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1.  Inflammatory Markers of Lung Disease in Adult Patients With Cystic Fibrosis 
Pediatric pulmonology  2007;42(3):256-262.
Progressive pulmonary disease associated with chronic bacterial infection and inflammation is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Identifying markers of inflammation that correlate with lung injury may be useful in monitoring disease progression and response to therapy. We hypothesized that levels of serum biomarkers would correlate with clinical course of CF as defined by pulmonary function testing (FEV1).
To determine whether biomarkers of systemic inflammation correlate with lung function in adults with CF.
Retrospective cross-sectional analysis of 63 individuals ≥30 years of age diagnosed with CF in childhood and followed at Children’s Hospital, Boston. We collected data on demographics, CFTR genotype, percent predicted forced expiratory volume in 1 sec (FEV1), C-reactive protein (CRP), serum IgE nd IgG, alpha1-antitrypsin, total white blood cell and neutrophil counts, and percent neutrophils. We used univariate analyses and multivariate linear regression modeling to examine whether markers of systemic inflammation varied with FEV1 (% predicted).
In two-covariate models including CRP and one other marker, CRP (P < 0.001) and IgG (P = 0.02) were significantly associated with FEV1 (% predicted). In the CRP and IgG model, percent predicted FEV1 decreased by 4.91% (P < 0.0001) for each twofold increase in CRP and by 1.56% (P = 0.02) for each 100 mg/dl increase in IgG. Results were unchanged by adjustment for number of DF 508 CFTR alleles. There was no association between any other marker and FEV1 (% predicted) after adjusting for CRP.
Severity of lung disease in long surviving adult CF patients is correlated with CRP and IgG levels. Our findings relating CRP and IgG levels and lung function provide a foundation for subsequent longitudinal studies and consideration of novel disease mechanisms and outcome measurements.
PMCID: PMC4469989  PMID: 17245735
cystic fibrosis; biological markers; airway inflammation; c-reactive protein in cystic fibrosis; lung function; IgG in cystic fibrosis
2.  Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age1–3 
Vitamin D deficiency and asthma are common at higher latitudes. Although vitamin D has important immunologic effects, its relation with asthma is unknown.
We hypothesized that a higher maternal intake of vitamin D during pregnancy is associated with a lower risk of recurrent wheeze in children at 3 y of age.
The participants were 1194 mother-child pairs in Project Viva—a prospective prebirth cohort study in Massachusetts. We assessed the maternal intake of vitamin D during pregnancy from a validated food-frequency questionnaire. The primary outcome was recurrent wheeze, ie, a positive asthma predictive index (≥2 wheezing attacks among children with a personal diagnosis of eczema or a parental history of asthma).
The mean (±SD) total vitamin D intake during pregnancy was 548 ± 167 IU/d. By age 3 y, 186 children (16%) had recurrent wheeze. Compared with mothers in the lowest quartile of daily intake (median: 356 IU), those in the highest quartile (724 IU) had a lower risk of having a child with recurrent wheeze [odds ratio (OR): 0.39; 95% CI: 0.25, 0.62; P for trend <0.001]. A 100-IU increase in vitamin D intake was associated with lower risk (OR: 0.81; 95% CI: 0.74, 0.89), regardless of whether vitamin D was from the diet (OR: 0.81; 95% CI: 0.69, 0.96) or supplements (OR: 0.82; 95% CI: 0.73, 0.92). Adjustment for 12 potential confounders, including maternal intake of other dietary factors, did not change the results.
In the northeastern United States, a higher maternal intake of vitamin D during pregnancy may decrease the risk of recurrent wheeze in early childhood.
PMCID: PMC4406411  PMID: 17344501
Vitamin D; pregnancy; dietary intake; childhood wheeze; asthma
4.  Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model 
Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition.
We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model.
We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases).
For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200.
Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly.
Clinical implications
Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.
PMCID: PMC3476046  PMID: 17904628
Omalizumab; cost-effectiveness; asthma; anti-IgE
5.  Maternal diet vs lack of exposure to sunlight as the cause of the epidemic of asthma, allergies and other autoimmune diseases 
Thorax  2007;62(9):746-748.
Role of vitamin D deficiency in allergic and autoimmune diseases
PMCID: PMC2117306  PMID: 17726168
6.  Comprehensive Testing of Positionally Cloned Asthma Genes in Two Populations 
Rationale: Replication of gene-disease associations has become a requirement in complex trait genetics.
Objectives: In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.
Methods: We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium–tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels.
Measurements and Main Results: Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes.
Conclusions: These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.
PMCID: PMC2048676  PMID: 17702965
bronchial hyperreactivity; immunoglobulin E; linkage disequilibrium; NPSR1; single-nucleotide polymorphism
7.  Modifying Effects of the HFE Polymorphisms on the Association between Lead Burden and Cognitive Decline 
Environmental Health Perspectives  2007;115(8):1210-1215.
As iron and lead promote oxidative damage, and hemochromatosis (HFE) gene polymorphisms increase body iron burden, HFE variant alleles may modify the lead burden and cognitive decline relationship.
Our goal was to assess the modifying effects of HFE variants on the lead burden and cognitive decline relation in older adults.
We measured tibia and patella lead using K-X-ray fluorescence (1991–1999) among participants of the Normative Aging Study, a longitudinal study of community-dwelling men from greater Boston. We assessed cognitive function with the Mini-Mental State Examination (MMSE) twice (1993–1998 and 1995–2000) and genotyped participants for HFE polymorphisms. We estimated the adjusted mean differences in lead-associated annual cognitive decline across HFE genotype groups (n = 358).
Higher tibia lead was associated with steeper cognitive decline among participants with at least one HFE variant allele compared with men with only wild-type alleles (p interaction = 0.03), such that a 15 μg/g increase in tibia lead was associated with a 0.2 point annual decrement in MMSE score among HFE variant allele carriers. This difference in scores among men with at least one variant allele was comparable to the difference in baseline MMSE scores that we observed among men who were 4 years apart in age. Moreover, the deleterious association between tibia lead and cognitive decline appeared progressively worse in participants with increasingly more copies of HFE variant alleles (p-trend = 0.008). Results for patella lead were similar.
Our findings suggest that HFE polymorphisms greatly enhance susceptibility to lead-related cognitive impairment in a pattern consistent with allelelic dose.
PMCID: PMC1940090  PMID: 17687449
cognitive decline; epidemiology; HFE; lead; longitudinal studies; neuropsychologic tests
8.  The Association of a SNP Upstream of INSIG2 with Body Mass Index is Reproduced in Several but Not All Cohorts 
PLoS Genetics  2007;3(4):e61.
A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.
Author Summary
Obesity is an epidemic in the United States of America and developing world, portending an epidemic of related diseases such as diabetes and heart disease. While diet and lifestyle contribute to obesity, half of the population variation in body mass index, a common measure of obesity, is determined by inherited factors. Many studies have reported that common sequence variants in genes are associated with an increased risk for obesity, yet most of these are not reproducible in other study cohorts, suggesting that some are false. Recently, Herbert et al. reported a slightly increased risk of obesity for people carrying two copies of the minor allele at a common variant near INSIG2. We present our attempts to further evaluate this potential association with obesity in additional populations. We find evidence of increased risk of obesity for people carrying two copies of the minor allele in five out of nine cohorts tested, using both family- and population-based testing. We indicate possible reasons for the varied results, with the hope of encouraging a combined analysis across study cohorts to more precisely define the effect of this INSIG2 gene variant.
PMCID: PMC1857727  PMID: 17465681

Results 1-8 (8)