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1.  Availability of 25-hydroxyvitamin D3 to antigen presenting cells controls the balance between regulatory and inflammatory T cell responses 
1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D3, is generally used as an indication of “vitamin D status”. However, utilization of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D3-1α-hydroxylase (CYP27B1) into active 1,25(OH)2D3. Using human T cells, we now show that addition of inactive 25(OH)D3 is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact resulting in the generation and release of 1,25(OH)2D3 which subsequently affects T cell responses. In most tissues, vitamin D binding protein (DBP) acts as a carrier to enhance the utilization of vitamin D. However, we show that DBP modulates T cell responses by restricting the availability of inactive 25(OH)D3 to DC. These data indicate that the level of “free” 25(OH)D3 available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses.
doi:10.4049/jimmunol.1200786
PMCID: PMC3504609  PMID: 23087405
2.  Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency 
Respiratory Research  2012;13(1):16.
Background
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).
We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.
Methods
The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.
Results
Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.
Conclusions
IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
doi:10.1186/1465-9921-13-16
PMCID: PMC3306733  PMID: 22356581
CHRNA3; Chronic obstructive pulmonary disease; Genetic association analysis; Genetic modifiers; IREB2
3.  Chronic obstructive pulmonary disease: towards pharmacogenetics 
Genome Medicine  2009;1(11):112.
Chronic obstructive pulmonary disease (COPD) is a common problem worldwide, and it is recognized that the term encompasses overlapping sub-phenotypes of disease. The development of a sub-phenotype may be determined in part by an individual's genetics, which in turn may determine response to treatment. A growing understanding of the genetic factors that predispose to COPD and its sub-phenotypes and the pathophysiology of the condition is now leading to the suggestion of individualized therapy based on the patients' clinical phenotype and genotype. Pharmacogenetics is the study of variations in treatment response according to genotype and is perhaps the next direction for genetic research in COPD. Here, we consider how knowledge of the pathophysiology and genetic risk factors for COPD may inform future management strategies for affected individuals.
doi:10.1186/gm112
PMCID: PMC2808747  PMID: 19951401
4.  The TNFalpha gene relates to clinical phenotype in alpha-1-antitrypsin deficiency 
Respiratory Research  2008;9(1):52.
Background
Genetic variation may underlie phenotypic variation in chronic obstructive pulmonary disease (COPD) in subjects with and without alpha 1 antitrypsin deficiency (AATD). Genotype specific sub-phenotypes are likely and may underlie the poor replication of previous genetic studies. This study investigated subjects with AATD to determine the relationship between specific phenotypes and TNFα polymorphisms.
Methods
424 unrelated subjects of the PiZZ genotype were assessed for history of chronic bronchitis, impairment of lung function and radiological presence of emphysema and bronchiectasis. A subset of subjects with 3 years consecutive lung function data was assessed for decline of lung function. Four single nucleotide polymorphisms (SNPs) tagging TNFα were genotyped using TaqMan® genotyping technologies and compared between subjects affected by each phenotype and those unaffected. Plasma TNFα levels were measured in all PiZZ subjects.
Results
All SNPs were in Hardy-Weinberg equilibrium. A significant difference in rs361525 genotype (p = 0.01) and allele (p = 0.01) frequency was seen between subjects with and without chronic bronchitis, independent of the presence of other phenotypes. TNFα plasma level showed no phenotypic or genotypic associations.
Conclusion
Variation in TNFα is associated with chronic bronchitis in AATD.
doi:10.1186/1465-9921-9-52
PMCID: PMC2478658  PMID: 18620570
5.  The genetics of chronic obstructive pulmonary disease 
Respiratory Research  2006;7(1):130.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation.
doi:10.1186/1465-9921-7-130
PMCID: PMC1626465  PMID: 17054776

Results 1-5 (5)