Original pre-clinical science
Single-nucleotide polymorphisms in the β-adrenergic receptor genes are associated with lung allograft utilization

https://doi.org/10.1016/j.healun.2010.08.011Get rights and content

Background

Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of β-adrenergic receptors (βARs). Single-nucleotide polymorphisms (SNPs) in βAR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in βAR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.

Methods

Nine hundred fifty-one organ donors were genotyped for 4 amino-acid-coding SNPs in the βAR genes. Lung allograft utilization was compared among donors stratified by genotypes.

Results

Utilization of donor lung allografts was 55% vs 35% (p = 0.02) among donors with GG vs AA/AG genotypes of the Ser49Gly SNP, 39% vs 32% (p = 0.04) with GG vs AA/AG genotype of Gly16Arg SNP and 37% vs 32% (p = 0.1) with CC vs GC/GG genotype of the Arg389Gly SNP. In the combined analysis, donors carrying 0 or 1 associated genotype had a utilization rate of 33%, whereas donors carrying 2 or 3 associated genotypes had utilization rates of 44% and 58%, respectively (p = 0.008). There was a stepwise decrease in chest radiograph infiltrates and an increase in partial pressure of oxygen/fraction of inspired oxygen (PaO2/FIO2) with an increasing number of these associated genotypes.

Conclusion

Genetic variants in the βAR genes among organ donors are associated with higher rates of lung allograft utilization. The increased utilization may be related to increased clearance of pulmonary edema and improved oxygenation in donors with favorable genotypes and suggests that βAR agonists may have a role in donor management.

Section snippets

Subjects

The study population was a cohort of consecutive organ donors managed by the California Transplant Donor Network (CTDN, Oakland, CA) from 2001 to 2005. Treating physicians at hospitals throughout the region identified potential brain-dead organ donors and consent for organ donation and collection of biologic materials was obtained from family members or next of kin. CTDN staff subsequently assumed management of the organ donors, and management was conducted according to protocols developed by

Subjects

A total of 951 organ donors, of a total of 1,223 managed by the CTDN from 2001 to 2005, had stored DNA available for analysis and defined the study cohort. The clinical characteristics of the cohort are shown in Table 1.

Association of clinical characteristics with lung utilization

From a total of 951 potential donors, lung allografts were used from 325 individuals, yielding an overall lung utilization rate of 34%. Both lungs were transplanted together from 216 (23%), both single lungs were transplanted from 47 (5%), only 1 single lung was transplanted

Discussion

In this study of 951 potential organ donors, we found that the GG genotype of the Ser49Gly SNP in the β1-adrenergic receptor gene and the GG genotype of the Gly16Arg SNP in the β2-adrenergic receptor gene are independently associated with increased lung allograft utilization from eligible donors. We also found that the combination of 3 favorable (associated with higher utilization) genotypes at 3 SNPs—the Ser49Gly SNP and Arg 389Gly SNPs, both in the β1-adrenergic receptor gene, and the

Disclosure statement

This work was initially presented as Abstract 551 (Session 38) at the 29th annual meeting of the International Society for Heart and Lung Transplantation, April 2009, Paris, France.

The study was supported by Research Grants NHLBI K23 HL085526 (to A.S.), NICHD HD047349 (to A.S.) and NHLBI HL51856 (M.A.M.).

The authors have no conflicts of interest to disclose.

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