-876)

Adult↗

PubMedDate not supplied

Predictors of bleach use among current African-American injecting drug users: a community study.

One hundred seventeen African-American current injecting drug users were interviewed in a closely matched pair of census tract communities in Dallas, Texas. A brief street intercept interview was administered that included an eligibility screener and questions on sexual behaviors with main or other partners and on injection drug paraphernalia bleaching behavior. Multiple regressions were conducted to determine significant predictors of frequency and duration of cleaning needles with bleach using different models (risk, attitude, exposure, and full). The variables measuring risk behaviors were age, frequency of sharing, exchanging sex for money, and sexual partner's use of injecting drugs. The predictors for the attitude model included normative, attitudinal, and self-efficacy items. The exposure to HIV information variables included seeing/hearing information; talking to someone about HIV, condoms, cleaning needles; and antibody testing for HIV. The full model combined predictors from each of the other models. Overall, bleach use is best explained in terms of specific attitudes rather than risk behaviors or information about HIV.

Adult↗

PubMed2006

Heritabilities and shared environmental effects were estimated from household clustering in national health survey data.

OBJECTIVES: The relative contributions of genetic and environmental variables to within-household clustering of quantitative traits in household surveys are poorly characterized. We estimated shared genetic and shared environmental contributions to within-household correlation for anthropometric variables and cardiovascular disease risk factors. STUDY DESIGN AND SETTING: Data were analyzed for the Health Survey for England 1998, a representative national household survey. Two-generation pedigrees were defined using information for relationships within households. After standardizing for age and sex, data were analyzed for 11 quantitative traits. Variance components models were fitted to estimate the proportion of variance due to additive genetic variance or shared environmental effects. RESULTS: Within-household correlation coefficients for all related and unrelated subjects ranged from 0.10 for C-reactive protein to 0.31 for height. Pairwise correlations between related individuals within households were consistently higher than those between unrelated individuals. Estimated heritability ranged from 6% for diastolic blood pressure to 40% for serum cholesterol. The proportion of variance attributable to shared environmental effects ranged from 8% for cholesterol to 24% for height. CONCLUSION: In this large, representative national sample of generally small families, estimates for heritability were generally lower than previously reported, whereas the contribution of shared environment and individual-level variation were greater.

Anthropometry↗

PubMed2004

Familial concordance of phenotype and microbial variation among siblings with CF.

The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P < 0.0001). Likewise, when the first sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P < 0.001). Meconium ileus (MI) was present in 20 patients (21%). In 10 families where the first-born sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P < 0.001). Pancreatic insufficiency (PI) also had high familial concordance (P < 0.0001). Percentile growth for weights and heights and lung function (FVC, FEV(1), and FEF(25-75)) at ages 7 and 10 years were similar between siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P < 0.0001). This familial concordance was not observed for S. aureus. By contrast, the age of first isolation of P. aeruginosa and S. aureus was significantly earlier in the second sibling than in the first for the two bacteria: 10.3 +/- 5.1 vs. 7.3 +/- 5.2 years (P < 0.05) for P. aeruginosa, and 11.5 +/- 5.4 years vs. 6.8 +/- 5.1 years (P < 0.05) for S. aureus. CF siblings tend to share similar phenotypes that are not mutation-dependent. The lack of variability between siblings in mode of initial CF presentation, rates of MI, pulmonary function, and nutritional status supports the role of modifier genes in the determination of these factors.

Adolescent↗