Michael C. Iannuzzi

Cystic fibrosis gene

The cystic fibrosis gene, located at 7q31, spans about 230 kb of genomic DNA and contains 27 exons. The cDNA of 6.2kb would predict an 1480 amino acid protein, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR has a high degree of homology with members of the ABC-transporter super family. The predicted protein structure consists of two membrane-spanning domains, each of 6 sub-units, anchoring CFTR in the apical membrane of specialized epithelial cells, 2 nucleotide binding folds (NBF) and a regulatory (R) domain. Disease-associated mutations in the CF gene are mainly clustered in the nucleotide-binding folds. The most common mutation, occurring in 70% of CF genes in Northern Europe and North America, is the deletion of amino acid phenylalanine at position 508 in the first NBF (ie delta F508).

Physical mapping of the cystic fibrosis region by pulsed-field gel electrophoresis

The gene for cystic fibrosis (CF) is known to be flanked by the closely linked DNA markers met and J3.11 on chromosome 7. Using the technique of pulsed-field gel electrophoresis, we have constructed a complete overlapping restriction map of approximately 3000 kb of DNA in this region. The met and J3.11 probes are found to be between 1300 and 1800 kb apart, which compares well with their genetic distance of 1-2 cM. The CF gene must be located within this interval, and the availability of this physical map should be of considerable utility in mapping additional clones as the search for the gene proceeds.

Cystic fibrosis-related diabetes is associated with HLA DQB1 alleles encoding Asp-57- molecules.

The incidence of insulin-dependent diabetes in individuals with cystic fibrosis is nearly 100 times greater than in the general population. In the latter group, strong associations with specific HLADQ/A1 andDQB1 alleles have been observed. To determine if a similar distribution of alleles occurs in cystic fibrosis patients with diabetes, a cohort of these individuals was typed forDQA1 andDQB1 alleles. HLADQB1*0201 (Asp57−) was more frequent in diabetics compared to controls (40.4 vs 28%), while the frequency of alleles encoding Asp57+ molecules was lower in diabetics relative to both the cystic fibrosisonly controls (P=0.025) and the general population (P=0.008). The presence of at least one protectiveDQA1-DQB1 heterodimer (i.e., Arg52− and Asp57+, respectively) in cis or trans was significantly lower in the diabetics than in either of the control groups. Thus, the HLA alleles known to be associated with insulindependent diabetes mellitus in the general population are also found in diabetics with cystic fibrosis.

Screening for Somatizing Patients in the Pulmonary Subspecialty Clinic

Somatizing patients present a history of vague, unexplained medical symptoms. This study compared somatizing patients with pulmonary control subjects by using the Diagnostic Interview Schedule (DIS-III-R), the Illness Attitude Scales (IAS), and the Minnesota Multiphasic Personality Inventory (MMPI-2). The groups differed in the number of somatization symptoms reported and in the frequency of somatization disorder diagnoses when the screening criteria were used. The somatizing group obtained higher scores on the bodily preoccupation and hypochondriacal beliefs subscales of the IAS; no differences were found on the MMPI-2. These findings indicate that the DSM-III-R somatization screening items can be useful for detecting somatization when patients present with unexplained respiratory complaints.

Health Care Utilization of Somatizing Patients in a Pulmonary Subspecialty Clinic

Somatizing patients present with medically unexplained physical complaints, repeat clinic visits, and a history of prior extensive testing. The authors reviewed 1,908 pulmonary consultation reports for 1990-1991 for evidence of somatization, yielding a group of 41 (2%) patients for study. Billing records were obtained and were compared to asthmatic patients and those in a health maintenance organization (HMO). Health care costs for the somatizing patients were significantly higher than the average cost for HMO patients and comparable to the health costs for patients with asthma. Half of the somatizing patients had psychological problems indicated in their medical records, but few received psychiatric referral or treatment. Management of the somatizing patient within the specialty clinic and on-site psychiatric treatment are suggested as ways to decrease unnecessary health care utilization.

Chromosome 6p microsatellite polymorphisms in African-Americans

Allele frequency distributions were determined for seven microsatellite DNA markers spanning the short arm of chromosome 6 in a population of African-Americans. A total of 196 chromosomes were analyzed. African-Americans differed from reported studies on Caucasians in the number of alleles, allele frequency and predominating alleles. These differences resulted in higher heterozygosity and polymorphic information content for these loci in the African-American population than in Caucasians. Each marker appeared to be in Hardy-Weinberg equilibrium within this population. These results demonstrate the need to determine population-specific allele frequency distributions for polymorphic markers when performing genetic linkage studies in racially defined groups. This study provides gene frequency data for this ethnic group in a region of the genome which has attracted attention as contributing genetic susceptibility to a number of diseases.

Prenatal diagnosis and linkage disequilibrium with cystic fibrosis for markers surrounding D7S8

SummaryThree polymorphic DNA markers surrounding the D7S8 locus were tested for their usefulness in the diagnosis of cystic fibrosis (CF) by linkage analysis. The markers correspond to the loci D7S424 and D7S426. These polymorphisms were studied by centers in the U.S., the United Kingdom, the Netherlands, and Italy, using samples from populations throughout Europe and North America. The additional information provided by these probes increased the heterogeneity of the region from 50% to 58% and was essential for a completely informative diagnosis in one family. A very high degree of linkage disequilibrium was found between these markers, which span a distance of approximately 250kb. In addition, linkage disequilibrium with CF was noted. Significant heterogeneity of linkage disequilibrium was found among the populations, both for the marker-marker pairs and between the markers and CF.

Anger experience and expression in chronic obstructive pulmonary disease

Emotion is involved in several medical problems, and respiratory difficulties can be exacerbated by emotion. Chronic obstructive pulmonary disease (COPD) is associated with depression and anger, but reports of anger are not consistent with theory about its effects on respiration in people with COPD. In this study, COPD patients ( N = 61) and healthy controls ( N = 45) participated in an interview about an angry or a neutral event. Self-reports of trait anger, and moods and anger experience in the interview were obtained. Physiological variables (heart and respiration rate) were measured during the interview, as were facial expressions. COPD patients reported more trait anger expression and less anger control; both groups reported increased anger experience in the anger interview. On the physiological variables, time by condition interactions demonstrated the differential effects of the two interviews, but did not indicate that the COPD subjects responded differently than controls. However, COPD subjects spent more time in negative facial expressions. These results show that expressions of overt anger and negative facial expressions occur more frequently in COPD patients, but there were no negative physiological consequences of anger experience. The social implications of anger in this group and the consequences of expressions involving exertion are unknown.