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PubMed1988

Normal polymorphic variations and transcription of the decay accelerating factor gene in paroxysmal nocturnal hemoglobinuria cells.

In paroxysmal nocturnal hemoglobinuria (PNH), an acquired hemolytic anemia, deficiency of decay accelerating factor (DAF) renders blood cells susceptible to increased deposition of autologous complement activation fragments (C3b) and complemented-mediated injury. To investigate the mechanism of the DAF defect, DNA and mRNA from normal and PNH leukocytes were compared in blot hybridization assays by using DAF cDNA and oligonucleotide probes. Southern analyses of DNA from normal cells revealed a single gene spanning approximately equal to 35 kilobases of DNA. Six HindIII banding patterns were distinguishable among normal individuals. In family studies, the patterns segregated as three homozygous and three heterozygous genotypes deriving from three haplotypes: A, B, and C with frequencies of 0.47, 0.36, and 0.17, respectively. Oligonucleotide mapping localized the polymorphic HindIII sites to two noncoding regions in the vicinity of exons encoding (i) the protein oligosaccharide-rich domain and (ii) the mRNA 3'-untranslated region. Analyses of DNA from DAF-negative leukocytes of eight PNH patients demonstrated restriction fragment profiles identical to those of normal individuals for all enzymes studied. Three patients had the BC (normals = 3/32), three patients had the AA (normals = 6/32), and two patients had the AC (normals = 8/32) HindIII genotype. Of the three PNH patients exhibiting the BC genotype, family studies of two demonstrated the expected inheritance patterns, and RNA gel blot analyses of two showed mRNA transcripts indistinguishable from those in normal cells. The absence of DAF gene or mRNA alterations in affected PNH cells that lack other glycolipid-anchored proteins as well as DAF argues that the lesion underlying PNH cells resides in the glycolipid-anchor pathway.

Blood Proteins↗
PubMed1998

Linkage and allelic association of atopy and markers flanking the IL4-receptor gene.

BACKGROUND: Atopy, a clinical syndrome characterized by heightened IgE responsiveness, is largely determined by genetic factors. The disease may well be heterogeneous but the mode of inheritance is unknown. Several genes have been named which affected IgE responsiveness. However, results are conflicting reflecting heterogeneity and a complicated inheritance pattern of the atopic syndrome. In 1994 linkage of the 5q32 gene region and elevated total IgE levels were reported, leaving the IL4 gene as a prominent candidate. OBJECTIVES: We were interested in a possible involvement of the IL4-receptor gene in the development of atopy. METHODS: We employed sib-pair linkage analysis using highly polymorphic microsatellite markers within and flanking the IL4 receptor gene in atopic families, characterized for specific sensitization to inhalant allergens and elevated total serum IgE. Allele sizes were determined for all microsatellite probes to allow transmission disequilibrium analysis. RESULTS: We found significant sharing of maternal but not paternal alleles in affected sibs from two independent populations, both of which presented enhanced IgE responsiveness. Linkage and maternal inheritance could be confirmed by transmission disequilibrium analysis. CONCLUSIONS: We conclude from our findings that maternal inheritance of a gene in the chromosome 16p12 region increases the risk for enhanced IgE responsiveness. The most prominent candidate in this region is represented by the IL4 receptor gene.

Adolescent↗
PubMed2005

[T-type calcium channel gene-CACNA1H is a susceptibility gene to childhood absence epilepsy].

OBJECTIVE: Childhood absence epilepsy (CAE) is one of the most frequently recognized syndromes among the idiopathic generalized epilepsies (IGEs). It is considered to be a hereditary disease. The possible inheritance pattern of CAE is polygenic. The genes responsible for CAE, however, have not yet been identified. The aim of this study was to further investigate based on the authors' recent work whether or not T-type calcium channel gene-CACNA1H is a susceptibility gene to childhood absence epilepsy. METHODS: The authors conducted the mutation screening of the exons 6-12 and the nearby partial introns of the CACNA1H gene using the method of direct sequencing of PCR products in 48 newly found CAE patients. RESULTS: The authors found 13 single nucleotide polymorphisms (SNPs). They also found 4 mutations which only existed in CAE patients. Both G773D and H515Y mutations were heterozygous. The mutation of H515Y has never been reported previously. The patient inherited the mutation from his mother. The authors found two CAE patients with the mutation of G773D previously. This is the third time that the authors found one more CAE family with this G773D mutation, and the patient with the mutation G773D inherited the mutation from his father. CONCLUSION: T-type calcium channel gene-CACNA1H might be a susceptibility gene to childhood absence epilepsy.

