Disclosure of genetic research results to members of a founder population.

There is currently extensive discussion and debate in the literature on how, when, and to whom genetic research results should be returned (see Genetics in Medicine, April 2012 issue). Here, we describe our experience in disclosing genetic information on Mendelian disorders discovered during the course of our research in the Hutterites. We first assessed attitudes toward the disclosure of carrier results, which revealed that many individuals wanted carrier information and that many intended to use the information in family planning. Based on this information, we developed a pilot study to test and disclose cystic fibrosis (CF) carrier status. Next, a larger scale project was developed in order to disclose genetic research results for 14 diseases to those interested in receiving the information. We developed brochures, offered a live interactive educational program, conducted a consent process, and disclosed results in letters mailed to the consented individuals. Overall, ~80% of individuals who participated in the educational program signed consent forms for the release of their results for 14 diseases. We describe our experience with returning individual genetic research results to participants in a population-based research study.

Genome-wide association study of lung function phenotypes in a founder population.

BACKGROUND: Lung function is a long-term predictor of mortality and morbidity. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. METHODS: We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. RESULTS: Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10(-8) to 3.4 × 10(-9)). Nine SNPs at or near 4 additional loci had P < 10(-5) with FEV1/FVC. Only 2 SNPs were found with P < 10(-5) for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of ß-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B. CONCLUSION: This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.

Obstructive sleep apnea in the formerly preterm infant: an overlooked diagnosis.

BACKGROUND: Obstructive sleep apnea syndrome (OSA) is a frequent disorder in children. The clinical characteristics of OSA in very young children under 2 years of age, and more particularly, in those born prematurely, and who have respiratory complications such as bronchopulmonary dysplasia (BPD), are not well defined. We therefore retrospectively reviewed our experience in a group of preterm infants with OSAS. METHODS: The records of premature infants with BPD followed in the Pediatric Pulmonary Clinic at the University of Chicago who were diagnosed with OSA from 2004 to 2009 were reviewed and analyzed. RESULTS: Twelve children, eight males, and four females with a mean gestational age of 27 weeks were found to have OSA. Mean age at diagnosis was 19 months. Inability to wean nighttime oxygen, the need to resume oxygen after intercurrent respiratory illness, and snoring were the most common presenting symptoms. The apnea-hypopnea index ranged from 1 to 120/h total sleep time (TST; mean: 29). SpO(2) nadir ranged from 50 to 91%. Despite adenotonsillectomy (AT), all children had persistent sleep disordered breathing. CONCLUSION: In preterm infants, while snoring is a frequent symptom, poor weight gain, and inability to wean nighttime oxygen may indicate the need for further investigation for OSA. In the former preterm infant structural changes in the airway may play an important role along with adenotonsillar hypertrophy. A high level of clinical awareness is required to identify OSA in the formerly preterm infant.

Rising prevalence of asthma is sex-specific in a US farming population.

BACKGROUND: Asthma prevalence is increasing worldwide in most populations, likely due to a combination of heritable factors and environmental changes. Curiously, however, some European farming populations are protected from asthma, which has been attributed to their traditional lifestyles and farming practices. OBJECTIVE: We conducted population-based studies of asthma and atopy in the Hutterites of South Dakota, a communal farming population, to assess temporal trends in asthma and atopy prevalence and describe the risk factors for asthma. METHODS: We studied 1325 Hutterites (ages 6-91 years) at 2 time points from 1996 to 1997 and from 2006 to 2009 by using asthma questionnaires, pulmonary function and methacholine bronchoprovocation tests, and measures of atopy. RESULTS: The overall prevalence of asthma increased over the 10- to 13-year study period (7.5%-11.1%, P = .049), whereas the overall prevalence of atopy did not change (45.0%-44.8%, P = .95). Surprisingly, the rise in asthma was only among females (5.8%-11.2%, P = .02); the prevalence among males remained largely unchanged (9.4%-10.9%, P = .57). Atopy, which was not associated with asthma risk in 1996 to 1997, was the strongest risk factor for asthma among Hutterites studied in 2006 to 2009 (P = .003). CONCLUSIONS: Asthma has increased over a 10- to 13-year period among Hutterite females and atopy has become a significant risk factor for asthma, suggesting a change in environmental exposures that are either sex limited or that elicit a sex-specific response.

