Citations

AbstractGenome-wide association and candidate gene studies implicate different genetic variants within the 6p21 chromosomal region with different non-Hodgkin lymphoma (NHL) subtypes. Complementing these efforts, we conducted human leukocyte antigen (HLA) class I and class II genotyping among 610 NHL cases and 555 controls of non-Hispanic white descent from a US multicenter study. Allele-disease associations were assessed by logistic regression for NHL and its subtypes. Statistically significant associations between HLA and NHL subtypes include HLA-DRB1*0101 for follicular lymphoma (odds ratio [OR] = 2.14, P < .001), HLA-DRB1*0401 for diffuse large B-cell lymphoma (DLBCL; OR = 0.45, P = .006), and HLA-DRB1*13 and follicular lymphoma (OR = 0.48, P = .008). We further observed significant heterozygote advantage for HLA class I alleles and NHL, and particularly DLBCL (P trend = .01 for elevated risk with increasing number of homozygous alleles). Our results support a role for HLA in the etiology of NHL and its subtypes.

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler’s virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.D1-H2 q /SgJ (B10.Q) mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encoded within the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development and we show a sevenfold increase in EGF expression in FVB compared to B10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the T H 1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair.

Background Golf provides an opportunity for relatively low-impact exercise for nearly all age groups and is considered a recommended activity for patients after total knee arthroplasty. Hypothesis We hypothesized that total knee arthroplasty would afford patients increased ability to participate in and enjoy golf, allowing a large percentage of these patients to walk the golf course. Study Design Case series; Level of evidence, 4. Methods Surveys were sent to 151 golfers who had undergone primary total knee arthroplasty from 1995 to 2000. The detailed survey included 33 questions specific to the patients’ golf performance, enjoyment of golf, frequency of participation, timing of return to play, presence of pain, use of a cart, and related golf-specific issues. Results We received and evaluated 93 responses (62%). Fifty-seven percent reported they had returned to golf within 6 months after total knee arthroplasty. Eighty-one percent of respondents reported golfing as frequently, or more frequently, than before knee replacement. Notably, golfers reported less pain while golfing after total knee arthroplasty than before (13% vs 83%; P < .0001), and 94% of respondents reported currently enjoying golf as much as or more than before surgery. Twenty-eight percent of respondents stated that they walked the course, rather than using a motorized golf cart, before surgery, while only 14% walked the course after surgery ( P = .02). Conclusion In this population of golfers, total knee arthroplasty reliably relieved pain that had been previously experienced while golfing, and increased or maintained this group’s enjoyment of playing golf. However, 86% of these patients reported using a cart while golfing. Further patient education is needed regarding the potential health benefits of walking during golf after total knee arthroplasty.

In this study, 65% (132/195) of level B/C obstetric recommendations are amenable to randomized clinical trials (RCTs) and seven were identified as most needed. The purpose of the survey was to evaluate levels B and C recommendations in obstetric practice bulletins (PBs) regarding the feasibility of performing RCT to elevate each subject to level A evidence. Eleven geographically dispersed physicians with experience in research reviewed levels B and C recommendations for the ethical and logistical feasibility of performing an RCT. In the 35 obstetric PBs, 195 level B/C recommendations were reviewed. The majority considered 47 (24%) topics unethical for an RCT and thought 16 (11%) did not need an RCT, thus leaving 132 (67%) levels B and C recommendations available for an RCT. Two-thirds of levels B and C recommendations in obstetric PB are amenable to RCTs and potentially becoming level A evidence.

BackgroundStrokes, vascular risk factors, and apolipoprotein E (APOE) genotype are associated with cognitive decline in the elderly, but definitive evidence that these affect cognition as early as middle age is limited.ObjectiveWe describe the relationships of APOE genotype, stroke, and vascular risk factors with cognitive change over a 14‐year follow‐up in the Atherosclerosis Risk in Communities (ARIC) Study cohort recruited while in middle age.MethodsParticipants included a subset of the ARIC Study who underwent assessments of cognitive function and vascular risk factors. Four cognitive assessments were performed between 1990–1992 and 2004–2006. Cognitive assessments included the Delayed Word Recall (DWR) Test, the Digit Symbol Substitution (DSS) Test, and the Word Fluency (WF) Test. Vascular risk factors were assessed during the baseline visit in 1990–1992. Incident stroke was recorded over the 14 years of follow‐up.ResultsThere were 1130 participants (mean age, 59 ± 4.3 [SD] years; 62% women; 52% African‐American) with longitudinal data. In multivariate, random‐effects linear models adjusted for age, education, gender, and race, the risk factors diabetes and APOE ɛ4 genotype were independently associated with a decline in performance on the DSS test (both P < .005), whereas hypertension and stroke were not. For DWR, stroke and APOE ɛ4 genotype were independent predictors of decline (both P < .001). For the WF test, metabolic syndrome, hypertension, and stroke were independently associated with decline (all P < .005). No evidence of differential effects of risk factors on cognitive decline by race, gender, or interactions between risk factors was found.ConclusionsThe vascular risk factors diabetes and hypertension, a history of stroke itself, and APOE ɛ4 genotype independently contribute to cognitive decline in late middle age and early elderly years.

Abstract Among all of the genetic factors associated with multiple sclerosis (MS) susceptibility, MHC class II molecules have the strongest association. Although a direct role of DR alleles in MS have been confirmed, it has been difficult to understand the role of DQ alleles in disease pathogenesis due to strong linkage disequilibrium with certain DR alleles. Population studies have indicated that DQ alleles may play a modulatory role in progression of MS. Using HLA class II transgenic (Tg) mice, we investigated gene complementation between DR and DQ genes in the disease process. Previously, using single Tg mice (expressing HLA-DR or DQ gene), we showed that PLP91–110 peptide induced experimental autoimmune encephalomyelitis (EAE) only in DR3.Aβ° mice, suggesting that DR3 (DRB1*0301) is a disease susceptibility gene in the context of PLP. We also showed that DQ6 protects development of EAE in DQ6/DR3 double Tg mice by production of anti-inflammatory IFN-γ. In this study, we investigated the ability of DQ8 to modulate disease in DR3/DQ8 double Tg mice. Introduction of DQ8 onto DR3 Tg mice led to higher disease incidence and increased disease severity on immunization with PLP91–110, indicating that DQ8 had an exacerbating effect on the development of EAE. Increased susceptibility in DR3/DQ8 Tg mice was due to increased production of proinflammatory cytokine IL-17 by DQ8-restricted T cells. HLA-DR3/DQ8 mice with EAE also demonstrated increased inflammation and demyelination in CNS as compared with single DR3 Tg mice. Thus double Tg mouse provides a novel model to study epistatic interactions between HLA class II molecules in inflammatory and demyelinating disease.

AbstractA venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)–based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in “functional regions” within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.