Amino Acid Sequence↗
PubMed2005

[Study on genetic epidemiology on 815 patients with vitiligo in Zhejiang area].

OBJECTIVE: Genetic factors are thought to be involved in the development of vitiligo. The aim of this study is to explore the possible genetic model of vitiligo by analyzing the genetic characteristics of 815 patients from Zhejiang province. METHODS: Data for 815 patients with vitiligo together with their first- and second-degree relatives were obtained using a standardized questionnaire. All these information was requested to confirm the answers about family history in order to reduce the possibility of 'recall' bias. The 815 probands would include 411 (50.43%) males and 404 (49.57%) females with a varied age from 2 months to 71 years old. Since the information on general prevalence of vitiligo in this area was absent, a control group was set up to facilitate the calculations of heritability degree. 468 persons of the control group were from non-vitiligo population with a sex ratio of 241(male): 227(female) with varied age of 4 months to 80 years old. Both gender and age were comparable between the vitiligo and the control population. The inheritance pattern estimation, heritability calculation and complex segregation analysis were performed with Penrose method, Falconer regression method and SAGE-REGTL program. RESULTS: In 815 vitiligo probands, 128 had and 687 had not family histories, with a heritability rate of 15.7%. The vitiligo prevalence in proband's first degree relatives was 2.580%, higher than the prevalence of 0.618% in second degree relatives, and both of them were higher than general prevalence: 0.192%. By Penrose method, the rates on different catagories were as follows: sibling prevalence rates s = 0.080 18; population prevalence rate q = 0.001 92; s/q = 41.76. The ratio of s/q did not approach 1/2q (260.42) or 1/4q (130.21), but approached 1/square root of q(22.82), suggesting vitiligo was consistent with a mode of polygenic inheritance. Using Falconer's method, heritabilities of vitiligo in first-and second degree relatives of probands were 59.61% (95% confidence interval 65.37-53.84) and 55.20% (95% confidence interval 43.88-66.52), respectively. The weighted average of heritability in all relatives was 58.7% (95% confidence interval 53.56-63.83). The results of complex segregation analysis suggested that major gene model including the Mendelian dominant, recessive and additive hypotheses were not rejected (P > 0.05). Purely environmental model and no transmission model were rejected at a 0. 001 significance level. According to AIC, Mendelian dominant inheritance was the best-fitted hypothesis. CONCLUSION: Genetic factors played an important role in the occurrence of vitiligo, and the genetic model of vitiligo could serve as the polygenetic or multifactorial inheritance with major gene trait.

Adolescent↗
PubMed2006

Study of inheritance of diabetes mellitus in Western Indian population by pedigree analysis.

OBJECTIVES: To study the inheritance pattern of diabetes mellitus in Western Indian population by analysing the pedigree of diabetes patients. METHODS: 3,921 individuals from 300 families were interviewed for family history in this study, out of which 770 were diabetic individuals. Statistical analysis of the data was carried out using T-test and Chi-square test. RESULTS: 37% cases of Type 1 DM and 58% cases of Type 2 DM showed family history of the disease. Of the cases showing family history for diabetes, 92% in case of Type 1 DM and 59% in case of Type 2 DM showed family history of Type 2 DM with a decrease in age of onset in the successive generations. Both the parents, when diabetic conferred equal risk of inheriting diabetes in offspring. The sex ratio of offspring suffering from diabetes was not influenced when only one of the parents was diabetic. However it was observed that the male offspring were highly susceptible when both parents were diabetic (Chi-square value=4.55 with 1 d.f.). The age of onset of diabetes did not show significant correlation with whether one or both the parents were diabetic. However, it was noteworthy that in case of familial history of diabetes there was a decrease in the age of onset in successive generations. CONCLUSION: This study suggests that family history of diabetes results in predisposition to early onset of the disease in successive generations and a cluster of genes involved in Type 2 DM may show a parental effect for predisposition to Type 1 DM in the offspring in this set of Indian population.

Adolescent↗
PubMed1999

Familial patent ductus arteriosus and bicuspid aortic valve with hand anomalies: a novel heart-hand syndrome.