Parental understanding of newborn screening for cystic fibrosis after a negative sweat-test.

BACKGROUND: Newborn screening for cystic fibrosis (CF) in Illinois uses an immunoreactive trypsinogen/DNA methodology; most false-positive results identify unaffected carriers. METHODS: Parents whose child received a negative result from the sweat test after a positive newborn screening for CF were surveyed ≥ 6 weeks later by telephone. All parents received genetic counseling while waiting for the sweat-test results. RESULTS: A total of 90 parents participated. Overall knowledge of CF was high (78%), but the ability to understand the CF screening results was mixed. Although 94% of the parents understood that their child did not have CF, only 79% (62 of 78) of participants whose child had a mutation knew their child was definitely a carrier, and only 1 of 12 parents whose child had no mutation understood that the child may be a carrier. Respondents stated that most relatives were not interested in genetic testing. Both parents had been tested in only 13 couples. Fewer than half (36 of 77 [47%]) of the untested couples expressed interest in genetic testing. Although most participants were satisfied with the process, parents expressed frustration because of the lack of prospective newborn screening discussions by prenatal and pediatric providers and lack of knowledge and sensitivity by those who initially notified them of the abnormal newborn screening results. Speaking to a genetic counselor when scheduling the sweat test decreased anxiety for many parents (53 of 73 [73%] were "very worried" at notification versus 18 of 73 [25%] after scheduling; P < .001). CONCLUSIONS: Parental knowledge about CF is high, but confusion about the child's carrier status and the concept of residual risk persist despite genetic counseling. Relatives express low interest in carrier testing.

Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function.

BACKGROUND: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function. METHODS: We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls. RESULTS: A promoter SNP (-131C-->G) in CHI3L1, the chitinase 3-like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1 x 10(-13)), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case-control populations (combined P=1.2 x 10(-5)) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9 x 10(-3) to 2.5 x 10(-4)). CONCLUSIONS: CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.

Bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic fibrosis patients: a randomized, controlled study.

OBJECTIVE: Several studies have reported omega-3 and omega-6 fatty acid imbalances in patients with cystic fibrosis (CF). Whether these imbalances contribute to or are manifestations of the pathophysiology of CF is unknown. The study objective was to determine bioavailability, tissue accretion, and safety of a large dose of an algal source of docosahexaenoic acid (DHA) triacylglycerol and to observe effects on lung function in patients with CF. METHODS: Twenty subjects with CF (8 to 20 y of age) were randomly assigned to receive algal oil providing 50 mg of DHA per kilogram per day (1 to 4.2 g of DHA per subject per day) or placebo for 6 mo. Fatty acids, liver enzymes, and lipid soluble antioxidants were measured in blood at baseline and at 1, 3, and 6 mo. Rectal biopsy specimens were collected at baseline and at 3 mo for fatty acid analysis. Lung function, anthropometrics, and adverse experiences were monitored throughout the study. RESULTS: Compared with placebo, DHA supplementation increased plasma, erythrocyte, and rectal DHA levels four- to five-fold (P < 0.001) with concomitant decreases in blood arachidonic acid levels and the ratio of arachidonic acid to DHA. Supplementation was well tolerated, with no treatment-related changes in liver enzymes, growth, or antioxidant status. DHA supplementation had no detectable effect on lung function during the course of this study. CONCLUSIONS: Algal DHA triacylglycerol oil is readily absorbed, well tolerated, and increases blood and tissue DHA levels in patients with CF. No adverse developments were associated with this large dose of DHA oil. Larger studies of longer duration are needed to determine whether DHA supplementation results in any clinically significant benefits in patients with CF.

Variation in ITGB3 is associated with asthma and sensitization to mold allergen in four populations.

