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Biomedical subjects

Richard A King

Publications and source records attributed to Richard A King.

At least 19 recordsLinked to original sources
PubMed2007

Novel insights into lung transplant rejection by microarray analysis.

Gene expression microarrays can estimate the prevalence of mRNA for thousands of genes in a small sample of cells or tissue. Organ transplant researchers are increasingly using microarrays to identify specific patterns of gene expression that predict and characterize acute and chronic rejection, and to improve our understanding of the mechanisms underlying organ allograft dysfunction. We used microarrays to assess gene expression in bronchoalveolar lavage cell samples from lung transplant recipients with and without acute rejection on simultaneous lung biopsies. These studies showed increased expression during acute rejection of genes involved in inflammation, apoptosis, and T-cell activation and proliferation. We also studied gene expression during the evolution of airway obliteration in a murine heterotopic tracheal transplant model of chronic rejection. These studies demonstrated specific patterns of gene expression at defined time points after transplantation in allografts, whereas gene expression in isografts reverted back to that of native tracheas within 2 wk after transplantation. These studies demonstrate the potential power of microarrays to identify biomarkers of acute and chronic lung rejection. The application of new genetic, genomic, and proteomic technologies is in its infancy, and the microarray-based studies described here are clearly only the beginning of their application to lung transplantation. The massive amount of data generated per tissue or cell sample has spawned an outpouring of invention in the bioinformatics field, which is developing methodologies to turn data into meaningful and reproducible clinical and mechanistic inferences.

Animals↗
PubMed2006

CD14 promoter polymorphisms in atopic families: implications for modulated allergen-specific immunoglobulin E and G1 responses.

BACKGROUND: CD14 promoter DNA sequence polymorphisms for the endotoxin receptor gene have been implicated in modulating allergen-specific immunoglobulin (Ig)E responses in randomly selected individuals with atopy. We sought to determine if a single nucleotide polymorphism in the CD14 promoter region is associated with atopy in atopic families, and to assess its influence on serum levels of CD14 and allergen-specific IgE and IgG1 responses. METHODS: We screened 367 members of 91 Caucasian nuclear families with a history of asthma for pulmonary function by spirometry, including methacholine challenge to detect bronchial hyperreactivity, and atopy by serum total IgE and skin prick test to 14 allergens. The CD14 promoter single nucleotide polymorphism was analyzed in DNA isolated from peripheral blood mononuclear cells to identify C/C, C/T and T/T genotypes. Serum tests were done for soluble CD14 (sCD14) and dust mite-specific antibody (Der p 1-IgG1). RESULTS: Serum sCD14 levels were not associated with clinical phenotypes (asthma, bronchial hyperreactivity or atopy). However, sCD14 levels were inversely related to both allergen-specific IgE and Der p 1-IgG1 production, but only among those with evidence of atopic sensitization. Linear regression analysis, accounting for random family effects, demonstrated a higher production of allergen-specific IgE or Der p 1-IgG1 associated with the T/T genotype and a lower level of specific IgE and IgG1 production associated with sCD14 levels. CONCLUSIONS: An element of the innate immune system (CD14) has profound effects upon modulating the acquired allergen-specific immunoglobulin responses among those with an inherited atopic predisposition.

Adolescent↗
PubMed2006

Correlation of grating acuity with letter recognition acuity in children with albinism.

PURPOSE: This study was undertaken to determine whether grating acuity in early childhood can be used as a predictor of letter recognition acuity in patients with albinism. METHODS: In this retrospective study, we compared the binocular grating acuities of children with albinism (30 at age 1, 29 at age 2, and 19 at age 3) to their letter recognition acuity at age 4-6 years. RESULTS: Mean binocular grating acuity was 2.0, 1.9, and 1.5 octaves below age matched norms at ages 1, 2, and 3 years, respectively (P<0.001 at all ages). Mean grating acuity at ages 1, 2, and 3 correlated moderately (r=0.458, 0.502, and 0.471, respectively; all with P<0.05) with mean binocular letter recognition acuity of the same children at ages 4-6. A subgroup analysis of 9 patients followed longitudinally showed strong correlation of binocular grating acuity at ages 1 and 2 with letter acuity (r=0.745, P=0.021; r=0.930, P<0.001, respectively) and moderate correlation at age 3 (r=0.685, P=0.042). In the larger group and the longitudinal subgroup, mean binocular grating acuity at ages 1 and 2 was worse than mean binocular letter recognition acuity at age 4-6 (paired-samples t-test, P<0.001). Mean binocular grating acuity at age 3 in both groups was not significantly different than mean binocular letter recognition acuity at age 4-6 (paired-samples t-test, P=0.790, 0.215, respectively). CONCLUSION: Parents should be informed that vision measured as grating acuity at age 3 provides an estimate of future letter recognition acuity in children with albinism.