The association between cardiac and limb defects, particularly those affecting the hand, has been well documented by the delineation of several heart-hand syndromes. Based on observations with a three-generation family with seven affected individuals, we describe a novel heart-hand syndrome comprising patent ductus arteriosus, bicuspid aortic valve, 5th metacarpal hypoplasia, and brachydactyly. The inheritance pattern was consistent with autosomal dominance, although X-linked dominance could not be excluded. Penetrance appeared to be complete, but there was variability of the cardiac and hand phenotypes. Because this new syndrome closely resembled Char syndrome (patent ductus arteriosus, 5th finger middle phalangeal hypoplasia, and minor facial anomalies), multipoint linkage analysis was performed using polymorphic DNA markers spanning the recently identified Char syndrome critical region at chromosomal bands 6p12-p21.1. This analysis formally excluded this 3-cM region, documenting that the two traits are not allelic. In sum, a novel heart-hand syndrome involving left ventricular outflow and aortic arch as well as an ulnar ray derivative has been identified. Because the hand anomalies can be subtle, thorough evaluation is suggested for families inheriting these cardiac defects as a mendelian trait.

Alleles↗
PubMed1995

HLA disease associations: models for the study of complex human genetic disorders.

The genes of the human leukocyte antigen (HLA) region, the major histocompatibility complex (MHC) of humans, control a variety of functions involved in immune response and influence susceptibility to over 40 diseases. Theoretical studies in the development of models to determine the modes of inheritance of the HLA-associated diseases have led to a better understanding of the inheritance patterns in insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, hemochromatosis, celiac disease, and others. It is now clear that many of the HLA-associated diseases involve heterogeneity in their HLA components, as well as non-HLA genetic factors. This review is presented using HLA-associated diseases, and in particular IDDM, as the example of interest, but the observations and techniques presented have direct relevance to the study of all human diseases with a complex genetic component. Three methods for localizing disease-predisposing genes are presented: (1) association studies, including population, family, and relative predispositional effects, (2) affected sib pair and other affected-relative methods, and (3) lod score analysis. A variety of complementary methods for studying the mode(s) of inheritance of the alleles at the disease-predisposing locus and for identifying the alleles and amino acids directly involved in the disease process also are presented.

Arthritis, Rheumatoid↗
PubMed2002

Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3.

BACKGROUND: Brugada syndrome is a form of idiopathic ventricular fibrillation characterized by a right bundle-branch block pattern and ST elevation (STE) in the right precordial leads of the ECG. Sodium channel blockers increase STE. Mutations of the cardiac sodium channel SCN5A cause the disorder, and an implantable cardioverter-defibrillator is often recommended for affected individuals. Mutations in other genes have not been identified, and it is not known if the efficacy of drug testing or the malignancy of arrhythmias correlates to the gene defect. METHODS AND RESULTS: We performed histories, physical examinations, ECGs, and drug testing on a large multigenerational family with Brugada syndrome. DNA isolated from blood samples, polymorphic genomic markers, and polymorphisms within candidate sodium channels were used for a genome-wide screen, fine mapping, and linkage analysis. We identified 12 affected individuals (right bundle-branch block, > or =1-mm STE) with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. Four affected individuals had syncope and 2 had documented ventricular arrhythmias, but there was minimal family history of sudden death. Procainamide infusions did not identify additional affected individuals. Linkage was present to an approximately equal 15-cM region on chromosome 3p22-25 (maximum LOD score=4.00). The sodium channel genes SCN5A, SCN10A, and SCN12A on chromosome 3 were excluded as candidates (LOD scores < or =-2). CONCLUSIONS: A Brugada syndrome locus distinct from SCN5A is associated with progressive conduction disease, a low sensitivity to procainamide testing, and a relatively good prognosis in a single large pedigree.

Adult↗
PubMed2001

Like mother, like daughter: evidence for non-genomic transmission of parental behavior and stress responsivity.

