Megan S. Reinalda

A genomewide association study of citalopram response in major depressive disorder.

BACKGROUND Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to determine whether common DNA variation influences antidepressant response. METHODS Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification. RESULTS We identified three SNPs associated with response with p values less than 1 x 10(-5) near the UBE3C gene (rs6966038, p = 4.65 x 10(-7)), another 100 kb away from BMP7 (rs6127921, p = 3.45 x 10(-6)), and a third that is intronic in the RORA gene (rs809736, p = 8.19 x 10(-6)). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values < or = .0001 for the response and remission phenotypes. CONCLUSIONS Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.

Incidence and Risk Factors of Prosthetic Joint Infection After Total Hip or Knee Replacement in Patients With Rheumatoid Arthritis

OBJECTIVE Prosthetic joint infection is one of the most dreaded complications after total joint arthroplasty, a common procedure in patients with rheumatoid arthritis (RA). We conducted a study to evaluate potential risk factors of prosthetic joint infection and to clarify if RA is an independent predictor of this complication. METHODS This study included all patients with RA who underwent total hip or knee replacement at the Mayo Clinic Rochester between January 1996 and June 2004. The association of potential risk factors with prosthetic joint infection was examined using Cox models. A matched cohort of patients with osteoarthritis (OA) was assembled to determine whether RA is an independent risk factor for prosthetic joint infection. RESULTS We identified 462 patients with RA who underwent a total of 657 hip or knee replacements. Overall, 23 (3.7%) joint arthroplasties were complicated by an infection during a mean +/- SD followup of 4.3 +/- 2.4 years. Revision arthroplasty (hazard ratio [HR] 2.99, 95% confidence interval [95% CI] 1.02-8.75) and a previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI 1.87-16.14) were significant predictors of postoperative prosthetic joint infection. Comparison of RA patients with a matched cohort of OA patients identified an increased risk of prosthetic joint infections (HR 4.08, 95% CI 1.35-12.33) in patients with RA. CONCLUSION Patients with RA who undergo total hip or knee replacement are at increased risk of prosthetic joint infection, which is further increased in the setting of revision arthroplasty and a previous prosthetic joint infection. These findings highlight the importance of perioperative prophylactic measures and vigilance during the postoperative period.

Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample.

BACKGROUND SLC6A4 encodes the serotonin transporter, the protein primarily responsible for the termination of serotonin neurotransmission. Because many antidepressants inhibit the transporter, it has been the focus of intense pharmacogenetic analysis. We sought to replicate our previous findings that SLC6A4 is associated with response to a selective serotonin reuptake inhibitor (SSRI) in a large case-control study. METHODS Genotypes at the SLC6A4 locus were obtained for 1,914 subjects in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and then tested for association to treatment response of the SSRI citalopram. RESULTS Nine tagging single nucleotide polymorphisms and two variants previously associated with antidepressant response, including a promoter repeat polymorphism, were genotyped. Single marker and haplotypic analyses failed to detect association with antidepressant response in the largest clinical sample studied to date. CONCLUSIONS The lack of association between response to an SSRI and variation at the SLC6A4 locus in this large sample, carefully characterized for response to citalopram, strongly suggests that SSRI response in major depression is not determined by DNA variation at this locus. These findings do not replicate findings of a number of studies with considerably smaller sample sizes. Other genetic determinants of SSRI response in depression should be sought.

Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample.

Background We sought to determine whether clinical response or tolerance to the Selective Serotonin Reuptake Inhibitor (SSRI) citalopram is associated with genetic polymorphisms in potentially relevant pharmacokinetic enzymes. Methodology We used a two-stage case-control study design in which we split the sample of 1,953 subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial into a discovery (n = 831) and validation set (n = 1,046). Fifteen polymorphisms from five (CYP2D6, ABCB1, CYP2C19, CYP3A4, and CYP3A5) pharmacokinetic genes were genotyped. We examined the associations between these polymorphisms and citalopram response and tolerance. Significant associations were validated in the second stage for those polymorphism found to be statistically significant in the first stage. Conclusions No genetic polymorphism in the pharmacokinetic genes examined was significantly associated with our response or tolerance phenotypes in both stages. For managing pharmacological treatment with citalopram, routine screening of the common pharmacokinetic DNA variants that we examined appears to be of limited clinical utility.

