|The European Cystic Fibrosis Twin and Sibling Study|
The European CF Twin and Sibling Study was initiated in 1995 by the CF research groups from Rotterdam and Hannover with the intention to unravel the cause of CF disease variability and the aim to identify factors that influence CF disease severity. The variability of CF disease severity can be attributed to the CFTR genotype, epigenetic factors and disease modulating genes.
The "European Cystic Fibrosis Twin and Sibling Study" pursues the classical approach of quantitative human genetics to address the impact of each factor by investigating affected patient pairs. In central European populations, approximately 70% of CF alleles bear the same CFTR mutation, F508del. Consequently, 50% of all patient pairs are homozygous for the same disease-causing lesion, a fact that facilitates analysis of the disease severity in a group with a homogeneous mutation genotype in the major disease-causing gene.
CF is the only disease where a sufficient number of patient pairs that fulfil these criteria can be recruited, due to the prevalence of one mutation genotype in a so-called monogenic disease that follows an autosomal recessive trait. Within the last years, selected informative patient pairs have been recruited for a thorough analysis of the clinical phenotype and the basic defect.
Twin study approach
Selection of highly informative patient pairs
Each of the selected cohorts displayed non-overlapping phenotypes as characterised by two clinical parameters that describe the patients' nutritional and pulmonary status, respectively. In a complementary approach, extreme phenotypes for the manifestation of the CF basic defect were defined.
This report summarises the major results from the association study of genetic modifiers in CF as well as the relative impact of inherited versus environmental factors on the CF phenotype.
Stanke F, Becker T, Kumar V, Hedtfeld S, Becker C, Cuppens H, Tamm S, Yarden J, Laabs U, Siebert B, Fernandez L, Macek M Jr, Radojkovic D, Ballmann M, Greipel J, Cassiman JJ, Wienker TF, Tümmler B.
Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia.
J Med Genet. 2010 Sep 12. PMID: 20837493
This publication reports on the correlation between the CF basic defect manifestation in nasal and intestinal tissue and CF disease severity.
Bronsveld I, Mekus F, Bijman J, Ballmann M, de Jonge HR, Laabs U, Halley DJ, Ellemunter H, Mastella G, Thomas S, Veeze HJ, Tummler B.
Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings.
J Clin Invest. 2001 Dec;108(11):1705-15. PMID: 11733566
Here, the inherited component of the CFTR-mediated basic defect manifestation in the intestine is described.
Bronsveld I, Mekus F, Bijman J, Ballmann M, Greipel J, Hundrieser J, Halley DJ, Laabs U, Busche R, De Jonge HR, Tümmler B, Veeze HJ.
Residual chloride secretion in intestinal tissue of ΔF508 homozygous twins and siblings with cystic fibrosis.
Gastroenterology. 2000 Jul;119(1):32-40. PMID: 10889152
This work describes the selection algorithm for concordant mildly affected, concordant severely affected and discordant patient pairs.
Mekus F, Ballmann M, Bronsveld I, Bijman J, Veeze H, Tümmler B.
Categories of ΔF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics.
Twin Research 2000, 3: 277-293. PMID: 11463149