Genetic Variability of Surfactant Protein-B and Respiratory Distress Syndrome: Clinical Implications

, Departments of Cellular and Molecular Physiology and Pediatrics; , Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pa.

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In This Article

Genetics and RDS

Genetic Contribution to the Pathogenesis of Disease

The etiology of most diseases is the result of the interplay between multiple factors and/or genes; thus, the etiology of most diseases is complex. One of the factors that contributes to any death (except perhaps one from trauma) and/or to any disease is genetics (Figure 5). What differs among various diseases is the extent of the genetic contribution -- whether it is 1%, 20%, 50%, 80%, and so on, and whether the genetic contribution is made by single or multiple genetic factors. The degree to which genetics contribute and the number of genetic factors involved in the etiology of a given disease determine the ease or difficulty with which one can identify the individual contributing genetic factors. Figure 6 schematically depicts the phenotype of a disease with a significant genetic contribution. Such a disease phenotype is the result of interactions among various factors -- these interactions occurring either among the disease-causing genes themselves (genetic factors) and/or among the genes and environmental factors, and/or among the genes and genetic or epigenetic (phenotypic/genotypic) modifiers.

Genetic basis of disease (or death).
Multiple factors contribute to the phenotype of a disease or trait with complex etiology. Concept adapted from: Floros J, Kala P: Surfactant proteins: Molecular Genetics of neonatal pulmonary diseases. Ann Rev Physiol 60:365-384, 1998.

Results of a number of studies, particularly epidemiologic studies, lead us to think that several factors may contribute to the etiology of RDS (ie, age, sex, and race), and that there is also a genetic contribution, at least in certain cases (reviewed in [27-29]). For example, the incidence of RDS in monozygous twins is higher than that in dizygotic twins.[21] Therefore, we hypothesized that the etiology of RDS is multifactorial and/or multigenic. Surfactant deficiency is clearly one of the contributing factors of RDS (Figure 7). Two of the proteins found in surfactant, SP-A and SP-B, have been shown to play an important role in surfactant function and are found in reduced amounts in infants who died or suffer from RDS.[31,32,33] Therefore, SP-A and SP-B genes seemed likely candidates for investigating the impact of genetic abnormalities on the pathogenesis of RDS.

Surfactant proteins and RDS. Etiology of RDS is multifactorial/multigenic; surfactant, and in particular, certain SP-A and SP-B alleles are thought to be some of the contributing factors.

Genotypes and RDS

In order to ascertain if these genes were good candidates, and because a number of alleles for human SP-A[27,34] and SP-B[16,18,35] have been identified and characterized, we investigated whether there were any associations between RDS and certain SP-B and/or SP-A alleles.

  1. Associations

    An SP-B polymorphic motif localized within the first half of intron IV was found in higher frequency in the RDS population (29.3% versus 16.8% in control, P<0.05; see Fig. 8).[18] This polymorphism, as discussed earlier (Fig. 2), is the result of the gain or loss in the number of copies of a composite motif. The significance of the gain or loss of copies of this motif on the structure, regulation, and/or function of SP-B is unknown. However, racial differences in the distribution of the SP-B intron IV alleles was observed.[35] Therefore, keeping the racial and/or ethnic composition of the control and experimental groups similar is important. Differences in the frequency of the SP-A alleles between races has also been observed.[36] Moreover, the frequency of one (1A0) of the SP-A alleles (the SP-A alleles are reviewed in [26]) is shown to be higher in a subgroup of RDS patients (Fig. 8).[36]

    Two individuals are said to have the same genotype for a given locus if they have the same alleles for that gene. If an allele or a genotype is found to occur with higher frequency in a disease group, that particular allele or genotype is considered to be associated with the disease phenotype. A significant association may indicate that the allele is a susceptibility/modifier factor for the disease, or is linked to a locus that is a susceptibility/modifier locus for the given disease, or the association may be an artifact due to population admixture. Matching the groups under study (at least for the known confounding parameters) is of primary importance because several confounding factors, such as gestational age, sex, and/or race, may contribute to the pathogenesis of RDS. In a study where the frequency of SP-A alleles in RDS and control groups was examined, differences as a function of sex were not observed.[36]

    Furthermore, to test the strength of an association and to overcome problems relating to population admixture, additional tests such as the Transmission/Disequilibrium test (TDT) can be used.[37,38] This test is based on the notion that a parent heterozygous (individuals with different alleles at a given locus are heterozygous at that locus) for an allele associated with a particular disease will transmit the associated allele to the affected offspring at a frequency higher than 0.5 (the random frequency of transmission of either allele is 0.5). Because the nontransmitted allele can serve as an internal control, the TDT overcomes problems relating to the use of nongenetically-matched controls. Another advantage of using TDT is that it can identify factors that make a modest contribution -- traditional linkage studies cannot easily identify genetic factors with small effects (reviewed in [28]). Thus, a combination of approaches is required for the study of the contributing factors in a disease with multifactorial/polygenic etiology.

  2. Synergy Between SP-A and SP-B

    Because the frequency of certain SP-A or SP-B alleles was found to be increased in the RDS population (Fig. 8), the frequency of the combined SP-A and SP-B alleles (each shown to be increased in cases of neonatal distress) in patients with RDS and control groups was studied. The results of these studies showed that the combined effect was synergistic, an aspect of epistasis, a phenomenon in human genetics that occurs when the combined effect of two or more genes on the phenotype (disease or trait) could not have been predicted as the sum of the separate effects.[39] The epistatic effect of two genes could be more than additive (synergistic), or together, the two genes could nullify each other's effect. For SP-A and SP-B, the epistatic effect appears to be that of synergism (Fig. 8). Synergism between two unlinked loci with products that interact functionally (as is the case for SP-A and SP-B; ie, both are required for one of the morphological forms of surfactant) has been observed in other systems as well.[40] Therefore, in the context of the multifactorial/multigenic etiology of RDS, we infer that SP-A and SP-B (shown in red in Figure 7) are two of the contributors. Our current hypothesis is based on these findings: prematurely-born infants with certain SP-A and/or SP-B alleles have a higher risk of developing RDS.


    Frequency of SP-A (1A0) and SP-B (SP-Bi) alleles in RDS and control. Reprinted with permission from Pediatric Research; 43(2):169-77, 1998. Copyright ©1998.

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