Albinism, Ocular↗
PubMed2006

Spectrum of foveal development in albinism detected with optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) has shown the absence of a foveal depression in an individual with oculocutaneous albinism, type 1 (OCA1) and best-corrected visual acuity (BCVA) of 20/400. However, the presence of an annular light reflex in the macula has been noted with indirect ophthalmoscopy in other patients with albinism who have better vision. We studied macular architecture in albinism with OCT when binocular BCVA was > or = 20/60 and compared this to detection of foveal development with binocular indirect ophthalmoscopy. METHODS: Eleven patients with albinism and BCVA > or = 20/60 were recruited for OCT. Average central macular thickness was recorded. Presence of an oval annular reflex was determined with binocular indirect ophthalmoscopy. RESULTS: Mean binocular BCVA was 20/39 (range: 20/20 to 20/50). Twelve eyes had a rudimentary annular reflex detected with ophthalmoscopy. OCT was reliable in 20 of 22 eyes. A foveal depression was identified with OCT in four eyes. Mean macular thickness for these four eyes was 233 microm (+/- 22.5 microm). We found a weak inverse correlation between BCVA (logMAR) and thickness (r = -0.21). CONCLUSIONS: OCT shows the spectrum of foveal development in albinism, from complete absence of development to a central depression corresponding to a rudimentary annular reflex detected with ophthalmoscopy. The reduced rate of detection of foveal development with OCT compared with ophthalmoscopy is likely related to poor fixation in patients with nystagmus.

Adolescent↗
PubMed2006

A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity.

BACKGROUND: Asthma and atopy represent complex traits for which genetic predisposition has been demonstrated. Pollen sensitivity, whether seasonal or chronic, appears to be a major contributor to the asthmatic phenotype. OBJECTIVE: Regions of the genome contributing to skin test reactivity to 5 seasonal allergens are to be identified in a genome-wide scan. These regions may be distinct from those contributing to risk for asthma and/or atopy. METHODS: In the Collaborative Study on the Genetics of Asthma, 4 sites collected 287 families with 2 or more members with asthma. Reactivity to individual pollens were determined on all family members. A genome scan was performed at 9-centiMorgan intervals, and skin test reactivity to 5 seasonal allergens was the focus of nonparametric genetic linkage analysis. RESULTS: Chromosomal regions that exhibited suggestive linkage (logarithm of the odds >1.18; P < .01) to seasonal pollen reactivity were identified on chromosomes 13q34, 20p12, and 21q21. Evidence of ethnic differences in linkage to seasonal allergens was demonstrated, with support for linkage in African American subjects on chromosomes 8, 10, and 12, in European American subjects on chromosomes 14, 19, 20, and 22, and in Hispanics on chromosome 21. In all families, evidence for linkage of skin test reactivity for Betula, Lolium, and Artemisia was strongest in a region on chromosome 21 that contained the candidate gene, A Disintegrin And Metalloprotease domain 33 (ADAM33). CONCLUSION: These results suggest both substantial genetic overlap and extensive heterogeneity in the genetic basis for the allergic response to seasonal allergens.

Adolescent↗
PubMed2005

P gene mutations associated with oculocutaneous albinism type II (OCA2).

Oculocutaneous albinism type II (OCA2) is the most common form of albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372_2373delTC, c.1555delG, c.1938_1939insC, c.2050delT, and c.1045_1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365_2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://albinismdb.med.umn.edu).

Albinism, Oculocutaneous↗
PubMed2005

A 'touch' of the White platelet syndrome.