The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma

The development of cytopenia in chronic lymphocytic leukaemia (CLL) patients can predict poor prognosis. All CLL patients seen in the Division of Hematology at Mayo Clinic Rochester from 1 January 1995 to 31 December 2004 (n = 1750) were evaluated for cytopenia, aetiology of cytopenia and clinical outcome. Cytopenia occurred in 423 (24·2%) patients and was attributable to CLL in 303 (17·3%) cases, with 228 (75%) of these having bone marrow (BM) failure and 75 (25%) having autoimmune disease (AID). Survival from onset of cytopenia was significantly better for patients with AID (median 9·1 years) compared to patients with BM failure (median 4·4 years, P < 0·001). Patients with AID diagnosed within 1 year of the diagnosis of CLL (n = 35) had similar survival from diagnosis compared to patients without CLL‐related cytopenia (median 9·3 vs. 9·7 years, P = 0·881). Although cytopenia caused by BM failure predicted a poorer prognosis in CLL, cytopenia caused by AID was not an adverse prognostic factor. These findings suggest that patients with cytopenia due to AID cannot be meaningfully classified by the current clinical staging systems. Revisions of the National Cancer Institute Working Group 96 criteria should consider the aetiology of cytopenia in staging CLL patients.

Age at Diagnosis and the Utility of Prognostic Testing in Patients With Chronic Lymphocytic Leukemia

A study was undertaken to analyze the survival of chronic lymphocytic leukemia (CLL) patients relative to age‐matched individuals in the general population and determine the age‐stratified utility of prognostic testing.

Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients

Although a diagnosis of chronic lymphocytic leukemia (CLL) can have a profound effect on the quality of life (QOL), few studies have objectively measured the QOL of CLL patients or compared it to the general population. We conducted an international, web‐based survey of patients with CLL using standardized instruments with published population norms to evaluate fatigue and QOL. Co‐morbid health conditions were assessed using the Charlson Co‐Morbidity Index. Between June and October 2006, 1482 patients with CLL responded to the survey. The physical, social/family, functional, and overall QOL scores of CLL patients were similar to or better than published population norms. In contrast, the emotional well‐being scores of CLL patients were dramatically lower than that of both the general population (P < 0·001) and patients with other types of cancer (P < 0·001). QOL scores were lower among individuals with advanced stage disease (all P < 0·05). Factors associated with lower overall QOL on multivariate analysis included older age, greater fatigue, severity of co‐morbid health conditions, and current treatment. CLL has a profound impact on QOL at all disease stages. The effects of CLL on QOL appear to differ from that of other malignancies with a more marked impact on emotional QOL. Research identifying efficacious psycho‐oncologic support interventions for patients with CLL is needed.

Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response

Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.

Determinants of Direct Medical Costs in Primary and Revision Total Knee Arthroplasty

BackgroundTKA procedures are increasing rapidly, with substantial cost implications. Determining cost drivers in TKA is essential for care improvement and informing future payment models.Questions/PurposesWe determined the components of hospitalization and 90-day costs in primary and revision TKA and the role of demographics, operative indications, comorbidities, and complications as potential determinants of costs.MethodsWe studied 6475 primary and 1654 revision TKA procedures performed between January 1, 2000, and September 31, 2008, at a single center. Direct medical costs were measured by using standardized, inflation-adjusted costs for services and procedures billed during the 90-day period. We used linear regression models to determine the cost impact associated with individual patient characteristics.ResultsThe largest proportion of costs in both primary and revision TKA, respectively, were for room and board (28% and 23%), operating room (22% and 17%), and prostheses (13% and 24%). Prosthesis costs were almost threefold higher in revision TKA than in primary TKA. Revision TKA procedures for infections and bone and/or prosthesis fractures were approximately 25% more costly than revisions for instability and loosening. Several common comorbidities were associated with higher costs. Patients with vascular and infectious complications had longer hospital stays and at least 80% higher 90-day costs as compared to patients without complications.ConclusionsHigh prosthesis costs in revision TKA represent a factor potentially amenable to cost containment efforts. Increased costs associated with demographic factors and comorbidities may put providers at financial risk and may jeopardize healthcare access for those patients in greatest need.Level of EvidenceLevel IV, economic and decision analyses. See Instructions for Authors for a complete description of levels of evidence

Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia

Previous studies suggested that patients with chronic lymphocytic leukaemia (CLL) are at a three‐ to fivefold increased risk of developing a second lymphoproliferative disorder (LPD). This observational cohort study used the Mayo Clinic CLL Database to identify factors associated with developing a second LPD. A second LPD was identified in 26 (2·7%) of 962 CLL patients during a median follow‐up of 3·3 years. Diffuse large B‐cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Patients previously treated for CLL had a trend toward higher prevalence of second LPD (4%) compared with previously untreated patients (2%; P = 0·053). More strikingly, patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008). No statistically significant association was observed between risk of second LPD and other CLL characteristics (ZAP‐70, CD38, IgVH mutation status or cytogenetic abnormalities). In this series, prior treatments with PNA or anthracyclines were the only significant factors associated with risk of developing a second LPD in patients with CLL. Physicians should strictly adhere to established criteria to initiate treatment for CLL patients who are not participating in clinical trials.