Considerable evidence demonstrates that the quality of the early environment influences patterns of development that, in turn, determine the health and productivity of the individual throughout their life span. However, the processes through which early life influences health are not clearly understood. Through the activation of the hypothalamo-pituitary-adrenal (HPA) axis and corticotropin-releasing hormone (CRH) pathways, prolonged or exaggerated responses to stress have profound effects on physiological and cognitive functions. Early maternal separation or handling of neonatal rats can program widespread and lifelong changes in various transmitter systems that regulate the HPA and CRH systems. Our studies show that a high level of maternal licking/grooming, and arched-back nursing correlates with reduced CRH mRNA expression and enhanced glucocorticoid negative feedback, and lower stress responses in the adult. This behavior is stably transmitted between generations and cross-fostering studies show that the offspring inherit the behavior from the nursing mother and not the biological mother. Such intergenerational transmission of maternal behavior is seen in rodents, primates and humans, and may underlie adaptive changes in the HPA axis. The neural basis of this inheritance pattern appears to reside in the central oxytocin system which determines features of maternal behavior. Through these various adaptive neural mechanisms the environmental demand on the mother is reflected in the quality of maternal care to her offspring. This, in turn, programs stress reactivity and maternal behavior patterns of the offspring. This not only determines certain health outcomes but also establishes the relationships between mother and offspring in the next generation. These findings suggest that for neurobiologists, the function of the family is an important level of analysis and the critical question is that of how environmental events regulate neural systems that mediate the expression of parental care.

Animals↗
PubMed2004

Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and patients with AF have a significantly increased risk for ischemic stroke. Approximately 15% of all strokes are caused by AF. The molecular basis and underlying mechanisms and pathophysiology of AF remain largely unknown. METHODS AND RESULTS: We have identified a large AF family with an autosomal recessive inheritance pattern. The AF in the family manifests with early onset at the fetal stage and is associated with neonatal sudden death and, in some cases, ventricular tachyarrhythmias and waxing and waning cardiomyopathy. Genome-wide linkage analysis was performed for 36 family members and generated a 2-point logarithm of the odds (LOD) score of 3.05 for marker D5S455. The maximum multipoint LOD score of 4.10 was obtained for 4 markers: D5S426, D5S493, D5S455, and D5S1998. Heterozygous carriers have significant prolongation of P-wave duration on ECGs compared with noncarriers (107 versus 85 ms on average; P=0.000012), but no differences between these 2 groups were detected for the PR interval, QRS complex, ST-segment duration, T-wave duration, QTc, and R-R interval (P>0.05). CONCLUSIONS: Our findings demonstrate that AF can be inherited as an autosomal recessive trait and define a novel genetic locus for AF on chromosome 5p13 (arAF1). A genetic link between AF and prolonged P-wave duration was identified. This study provides a framework for the ultimate cloning of the arAF1 gene, which will increase the understanding of the fundamental molecular mechanisms of atrial fibrillation.

Adolescent↗
PubMed2003

Genetics of preeclampsia: what are the challenges?

Despite recent efforts to identify susceptibility genes of preeclampsia, the genetic determinants of the condition remain ill-defined, as is the situation for most disorders of complex inheritance patterns. The angiotensinogen, factor V, and methylenetetrahydrofolate reductase genes have been investigated in different populations, as have other genes involved in blood pressure, vascular volume control, thrombophilia, lipid metabolism, oxidative stress, and endothelial dysfunction. The study of the genetics of complex traits is faced with both methodological and genetic issues; these include adequate sample size to allow for the identification of modest genetic effects, of gene-gene and gene-environment interactions, the study of adequate quantitative traits and extreme phenotypes, haplotype analyses, statistical genetics, genome-wide (hypothesis-free) versus candidate-gene (hypothesis-driven) approaches, and the validation of positive associations. The use of genetically well-characterized populations showing a founder effect, such as the French-Canadian population of Quebec, in genetic association studies, may help to unravel the susceptibility genes of disorders showing complex inheritance, such as preeclampsia. It is necessary to better evaluate the role of the fetal genome in the resulting predisposition to preeclampsia and its complications. Eventually, we may be able to integrate genetic information to better identify the women at risk of developing preeclampsia, and to improve the management of those suffering from this condition.

Adult↗
PubMed1997

Congenital absence of the uterus and vagina is not commonly transmitted as a dominant genetic trait: outcomes of surrogate pregnancies.