RATIONALE: Recent genetic studies have implicated integrins in asthma and atopy susceptibility. We therefore evaluated the integrin-beta3 gene (ITGB3), an integrin gene within an asthma linkage peak on chromosome 17, as a candidate for susceptibility to asthma- and atopy-related phenotypes. METHODS AND MEASUREMENTS: We genotyped and performed association tests on 19 single nucleotide polymorphisms in ITGB3 in the Hutterites, a founder population, and in three outbred replication populations. MAIN RESULTS: Variation in ITGB3 was strongly associated with susceptibility to bronchial hyperresponsiveness and protection from allergic sensitization to mold allergens in this population. Three independent case-control populations representing Caucasians and African Americans were used to replicate this finding, also revealing ITGB3 alleles that are associated with asthma susceptibility and protection from mold allergen sensitization. CONCLUSIONS: This study provides evidence that ITGB3 plays a role in the pathogenesis of asthma and sensitization to mold allergens.

Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21.

Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.

Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease.

Our objective was to study the effect of tobramycin solution for inhalation (TSI; TOBI, Chiron Corp.) on lung function decline rate in 400 young persons with cystic fibrosis (CF) and mild lung disease. Effects on hospitalization, antibiotic use, school days missed, and nutritional status also were determined. This was an open-label, randomized (stratified by sex and age group, i.e., 6-10 and 11-15 years), parallel-group, multicenter study. Routine subject management (control group) was compared to routine management plus 28 days of twice-daily TSI inhalation, followed by 28 days off the drug (TSI group) for 56 weeks. Primary efficacy endpoints included rate of lung function decline (as measured by forced expiratory volume in 1 sec; FEV(1)), hospitalization, and concomitant antibiotic use. Safety was assessed by analysis of treatment-emergent adverse events. Only 184 of 400 planned subjects were recruited and randomized (93 to the TSI group, and 91 to the control group). Enrollment was ended after 2 years because of difficult recruitment. An interim safety review showed a 2.42-fold risk of respiratory hospitalization for control group subjects (P = 0.020), and the study was terminated. Sixty-three subjects (34.2%) completed the entire study (30 in the TSI group, or 32.3%; and 33 in the control group, or 36.3%). Significantly fewer TSI subjects were hospitalized for worsening of respiratory symptoms (11.0% vs. 25.6%; P = 0.011), and fewer TSI subjects were hospitalized overall (16.5% vs. 27.8%; P = 0.065). Fewer TSI subjects received antibiotics other than the study drug (78.0% vs. 95.6%), and significantly fewer received oral antibiotics (76.9% vs. 91.1%; P = 0.009). No other safety or adverse event differences were observed. In conclusion, significant reductions in respiratory hospitalizations, concomitant antibiotic use, and a trend towards improvement in percent predicted forced expiratory flow (FEF(25-75)) provide evidence of a clinical benefit of TSI use in young persons with CF and mild lung disease. An effect on lung function decline rate could not be evaluated as planned, due to inadequate enrollment and early study termination.

Effect of family history on disclosure patterns of cystic fibrosis carrier status.

As general population screening becomes more common, an increasing number of cystic fibrosis (CF) carriers will be identified who do not have a family history of CF. Whether these carriers inform their relatives of their carrier status and whether their relatives are motivated to pursue carrier screening is unknown. We surveyed CF carriers with and without a family history of CF to understand whether and how information dissemination patterns differ, why information is or is not shared, and to what extent relatives are known to undergo testing. CF carriers were identified from a general population carrier screening clinic (group B = 18) or were parents of affected children followed at a CF clinic (group A = 30). CF carriers with a family history told essentially 100% of their living parents, siblings, and half-siblings, while those without a family history told 84% of living parents and 56% of siblings (P < 0.05). Despite the high rate of information dissemination in both groups, few siblings were known to have undergone carrier screening (14/74). Significantly fewer second- and third-degree relatives were informed about carrier status or were known to have undergone carrier screening. Group A was more likely to inform second- and third-degree relatives about carrier status. Our study documents that the frequency and reasons for disclosing CF carrier status differ between individuals with and without a family history of CF despite the fact that the reproductive risks for their relatives are the same.