Prospective Cohort Study

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

Because the lungs function as the body's gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response that could damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses.

Immunoregulatory functions of surfactant proteins.

Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types. The past few years have seen a quantum leap in our understanding of the formation, dynamics and functions of these enigmatic structures. Caveolae have now emerged as vital plasma membrane sensors that can respond to plasma membrane stresses and remodel the extracellular environment. Caveolae at the plasma membrane can be removed by endocytosis to regulate their surface density or can be disassembled and their structural components degraded. Coat proteins, called cavins, work together with caveolins to regulate the formation of caveolae but also have the potential to dynamically transmit signals that originate in caveolae to various cellular destinations. The importance of caveolae as protective elements in the plasma membrane, and as membrane organizers and sensors, is highlighted by links between caveolae dysfunction and human diseases, including muscular dystrophies and cancer.

Caveolae as plasma membrane sensors, protectors and organizers

Outcomes of children of extremely low birthweight and gestational age in the 1990's.

(1987). The Sex Difference in Fetal Lung Surfactant Production. Experimental Lung Research: Vol. 12, No. 1, pp. 1-19.

The Sex Difference in Fetal Lung Surfactant Production

It has been recognized that male infants are at greater risk of respiratory distress syndrome than are female infants. Amniotic fluid was obtained from 73 male and 76 female fetuses between 28 and 40 wk of gestation. To assess fetal pulmonary maturity, we determined the lecithin-sphingomyelin ratio and concentrations of saturated phosphatidyl choline and cortisol in all of these fluids. Analysis of covariance showed that female infants had higher indexes of pulmonary maturity than did male infants. The difference in degree of fetal pulmonary maturity was 1.2 to 2.5 wk, on the basis of these measurements, with females ahead of males. We conclude that there is a biochemical basis for the increased risk of respiratory distress syndrome in male infants.

Sex differences in fetal lung maturation.

Deficiency of the lipoprotein complex, surfactant, can lead to respiratory distress syndrome (RDS) in the prematurely born infant. The surfactant proteins (SP) play important roles in the function of surfactant. Previously, we have characterized four allelic variants of the SP-A1 gene (6A, 6A2, 6A3, and 6A4) and five allelic variants of the SP-A2 gene (1A, 1A0, 1A1, 1A2, and 1A3). We hypothesized that specific SP-A alleles/genotypes are associated with increased risk of RDS. Because race, gestational age (GA), and sex are risk factors for RDS, we first studied the distribution and frequencies of SP-A alleles/genotypes while adjusting for these factors as confounders or effect modifiers in control (n = 86 white and 12 black subjects) and RDS (n = 106 white and 37 black subjects) populations with GAs ranging from 24 wk to term. Although the odds ratios of several alleles and genotypes were in the opposite directions for black and white subjects, the homogeneity of odds ratio reached statistical significance only in the case of 6A3/6A3. Although differences were observed in subgroups with different GAs ( 28 wk) of the RDS white population, definitive conclusions cannot be made regarding the effect of modification by GA. No differences were observed as a function of sex. Second, we compared the frequencies of SP-A genotypes and alleles between control (n = 83) and RDS (n = 82) patients in the >28-wk white population. Differences between the two groups were observed for the 1A0 allele and 1A0 genotypes. Moreover, a significant synergistic positive association was observed between 1A0 allele + SP-B polymorphic variant and RDS. We conclude that 1) the genetic analyses of RDS and SP-A locus should be performed separately for black and white populations and 2) SP-A alleles/genotypes and SP-B variant may contribute to the etiology of RDS and/or may serve as markers for disease subgroups.

/pdf/association-of-pulmonary-surfactant-protein-a-sp-a-gene-and-13j0kxo7ho.pdf

Association of Pulmonary Surfactant Protein A (SP-A) Gene and Respiratory Distress Syndrome: Interaction with SP-B

Males have a higher morbidity and mortality for neonatal respiratory distress syndrome (RDS) than females, and respond less well to hormone therapy designed to prevent RDS by stimulating fetal pulmonary surfactant production. We have shown that male fetuses exhibit delayed production of pulmonary surfactant. We tested the hypothesis that the sex difference in fetal pulmonary surfactant production is under hormonal control. Pulmonary surfactant was measured as the saturated phosphatidylcholine/sphingomyelin ratio (SPC/S) in the lung lavage of fetal rabbits at 26 d gestation. There was an association between the sex of neighboring fetuses and the SPC/S ratio of the female fetuses, such that with one or two male neighbors, respectively, females had decreasing SPC/S ratios (P males, P = 0.03). In the 1-mg/d group there was no sex difference in androgen levels and the sex difference in the SPC/S ratio was also eliminated as the female values were lowered to the male level. Higher doses of DHT (10, 25 mg/d) further reduced the SPC/S ratios. We injected the anti-androgen Flutamide (25 mg/d) from day 12 through day 26 of gestation. This treatment eliminated the normal sex difference in the lung lavage SPC/S ratio by increasing the male ratios to that of the females. We conclude that androgens inhibit fetal pulmonary surfactant production. An understanding of the mechanism of the sex difference in surfactant production may allow development of therapy that is as effective in males as in females for preventing RDS.

/pdf/dihydrotestosterone-inhibits-fetal-rabbit-pulmonary-3mk3egqh3z.pdf

Dihydrotestosterone Inhibits Fetal Rabbit Pulmonary Surfactant Production

BACKGROUND: We have previously shown that the Hox gene Hoxb-5 is necessary for normal mouse lung branching morphogenesis Abnormal Hoxb-5 regulation causes specific alterations in airway branching We hypothesized that Hoxb-5 is similarly involved in human lung branching morphogenesis, and is abnormally expressed in bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM), both of which are congenital lung malformations with abnormal airway development METHODS: The temporal, spatial, and cellular expression of the Hoxb-5 protein was evaluated in normal human lung and BPS and CCAM tissue using Western blot analysis and immunocytochemistry RESULTS: The expression of Hoxb-5 during human lung development showed strong similarities to that during mouse lung development Western blots showed high Hoxb-5 protein levels in the pseudoglandular period (PSG), decreased but sustained levels in the canalicular period (CAN), and negligible levels during the alveolar period (ALV) Immunocytochemistry showed Hoxb-5 protein expression in mesenchymal cells around branching airways in the pseuodglandular period, subepithelial fibroblast localization (especially at airway branch points) in the CAN and minimal expression in the ALV In BPS and CCAM tissue, Hoxb-5 protein levels were increased compared to age- and developmentally-matched lung tissue, and were more similar to the PSG and CAN with Hoxb-5-positive cells in mesenchyme surrounding abnormally branched airways CONCLUSIONS: Hoxb-5 expression during human lung branching morphogenesis, which is similar to that observed in mouse lung development, indicates that it plays a role in controlling airway patterning This notion is supported by results from BPS and CCAM tissue, in which Hoxb-5 is maintained in a manner typical of an earlier developmental stage and is associated with development of abnormal lung tissue

Heber C. Nielsen

Papers

The Sex Difference in Fetal Lung Surfactant Production

Sex differences in fetal lung maturation.

Association of Pulmonary Surfactant Protein A (SP-A) Gene and Respiratory Distress Syndrome: Interaction with SP-B

Dihydrotestosterone Inhibits Fetal Rabbit Pulmonary Surfactant Production

Expression of Hoxb-5 during human lung development and in congenital lung malformations.