The Relation between Genotype and Phenotype in Cystic Fibrosis — Analysis of the Most Common Mutation (ΔF<sub>508</sub>)

Kerem, Eitan; Corey, Mary; Kerem, Batsheva; Rommens, Johanna M.; Markiewicz, Danuta; Levison, Henry; Tsui, Lap‐Chee; Durie, Peter R.

doi:10.1056/nejm199011293232203

Cited by 672 publications

(401 citation statements)

References 19 publications

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“…FEV1 decreases and IgG increases with factors contributing to lung morbidity and overall mortality in CF. These were consistently shown to be age, female gender, pancreatic insufficient phenotype, infection/colonization, worse nutritional status (Konstan et al, 2007), F508del homozygous genotype (Kerem et al, 1990) and additional diagnosis of CFRD (Schaedel et al, 2002). On the contrary, IgG and FEV1 were reported to decrease and increase, respectively, upon treatment with anti-inflammatory agents, such as oral steroids (Auerbach et al, 1985), and are most likely being positively influenced by the recently documented immunomodulatory effect of macrolides (Shinkai et al, 2008).…”

Section: Inverse Relation Between Vitamin D and Serum Igg T Pincikovamentioning

confidence: 99%

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Pincikova

Nilsson²,

Moen³

et al. 2010

Eur J Clin Nutr

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Background/Objectives: The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, we aimed to assess the relationship between vitamin D and IgG levels. Subjects/Methods: Eight hundred and ninety-six CF patients were included (0.53-65.9 years) from seven centers in Denmark, Norway and Sweden. Serum 25-hydroxyvitamin D (25OHD) and total IgG were measured, spirometry was carried out and vitamin D intake data were gathered using a 7-day dietary food record. Multiple linear regression analyses were performed for IgG and forced expiratory volume in 1ls (FEV1) as dependent variables, and serum 25OHD, daily food and supplemented vitamin D sources of intake as independent variables. The model was controlled for age, gender, genotype, CF-related diabetes, season, infection/colonization status, long-term oral corticosteroid treatment, long-term treatment with macrolide antibiotics, pancreatic insufficient phenotype and body mass index z-score. Results: Serum total IgG levels were negatively associated with serum 25OHD (adjusted R 2 ¼ 0.376; beta ¼ À0.02; Po0.001), supplemented vitamin D intake per kg bodyweight (adjusted R 2 ¼ 0.375; beta ¼ À0.82; Po0.001) and total vitamin D intake per kg bodyweight (adjusted R 2 ¼ 0.398; beta ¼ À0.60; P ¼ 0.002). Serum 25OHD was positively associated with FEV1 (adjusted R 2 ¼ 0.308; beta ¼ 0.0007; P ¼ 0.025). Conclusions: Increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies.

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Section: Inverse Relation Between Vitamin D and Serum Igg T Pincikovamentioning

confidence: 99%

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Pincikova

Nilsson²,

Moen³

et al. 2010

Eur J Clin Nutr

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“…Only one mutation, the F508del accounts for B70% of CFTR mutant alleles in Europe but this also differs between populations. 12,13 In Polish CF patients the frequency of the F508del mutation is estimated as 53-57%. 14,15 According to the a panel of the most frequent mutations in Polish CF patients published in 2009 16 and our personal experience (unpublished data), mutations such as K710X and 2184insA have a frequency 40.45%.…”

Section: Introductionmentioning

confidence: 99%

Newborn screening for cystic fibrosis: Polish 4 years’ experience with CFTR sequencing strategy

Sobczyńska-Tomaszewska¹,

Ołtarzewski²,

Czerska³

et al. 2012

Eur J Hum Genet

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Newborn screening for cystic fibrosis (NBS CF) in Poland was started in September 2006. Summary from 4 years' experience is presented in this study. The immunoreactive trypsin/DNA sequencing strategy was implemented. The group of 1 212 487 newborns were screened for cystic fibrosis during the programme. We identified a total of 221 CF cases during this period, including, 4 CF cases were reported to be omitted by NBS CF. Disease incidence in Poland based on the programme results was estimated as 1/4394 and carrier frequency as 1/33. The frequency of the F508del was similar (62%) to population data previously reported. This strategy allowed us to identify 29 affected infants with rare genotypes. The frequency of some mutations (eg, 2184insA, K710X) was assessed in Poland for the first time. Thus, sequencing assay seems to be accurate method for screening programme using blood spots in the Polish population.

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“…Pseudomonas aeruginosa, an opportunistic gram-negative bacilliform bacterium, often affects patients with compromised host defense. Interestingly, variability in pulmonary disease severity is observed among CF patients and even among CF patients homozygous for CFTR mutations (19,33,36,51,55). Thus it is probable that other modifier genes are responsible for the individual variability in the severity of pulmonary symptoms in patients with CF or with other lung disease.…”

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confidence: 99%

SP-A1 and SP-A2 variants differentially enhance association ofPseudomonas aeruginosawith rat alveolar macrophages

Mikerov¹,

Umstead²,

Huang³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

125

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aeruginosa. Two genes, SP-A1 and SP-A2, encode human SP-A. We hypothesized that genetically determined differences in the activity of SP-A1 and SP-A2 gene products exist. To test this, we studied association of a nonmucoid P. aeruginosa strain (ATCC 39018) with rat alveolar macrophages in the presence or absence of insect cellexpressed human SP-A variants. We used two trios, each consisting of SP-A1, SP-A2, and their coexpressed SP-A1/SP-A2 variants. We tested the 6A 2 and 6A 4 alleles (for SP-A1), the 1A 0 and 1A alleles (for SP-A2), and their respective coexpressed SP-A1/SP-A2 gene products. After incubation of alveolar macrophages with P. aeruginosa in the presence of the SP-A variants at 37°C for 1 h, the cell association of bacteria was assessed by light microscopy analysis. We found 1) depending on SP-A concentration and variant, SP-A2 variants significantly increased the cell association more than the SP-A1 variants (the phagocytic index for SP-A1 was ϳ52-95% of the SP-A2 activity); 2) coexpressed variants at certain concentrations were more active than single gene products; and 3) the phagocytic index for SP-A variants was ϳ18 -41% of the human SP-A from bronchoalveolar lavage. We conclude that human SP-A variants in vitro enhance association of P. aeruginosa with rat alveolar macrophages differentially and in a concentration-dependent manner, with SP-A2 variants having a higher activity compared with SP-A1 variants.

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The Relation between Genotype and Phenotype in Cystic Fibrosis — Analysis of the Most Common Mutation (ΔF₅₀₈)

Abstract: The variable clinical course in patients with cystic fibrosis can be attributed at least in part to specific genotypes at the locus of the cystic fibrosis gene.

Cited by 672 publications

References 19 publications

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Newborn screening for cystic fibrosis: Polish 4 years’ experience with CFTR sequencing strategy

SP-A1 and SP-A2 variants differentially enhance association ofPseudomonas aeruginosawith rat alveolar macrophages

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The Relation between Genotype and Phenotype in Cystic Fibrosis — Analysis of the Most Common Mutation (ΔF508)

Abstract: The variable clinical course in patients with cystic fibrosis can be attributed at least in part to specific genotypes at the locus of the cystic fibrosis gene.

Cited by 672 publications

References 19 publications

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Newborn screening for cystic fibrosis: Polish 4 years’ experience with CFTR sequencing strategy

SP-A1 and SP-A2 variants differentially enhance association ofPseudomonas aeruginosawith rat alveolar macrophages

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The Relation between Genotype and Phenotype in Cystic Fibrosis — Analysis of the Most Common Mutation (ΔF₅₀₈)