Investigations into structural defects in platelets from a large family with the White platelet syndrome (WPS) separated the members into three groups. The first group of 22 members was the subject of our first report (White JG, Key NS, King RA, Vercellotti GM. The white platelet syndrome: A new autosomal dominant platelet disorder. Platelets 2004;15:173-184). A third group of 13 members had no abnormalities of platelet ultrastructure. The second group of 17 members, the focus of the present study, had a 'touch' of the WPS. Platelet counts, mean platelet volumes (MPVs) and platelet responses to aggregating agents were normal in 'touch' patients in contrast to platelets of those with the full WPS in whom these parameters were abnormal. Up to 13% of the full WPS platelets contained large, fully developed Golgi complexes, up to seven in number, extruding innumerable vesicles from the trans-Golgi face and filling the cytoplasm of many platelets. Many Golgi complexes had centrioles associated with them. 'Touch' platelets had one or two Golgi complexes of intermediate size in 3-5% of their platelets. Golgi vesicles were uncommon and centrioles absent. Gray platelets and hypogranular cells were infrequent in patients with a 'touch' of the WPS, whereas up to 44% of the platelets from those with the WPS were gray or hypogranular. Elements of the dense tubular system were prominent in full WPS platelets, together with their formation into areas of cytoplasmic sequestration and autodigestion. These features were absent in 'touch' platelets. As commonly observed in full WPS platelets, mitochondria were larger and more numerous than alpha granules in some 'touch' cells. Both 'touch' and full WPS platelets frequently contained giant and rod-shaped granules. Dense bodies, however, were normal in size and number in 'touch' platelets, and half normal size in full WPS platelets. The separation of ultrastructural abnormalities in the two varieties of the WPS suggests that genetic defects involve more than a single gene and the genes are variable in their penetrance. Genetic studies to determine if this is the case are currently in progress.

Blood Coagulation Disorders, Inherited↗
PubMed2005

Gene expression profiling in murine obliterative airway disease.

Lung and heart-lung transplantation are effective treatments for many diseases unresponsive to other therapy. However, long-term survival of recipients is limited by the development of obliterative bronchiolitis (OB). In this study, microarray analysis of a heterotopic mouse model of obliterative airway disease (OAD) was used to test the hypothesis that the expression and patterns of genes will correlate with specific changes in tracheal tissue developing a response to allotransplantation and the infiltrating cells manifesting these changes. Expression profiles observed were in accordance with the current paradigm of a predictable sequence of events, beginning with airway injury; an innate immune response followed by an adaptive immune response, including both cell-mediated and humoral components; and eventual loss of airway epithelial cells. These observations confirm and expand the list of genes and molecular processes that can be studied as potential surrogate markers or targets for intervention of OB.

Animals↗
PubMed2004

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.

Adolescent↗
PubMed2004

Positive angle kappa in albinism.

BACKGROUND: Albinism is an inherited disorder of deficient melanin production. There is a high prevalence of strabismus in patients with albinism. We investigated the prevalence of a positive angle kappa in patients with albinism and report its effect on assessment of binocular alignment. METHODS: We retrospectively reviewed the charts of 207 consecutive patients with the diagnosis of albinism seen at the University of Minnesota between 1984 and 2002. Angle kappa and alignment using prism and alternate-cover test (PACT) and Krimsky measurements were recorded. RESULTS: In 99.6% of our patients with albinism, angle kappa was noted to be positive. The mean difference between PACT and Krimsky measurements was 17.11 prism diopters in the more exotropic (or less esotropic) direction per Krimsky test. Because of the high prevalence of a positive angle kappa, esodeviations often appeared less and exodeviations appeared greater than when measured using PACT. CONCLUSIONS: Positive angle kappa can be considered another clinical feature of albinism. Consideration should be given to the effect of positive angle kappa on alignment as observed by Krimsky measurement when planning extraocular muscle surgery, particularly when preoperative sensory testing suggests binocular potential.

Albinism, Oculocutaneous↗
PubMed2004

Efficacy of spectacles in persons with albinism.

