Respiratory distress syndrome: evaluation of genetic susceptibility and protection by transmission disequilibrium test

Based on epidemiological data and genetic association studies, neonatal res piratory distress syndrome (RDS) is a complex disease with a multigenic bac kground. The genes coding for surfactant proteins (SP) A and B have been as signed as the most likely genes in the etiology of RDS. The major factor pr edisposing to RDS is prematurity, and thus the phenotype of a very prematur e newborn infant that does not develop the disease can be regarded as hyper normal. Altogether 107 father-mother-offspring trios were divided into two sets according to the proband's phenotype, to evaluate familial segregation of candidate gene polymorphisms by the transmission disequilibrium test. A set of 76 trios were analyzed for transmission disequilibrium from parents to affected offspring. Another set of 31 trios were studied for allele tra nsmission from parents to hypernormal offspring born very prematurely befor e the gestational age of 32 weeks. SP-A1-A2 haplotype 6A(2)-1A(0) showed si gnificant excess transmission to affected infants and SP-A1 allele 6A(2) de creased transmission to the hypernormals. The present family study provides strong support for a direct or indirect role of the SP-A alleles as geneti c predisposers to RIDS in premature infants. The inclusion of parent-hypern ormal offspring trios in transmission disequilibrium test is a useful appro ach to test for genetic protection against a disease.