Donor and recipient CMV serostatus and antigenemia after renal transplantation: an analysis of 486 patients.

BACKGROUND: Cytomegalovirus infection in renal transplant recipients is a major clinical problem, with both short and long term sequelae. Infection can occur as a result of reactivation of latent virus or new infection from donor tissues. The impact of donor and recipient serostatus on viremia is well recognised, with seronegative recipients at greatest risk after transplantation of an organ from a seropositive donor. However, the impact of grafting such organs into seropositive recipients is less clear. OBJECTIVES: To assess the impact of recipient serostatus on the risk of CMV antigenemia in a large renal transplant cohort. STUDY DESIGN: We prospectively quantified CMV antigenemia over time in a cohort of 486 recipients. We analysed the antigenemia status according to donor and recipient serostatus. RESULTS: Antigenemia was most common in seronegative recipients of organs from seropositive donors (D+/R-). Nevertheless, we observed that even in CMV seropositive recipients, the impact of donor serostatus on CMV antigenemia is still substantial (p=0.006; OR=2.2). CONCLUSIONS: In this large study, donor serostatus clearly plays a significant role in determining CMV risk, even in seropositive recipients.

Endothelin axis polymorphisms in patients with scleroderma.

OBJECTIVE: To evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets. METHODS: Two hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence-specific primer-polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, -1370 (T-1370G) of the promoter, +138 of exon 1 (+138 A/-), +85 of exon 3 (E106E), and +23 of exon 5 (K198N); for EDNRA, -231 of exon 1 (G-231A), and +69(H323H) and +105 (E335E) of exon 6; for EDNRB, +2841 of exon 2 (EDNRB-3), -2547 of exon 3 (EDNRB-2), and -2446 of exon 3 (EDNRB-1). RESULTS: No significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB-1A (76.8% versus 54.4%; P = 0.002), EDNRB-2A (79.7% versus 60.2%; P = 0.006), and EDNRB-3G (79.7% versus 56.6%; P = 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti-RNA polymerase (anti-RNAP) antibodies, compared with both anti-RNAP-negative SSc patients (P < 0.05) and control subjects (P < 0.005). CONCLUSION: The finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies.

Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients.

Pain is one of the most common and often most feared symptoms in patients with cancer. Ongoing or progressive pain is physically debilitating and has a marked impact on quality of life. Since a third of the population will die from cancer, and of these, 80% will experience severe pain in their final year of life, effective treatment of cancer-related pain remains both a high priority and an ongoing challenge in clinical practice. Individuals with moderate to severe cancer-related pain require treatment with strong analgesics, namely opioids. There is evidence to support the therapeutic maneuver of opioid switching in clinical practice, but further evidence is needed to elucidate the underlying mechanisms for interindividual differences in response to different opioids. Large, robust clinical trials will be needed if clinical differences among side-effect profiles of different opioids are to be clearly demonstrated. This review discusses candidate genes, which contribute to opioid response; many other genes have also been implicated in "pain" from animal or human studies. In order to continue to evaluate the genetic contributions to both pain susceptibility and analgesic response, further candidate genes need to be considered. Good pain control remains a high priority for clinicians and patients, and there is much work to be done to further individualize analgesic therapy for patients with cancer.

Analysis of KL-6 and SP-D as disease markers in bird fancier's lung.

BACKGROUND AND AIM: KL-6 and SP-D are potential serum markers in interstitial lung diseases. Their discriminative value, and ability to reflect pulmonary disease activity and prognosis in bird fancier's lung were analyzed. METHODS: We studied 49 patients, 38 unexposed and 9 exposed controls. Serum KL-6 and SP-D concentrations were measured at presentation and a second sample, taken after antigen avoidance, was available in 17 patients. Pulmonary function tests were analyzed at presentation and 2-year follow-up. RESULTS: KL-6 and SP-D were significantly elevated in patients compared to controls (p < 0.0001). ROC curve analysis revealed that both are equally useful in discriminating patients from controls. Analysis of their value as activity markers showed that both correlated with pulmonary function impairment; however, KL-6 correlated best with diffusing capacity. Evaluation of their predictive value showed that higher levels at onset were associated with improvement of diffusing capacity during follow-up. Further, it was noted that KL-6 and SP-D levels decreased after more than one month of allergen avoidance. CONCLUSIONS: KL-6 and SP-D appear useful serum markers in bird fancier's lung. Since higher levels are associated with more severe lung function impairment at presentation, and better recovery over time, we postulate that in this disease they are especially markers of disease activity.

The impact of thiopurine S-methyltransferase polymorphisms on azathioprine dose 1 year after renal transplantation.

Azathioprine metabolism is influenced by activity of the enzyme thiopurine S-methyltransferase (TPMT), which varies markedly between individuals. In this study we examined the influence of TPMT gene polymorphisms on azathioprine dose 1 year after renal transplantation. TPMT coding and promoter genotypes were determined using PCR-based assays. Azathioprine dose, white cell count, and intercurrent events throughout the first year after renal transplantation were ascertained from contemporaneous clinical notes. All patients analysed ( n=172) received an initial azathioprine dose of 1.5 mg/kg per day. Twelve individuals with one variant TPMT coding allele were detected (*3A n=11, *3C n=1). Of these, 58% required azathioprine dose reduction because of leucopenia, compared to only 30% of homozygous wild-type patients ( P=0.04). A significant correlation between the presence of >/=11 variable number tandem repeats (VNTRs) in the TPMT promoter and reduction in azathioprine dose was also identified ( P=0.001). We concluded that when azathioprine is administered at an initial dose of 1.5 mg/kg per day, both coding and promoter TPMT polymorphisms influence the dose tolerated.