INTRODUCTION: Patients with albinism have varying degrees of reduced vision, strabismus, iris transillumination, nystagmus, fundus hypopigmentation, and foveal hypoplasia. High refractive errors are common, but reduced vision persists due to nonrefractive factors, causing reluctance by some clinicians to prescribe spectacles. We sought to evaluate the effect of spectacle correction of refractive error on clinical findings and recorded compliance with refractive corrections, as little detailed data exist. METHODS: We prospectively examined 35 consecutive patients with albinism for whom glasses had been prescribed to determine if objective improvement in recognition visual acuity (VA), strabismus, anomalous head posture (AHP), fusion, or stereoacuity occurred with refractive correction. Parents or patients reported compliance with glasses wear (excellent: >75% of awake hours; good: 50-75% of awake hours; fair: 26-50% of awake hours; poor: <25%). RESULTS: Median age was 9.5 years (range: 3 to 30). Median refractive correction was 1.875 D spherical equivalent (range: -9.75 to +8.88 D). Glasses wear was initiated at a median age of 14 months (range: 3 months to 14 years). Mean binocular VA at distance was 20/80.9 corrected and 20/107.6 uncorrected ( P < 0.001). Mean VA at near was 20/28.4 corrected and 20/41 uncorrected ( P < 0.001). Mean strabismic deviation was 7.2 PD with glasses and 10.0 PD without glasses at distance ( P = 0.006) and 10.8 PD with glasses and 14 PD without glasses at near ( P = 0.042). Mean AHP at distance was 8.3 degrees with glasses and 7.3 degrees without glasses at distance ( P = 0.327) and 4.7 degrees both with and without glasses at near ( P = 0.308). Twenty-one patients had fusion with or without glasses, two had fusion only with glasses, and one patient had fusion only without glasses. The other patients did not have any detectable degree of fusion. Twenty-seven individuals had no stereoacuity with or without glasses, five had gross stereoacuity of 3000 seconds of arc both with and without glasses, and three had gross stereoacuity only while wearing glasses. Compliance was excellent in 29 patients, fair in four, and poor in two. CONCLUSION: This prospective study showed a significant improvement in corrected VA and alignment in persons with albinism, despite overall subnormal acuity. Some individuals also experienced improvement in binocular alignment and AHP. Compliance with spectacles was generally good. Therefore, refractive correction should be encouraged in persons with albinism as improvement in visual function is likely to occur.

Adolescent↗
PubMed2004

The White platelet syndrome: a new autosomal dominant platelet disorder.

The present study has evaluated 46 members from four generations of a large family with mild to moderate bleeding symptoms, prolonged bleeding times and poor responses to all aggregating agents. Twenty-one members of the family had all of the abnormal structural features of the disorder brought to Minnesota in 1870 by Esther White and, therefore, referred to as the White platelet syndrome (WPS). Their platelet counts were decreased and mean platelet volumes increased. Four to 13% of their platelets contained large, fully developed Golgi complexes actively budding smooth and coated vesicles and frequently associated with centrioles. Such structures are usually present in megakaryocytes only during the major phase of granulopoiesis. As many as seven Golgi complexes and five centrioles were present in single platelets. Alpha granule formation appeared incomplete in patient platelets. The organelles were often immature in appearance and markedly decreased in number in many of their cells. As a result 30% or more of WPS platelets were "gray platelets" similar to, yet very different from the cells in patients with the gray platelet syndrome. Other abnormal features included cytoplasmic sequestration by residual dense tubular system membranes, autodigestion, larger than normal mitochondria and half normal-sized dense bodies. Thirteen of the 46 family members had a "touch" of WPS. Three to 5% of their platelets contained Golgi complexes. However, gray platelets were not present among their circulating cells. The WPS is a unique autosomal dominant condition that can be classified among the platelet granule deficiency disorders.

Blood Coagulation Disorders, Inherited↗
PubMed2004

Functional genomics tools for the analysis of zebrafish pigment.

Genetic model organisms are increasingly valuable in the post-genomics era to provide a basis for comparative analysis of the human genome. For higher order processes of vertebrate pigment cell biology and development, the mouse has historically been the model of choice. A complementary organism, the zebrafish (Danio rerio), shares many of the signaling and biological processes of vertebrates, e.g. neural crest development. The zebrafish has a number of characteristics that make it an especially valuable model for the study of pigment cell biology and disease. Large-scale genetic screens have identified a collection of pigmentation mutants that have already made valuable contributions to pigment research. An increasing repertoire of genomic resources such as an expressed sequence tag-based Gene Index (The Institute for Genomic Research) and improving methods of mutagenesis, transgenesis, and gene targeting make zebrafish a particularly attractive model. Morpholino phosphorodiamidate oligonucleotide (MO) 'knockdown' of pigment gene expression provides a non-conventional antisense tool for the analysis of genes involved in pigment cell biology and disease. In addition, an ongoing, reverse-genetic, MO-based screen for the rapid identification of gene function promises to be a valuable complement to other high-throughput microarray and proteomic approaches for understanding pigment cell biology. Novel reagents for zebrafish transgenesis, such as the Sleeping Beauty transposon system, continue to improve the capacity for genetic analysis in this system and ensure that the zebrafish will be a valuable genetic model for understanding a variety of biological processes and human diseases for years to come.