OBJECTIVE: To determine the inheritance pattern of congenital absence of the uterus and vagina in affected women undergoing surrogacy IVF with this disorder. DESIGN: Retrospective study. SETTING: A hospital-based reproductive endocrinology and infertility center. PATIENT(S): Women diagnosed with congenital absence of the uterus and vagina undergoing IVF with subsequent transfer of embryos to a surrogate uterus. INTERVENTION(S): Questionnaires were sent to all infertility treatment centers performing surrogate procedures. MAIN OUTCOME MEASURE(S): Number, gender, and frequency of congenital anomalies in progeny. RESULT(S): Thirty-two of 53 surveyed programs responded (60%). One hundred sixty-two IVF cycles were performed, and 34 liveborn children were delivered (half female). No congenital anomalies were found, except for one male child with a middle ear defect and hearing loss. CONCLUSION(S): These results strongly suggest that congenital absence of the uterus and vagina, if genetically transmitted, is not inherited commonly in a dominant fashion.

Congenital Abnormalities↗
PubMed1992

Study of color vision in fragile X syndrome.

Various theories have been postulated to account for the unusual inheritance pattern observed in the fragile X syndrome. The recent finding of a secondary amplification of the fragile X mutation in the offspring of carrier females [Oberle et al., 1991; Yu et al., 1991] is consistent with a maternal imprinting process. Laird [1987] has proposed that the fragile X mutation blocks complete reactivation of a previously inactivated fragile X chromosome. We have tested whether or not such a localized block extends as far distal as the red/green color-vision complex at Xq28. We found no evidence of color-vision defects among 25 male subjects with the fragile X syndrome. A fragile X positive woman also had normal color vision, despite being an obligate carrier of her father's gene for red/green color blindness. We conclude that the fragile X gene does not affect the function of neighboring color-vision genes, nor does it affect their ability to compensate adequately for inherited color deficiency on the homologous X chromosome in females.

Adolescent↗
PubMed2005

Identification of a novel mitochondrial mutation in Dupuytren's disease using multiplex DHPLC.

Dupuytren's disease is a familial fibroproliferative disorder of late onset affecting the hands. It is extremely common in individuals of Northern European extraction. Genetic studies have yet to identify the genes involved in the formation of the disease. Mitochondria play a critical role in cell metabolism and apoptosis. It is known that defective mitochondria generate abnormally high levels of reactive oxygen species by means of electron leak and that antioxidant enzyme activities decrease with age in skin fibroblasts. Respiratory function of mitochondria is also impaired in aging human tissues. Oxidative stress and production of free radicals may be important factors in the pathogenesis of Dupuytren's disease. Mitochondrial genes are also included in the regulation of apoptosis. Diseased tissue contains large numbers of myo- fibroblasts, which disappear by apoptosis during normal wound healing. High numbers of mitochondria have been observed in fibroblasts derived from diseased tissue. In the light of this evidence, the mitochondrial genome represents a potential location for candidate susceptibility genes for this late-onset disorder. In this study, the authors investigated the presence of mutations within the mitochondrial genome in 40 subjects; 20 Caucasian Dupuytren's disease patients with a maternally transmitted inheritance pattern and 20 control subjects were matched for age, sex, and race using a multiplex denaturing high-performance liquid chromatography approach. A hitherto unknown heteroplasmic mutation located within the mitochondrial 16s rRNA region was evident in 90 percent of patients and absent from all control subjects (p < 0.001; chi2 = 16.1). This mutation may be important in the pathogenesis of Dupuytren's disease.

Adult↗
PubMed1996

Molecular basis of glucocorticoid-resistant syndromes.

Generalized inherited glucocorticoid resistance (GIGR) is a rare syndrome characterized by elevated levels of plasma cortisol but lacking the symptoms of Cushing's syndrome. Biochemically, the condition is characterized by a relative resistance to glucocorticoids that can be compensated for by the elevated levels of cortisol. The inheritance pattern of GIGR is incompletely understood, and one of the central questions is whether there is a correlation between genotype and phenotype. Analysis of mutations within the receptor resulting in relative glucocorticoid resistance has identified two regions of clustered mutations in the proximity of previously identified affinity-labeled residues, the putative steroid-binding site. In the majority of cases, the mutation affects steroid binding and transactivation to the same degree, with the exceptions suggesting an explanation for the variability of the clinical manifestations. From a clinical point of view, in addition to preexisting genetic resistance to glucocorticoids, it is important to consider acquired changes in glucocorticoid receptor (GR) gene structure and organization, including alterations of noncoding sequences, and the importance of the resultant mutations, deletions, and other changes affecting receptor function. Finally, studies of New World primates and cell lines derived from hematologic malignancies constitute animal and human models for the molecular basis of glucocorticoid resistance where a number of inherited and acquired mutations in the GR gene have been demonstrated.