The Clara cell10 adenine38guanine polymorphism and sarcoidosis susceptibility in Dutch and Japanese subjects.

CC10 (CC16, uteroglobin) is a pulmonary protein postulated to play a counter regulatory role in sarcoidosis pathogenesis. The adenine38guanine (A38G) polymorphism of the encoding CC10 gene (SCGB1A1) is functional. Recently, an association between the low CC10 producing 38A allele and sarcoidosis susceptibility has been reported in Japanese patients from Hokkaido. The aim of the present study was to confirm this association in a clinically well characterized population of Dutch white and Kyoto Japanese patients with sarcoidosis and control subjects. No difference in genotype or allele frequency was found between patients with sarcoidosis and control subjects in either ethnic population. Remarkably, however, a significant difference was found between the control subjects from Kyoto and Hokkaido, but not between the Japanese groups of patients with sarcoidosis. Furthermore, review of previously published A38G genotyping results showed a consistent difference in CC10 A38G allele frequencies between whites and Japanese subjects. We conclude that the CC10 A38G polymorphism does not influence sarcoidosis susceptibility in Dutch whites or in Japanese subjects from Kyoto. This stresses the importance of studying the influence of polymorphisms on disease susceptibility in multiple ethnically and geographically distinct disease and control populations before reaching conclusions.

Oxygen free radical scavenger enzyme polymorphisms in systemic sclerosis.

We performed a case-control study of polymorphisms of glutathione S-transferase (GST) isoenzymes and manganese superoxide dismutase (MnSOD) in black South Africans with systemic sclerosis (SSc). The frequency of the GSTM1*B phenotype was significantly decreased in the overall SSc group compared with controls (OR=0.19, p(corr)<.05), implying a possible protective effect against development of the disease. There was also a trend toward increased MnSODAla allele and phenotype frequencies in the diffuse cutaneous SSc subset compared with controls (OR=2.11 and 3.15, respectively, p(corr)<.1). Our findings provide new data on the distribution of GST and MnSOD polymorphisms in healthy Africans and further evidence that genetic factors may have a contributory role to play in predisposing to oxidative stress in SSc.

The impact of endothelial nitric oxide synthase polymorphisms on long-term renal allograft outcome.

A major manifestation of chronic allograft failure (CAF) is the accelerated onset of atherosclerotic lesions within the graft. Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been implicated in the pathogenesis of native atherosclerosis. This study tested the hypothesis that polymorphisms in eNOS are associated with susceptibility to CAF after cadaveric renal transplantation. The patient cohort comprised 140 renal transplant recipients who had received their transplants between 1985 and 1997 at the Oxford Transplant Centre and included 61 patients with biopsy-proven CAF and 79 with stable graft function for at least 10 years (long-term survivors, LTS). Genotyping for one polymorphism in the promoter region and two polymorphisms in the coding regions of the eNOS gene was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP). No association was found between any genetic variant and the development of CAF, even after stratification for other known risk factors. Statistical analysis revealed that all three polymorphisms were closely linked. We conclude that recipient eNOS gene polymorphisms do not alter the risk of CAF after renal transplantation.

Mapping the HLA association in Behçet's disease: a role for tumor necrosis factor polymorphisms?

OBJECTIVE: Experimental evidence suggests that inappropriate regulation of tumor necrosis factor alpha (TNF alpha) may play a role in the pathogenesis of Behçet's disease (BD). This is supported by recent reports highlighting the efficacy of anti-TNF alpha agents in the treatment of this disease. The TNF gene is encoded in the class III region of the HLA complex adjacent to HLA-B. This genetic proximity to a gene that is already widely implicated in disease susceptibility led us to investigate the association between TNF promoter polymorphisms and susceptibility to BD. METHODS: We studied 133 UK white Caucasoid patients with BD and 354 healthy controls. We attempted to dissect the contribution of individual polymorphisms in this gene-dense region by linkage disequilibrium mapping across 6 adjacent genes. RESULTS: We report a novel association with the TNF promoter allele TNF-1031C. Subsequent analysis identified 2 extended HLA haplotypes associated with BD. One of them contained the previously recognized susceptibility gene HLA-B*51, while the other was defined by HLA-B*5701. Both of these haplotypes contained the TNF promoter polymorphism -1031C, an allele that was associated with disease even in individuals who did not carry either HLA-B*51 or HLA-B*5701. CONCLUSION: The TNF-1031C allele is independently associated with susceptibility to BD in Caucasoid patients. Further studies will be required to determine the functional effects of this polymorphism, its influence in disease pathogenesis, and its role in other ethnic groups.

Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC.

Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite for population-based disease gene mapping. Variable patterns across the human genome are now recognized, both between regions and populations. Here, we demonstrate that LD may also vary within a genomic region in a haplotype-specific manner. In 864 Caucasian unrelated individuals, we describe haplotype-specific LD patterns across the human MHC by the construction of gene-specific allelic haplotypes at 25 loci between HLA-A and Tapasin. Strong and extensive LD is found across both common and rare haplotypes, suggesting that haplotype structure is influenced by factors other than genetic drift, including both selection and differential haplotype recombination. Knowledge of haplotype-specific LD in the HLA may explain the apparent discrepant data from previous studies of global LD, help delineate key areas in mapping HLA-associated diseases and, together with recombination data, provide valuable information about a population's demographic history and the selective pressures operating on it.

Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28.

The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules.

The molecular classification of the clinical manifestations of Crohn's disease.

BACKGROUND & AIMS: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. METHODS: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. RESULTS: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. CONCLUSIONS: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.