Animals↗
PubMed2003

A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma.

Atopy is an IgE-mediated condition known to aggregate in families and is a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome-wide scan for atopy, defined by skin sensitivity to one or more common environmental allergens, was conducted in 287 CSGA families (115 African American, 138 Caucasian and 34 Hispanic). Using a nonparametric genetic analysis approach, two regions were observed in the sample of all families that yielded multipoint lod scores >1.5 (chromosome 11q, lod=1.55 between D11S1986 and D11S1998; chromosome 20p between D20S473 and D20S604, lod=1.54). Modeling that included multiple genomic positions simultaneously indicated that four chromosomal regions accounted for the majority of evidence for linkage in the combined families. These four regions are on chromosomes 10p near D10S1412 (lod=0.94), 11q near D11S1986 (lod=1.76), 17q near D17S784 (lod=0.97) and 20p near D20S473 (lod=1.74). In the subset of pedigrees giving positive evidence for linkage on chromosome 11q, the evidence for linkage increased by lod scores greater than one in four other chromosomal regions: 5q (D5S1480, lod=1.65), 8p (D8S1113, lod=1.60), 12p (D12S372, lod=1.54) and 14q (D14S749, lod=1.70). These results suggest that several regions may harbor genes contributing to the risk for atopy and these may interact with one another in a complex manner.

Adolescent↗
PubMed2003

Identification of genes expressed in a human scleral cDNA library.

PURPOSE: Clones established from a human scleral cDNA library were systematically sequenced. Public database sequence comparisons were performed to generate a profile of genes expressed in the human sclera and identify candidate genes for inherited diseases with scleral involvement. METHODS: A directionally cloned pCMV-PCR cDNA library was constructed from RNA isolated from scleras of human donor eyes with known plano refractive history. Plasmid DNA was extracted from randomly selected cDNA clones, and the insert sequences were determined by 5' end single-pass sequencing. Expressed sequence tags (ESTs) were generated and analyzed with the GenBank BLASTN program to identify sequence homologies to known genes. RESULTS: A total of 609 ESTs underwent BLAST analysis. Of these, 341 (56%) matched 228 known human genes and 4 non-human genes, 252 matched uncharacterized ESTs, and 16 showed no significant homology to human or non-human known sequences. The most redundant connective tissue-related genes were alphaA-crystalline, Xalpha-1 collagen, and beta-5 integrin. Other extracellular matrix gene matches were biglycan, syndecan, decorin, fibromodulin, proline arginine-rich end leucine-rich repeat protein, transgelin, TIMP-1, and fibulin 1. Human scleral expression of all but decorin and biglycan has not previously been reported. CONCLUSIONS: This effort provides the first partial list of genes expressed in human sclera. Identification of genes expressed in the sclera contributes to our understanding of scleral biology, and potentially provides positional candidate genes for scleral disorders such as high myopia.

Adult↗
PubMed2003

Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype.

Oculocutaneous albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.

Adolescent↗
PubMed2003

Gene expression profiling of bronchoalveolar lavage cells in acute lung rejection.

Lung transplantation is effective for many diseases that are unresponsive to other therapy. However, long-term survival of recipients is limited by the development of bronchiolitis obliterans syndrome. Acute rejection is a major risk factor for bronchiolitis obliterans syndrome, but noninvasive biomarkers have not been identified. To address this deficiency, gene expression microarrays were performed using bronchoalveolar lavage cells of lung transplant recipients with acute rejection (n = 7) and with no rejection (n = 27). The cell and differential counts were similar. Signal values for genes between groups were compared using t tests. One hundred thirty-five genes were upregulated in the acute-rejection group, including genes involved in acute rejection, immune response genes with an unknown role in rejection, genes not known to have a role in rejection, and genes of unknown function. Two-dimensional hierarchical clustering grouped all acute rejection samples into one cluster and the majority of the no-rejection samples into a second cluster. The acute-rejection samples showed significant changes in gene expression for seven biological pathways. Bronchoalveolar lavage cells are a reliable RNA source for microarray analysis, which is powerful in identifying acute-rejection genes. The individual genes, patterns of gene expression, or biologic pathways identified may represent novel biomarkers for acute rejection.

Acute Disease↗