Transmission ratio distortion and maternal effects confound the analysis of modulators of cystic fibrosis disease severity on 19q13.

Two entities localised within in a 5 Mb interval on 19q13, that is the transforming growth factor beta 1 (TGFbeta1) and the cystic fibrosis modifier 1, have been reported to modulate disease severity of cystic fibrosis (CF), albeit the designation of the risk allele for TGFbeta1 differs between studies. We have analysed genotyping data at seven microsatellite loci and four single nucleotide polymorphisms targeting the 19q13 area from 37 nuclear CF families with two affected offspring exhibiting extreme clinical phenotypes for indicators of transmission-ration distortion, maternal genetic or maternal non-genetic effects. Evidence for a transmission-ratio distortion was obtained at D19S112 (P=0.0304) near the recently characterised myotonic dystrophy locus myotonic dystrophy protein kinase (DMPK). Maternal and paternal genotype distributions were significantly different at rs1982073 (Leu10Pro at TGFbeta1) whereby all CF sibs heterozygous at rs1982073 inherited the Leu10 allele from their mother (P=0.000132) in our sibling panel. To ask whether the improved survival in CF over the last decades has any influence on TGFbeta1 allele frequencies, we analysed unrelated F508del homozygotes who were stratified by birth cohort. Sensitivity with respect to the survivor bias was reflected by significantly higher incidence of mild cystic fibrosis transmembrane conductance regulator mutation genotypes in the early born patient cohort (P=0.0169), and an allelic imbalance was also observed at TGFbeta1 (P=0.0664). In conclusion, the role of TGFbeta1 as a CF modulator, suggested from studies with a case-control setting, needs to be interpreted with caution unless family-based analysis is carried out to identify parental genetic and non-genetic effects.