Animals↗
PubMed2006

North American white mitochondrial haplogroups in prostate and renal cancer.

PURPOSE: While the mitochondrion is known to be a key mediator of apoptosis, there has been little inquiry into the inheritance pattern of mitochondria in patients with cancer. We compared the mtDNA haplotype in patients with prostate and renal cancer to that in controls to determine if there is an association between mitochondrial genotype and cancer. MATERIALS AND METHODS: Haplotyping was performed using polymerase chain reaction/digest identification of key polymorphic sites in the mitochondrial genome. A total of 121 and 221 white men with renal and prostate cancer, respectively, were identified following pathological confirmation of cancer, while 246 white controls were selected randomly from a bank of cadaveric organ donor DNA. Statistical analysis was performed and ORs were calculated. RESULTS: Mitochondrial haplogroup U was a highly significant risk factor for prostate and renal cancer vs controls (16.74% and 20.66% vs 9.35%, Fisher's exact test p = 0.019 and 0.005, respectively). The association remained statistically significant in renal cancer even after Bonferroni adjustment for multiple comparisons. Haplogroup U carried an OR of 1.95 for prostate cancer and an OR of 2.52 for renal cancer. CONCLUSIONS: The inheritance of mitochondrial haplogroup U is associated with an approximately 2-fold increased risk of prostate cancer and 2.5-fold increased risk of renal cancer in white North American individuals. Therefore, individuals with this mitochondrial haplotype are in a high risk group. Because mitochondrial haplogroup U is found in 9.35% of the white United States population, there are more than 20 million individuals in this high risk group.

Adolescent↗
PubMed2004

Familial hyperinsulinaemia associated with epilepsy and mental retardation--a syndrome of familial insulin resistance.

BACKGROUND: Variants of type A insulin resistance, characterized by female hyperandrogenism and 'acromegaloid' features, have been ascribed to genetic defects of the insulin receptor or post-receptor pathways via autosomal dominant or recessive inheritance patterns. Whilst a variety of congenital syndromes of insulin resistance are identified by their characteristic clinical phenotypes, an association with epilepsy and mental retardation has not previously been reported. CASE REPORT: We describe three female siblings (aged 12, 19 and 21) with fasting hyperinsulinaemia (116-443 pmol/l; normal range < 80 pmol/l) and mental retardation. Two siblings also have epilepsy. The eldest has features of severe insulin resistance with dyslipidaemia, acanthosis nigricans, 'acromegaloid features' and diabetes requiring high dose insulin therapy in combination with a glitazone. Their mother has fasting hyperinsulinaemia (113 pmol/l), mental retardation and epilepsy. None had clinical or biochemical features of hyperandrogenism or evidence of pigmentory retinopathy, deafness or renal insufficiency. Autoantibody screens were negative. Interestingly, there is no evidence of mental retardation or epilepsy among males in the family. CONCLUSION: This family suggests the presence of a yet-undefined syndrome of familial insulin resistance affecting female kindred. Further studies are being undertaken to clarify the genetic defects and mode of inheritance.

Adult↗
PubMed2004

Segregation analysis of bronchial hyperresponsiveness in a general population in north Italy.

Bronchial hyperresponsiveness (BHR) is an intermediate phenotype of asthma, with a heritability component of 30-67% and possible linkage to regions on chromosome arms 5q, 11q, and 20p. Familial correlation analysis and segregation analysis for BHR, using the FCOR and REGC programs of the S.A.G.E package, were performed to examine inheritance patterns of BHR in a general population of 1167 subjects in 550 families from the Po River Delta. BHR was assessed using the log(10) of the slope of the methacholine dose-response curve (log slope) for each subject who met inclusion criteria. Using multiple linear regression analysis, the log slope values were adjusted for age, age(2), sex, and height, and used in the familial correlation and segregation analyses. Father-offspring correlations are statistically significant, due specifically to high father-son correlations (r = 0.296, P < 0.001, adjusted values). Segregation analysis of BHR in the overall population, with and without a smoking covariate (number of packyears smoked), indicates an apparent absence of genetic transmission within families. However, in a segregation analysis of BHR in smoking families only, after adjusting for number of packyears smoked, the Mendelian transmission models could not be rejected. This may be evidence of a gene by smoking effect, and suggests that in families of smokers, a single locus gene may in part explain the inheritance of a compound phenotype (BHR x packyears).

Adult↗