Heit, John A.

AbstractSynthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

Objectives To provide nursing home ( NH )‐specific estimates to assess whether venous thromboembolism ( VTE ) risk factors identified for the general population apply to NH residents. Design Population‐based case–control study. Setting O lmsted C ounty, M innesota. Participants All county residents with symptomatic objectively diagnosed incident VTE while resident in a NH from 1988 through 2000 (N = 182) and two age‐, sex‐, calendar‐year‐matched non‐ VTE O lmsted C ounty NH residents per case (N = 364). Measurements Provider‐linked medical records were reviewed to obtain information on active malignancy and recent hospitalization, surgery, trauma, or fracture as of index date (case's VTE date; respective provider registration date for controls). Risk factor prevalence and VTE ‐associated odds ratios ( OR ) were estimated and compared with previously obtained data for all O lmsted C ounty residents from 1988 through 2000. For analyses, both groups were limited to individuals aged 65 and older. Results In NH residents, active malignancy, recent hospitalization, and recent surgery significantly increased VTE risk, but the magnitude of risk appeared much lower than general population estimates (e.g., for major surgery, OR = 2.5, 95% confidence interval ( CI ) = 1.4–4.3 for NH residents vs OR = 11, 95% CI = 7.0–17 for general population). In general, the prevalence of all evaluated VTE risk factors appeared much higher in NH controls than in general population controls. Thromboprophylaxis rates appeared higher for NH cases and controls than in the general population; disconcertingly, 47% of NH cases received prophylaxis. Conclusion Although general population VTE risk factors (active cancer and recent hospitalization or surgery) can identify NH residents at higher risk for VTE , these exposures do not adequately stratify VTE risk for thromboprophylaxis recommendations. Further research into NH ‐specific risk factors and prophylaxis effectiveness is required.

AbstractTo further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol‐dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

AbstractThe endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37 415 cases and 84 406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.

Abstract To test recommended anticoagulation measures as predictors of 180-day venous thromboembolism (VTE) recurrence, we identified all Olmsted County, MN residents with incident VTE over the 14-year period of 1984-1997, and followed each case (N = 1166) forward in time for VTE recurrence. We tested the activated partial thromboplastin time (APTT), international normalized ratio (INR), and other measures of heparin and warfarin anticoagulation as predictors of VTE recurrence while controlling for baseline and time-dependent characteristics using Cox proportional hazards modeling. Overall, 1026 (88%) and 989 (85%) patients received heparin and warfarin, respectively, and 85 (8%) developed VTE recurrence. In multivariable analyses, increasing proportions of time on heparin with an APTT ≥ 0.2 anti-Xa U/mL and on warfarin with an INR ≥ 2.0 were associated with significant reductions in VTE recurrence, while the hazard with active cancer was significantly increased. Time from VTE onset to heparin start, duration of overlapping heparin and warfarin, and inferior vena cava (IVC) filter placement were not independent predictors of recurrence. At a heparin dose ≥ 30 000 U/d, the median proportion of time with an APTT ≥ 0.2 anti-Xa U/mL was 92%, suggesting that routine APTT monitoring and heparin dose adjustment may be unnecessary. In summary, lower-intensity heparin and standard-intensity warfarin anticoagulation are effective in preventing VTE recurrence.

The role of venous stasis syndrome (VSS) mechanisms (i.e. venous outflow obstruction [VOO] and venous valvular incompetence [VVI]) on quality of life (QoL) and activities of daily living (ADL) is unknown. The objective of this study was to test the hypotheses that venous thromboembolism (VTE),VSS,VOO and VVI are associated with reduced QoL and ADL. This study is a follow-up of an incident VTE case-control study nested within a population-based inception cohort of residents from Olmsted County, MN, USA, between 1966 and 1990. The study comprised 232 Olmsted County residents with a first lifetime VTE and 133 residents without VTE. Methods included a questionnaire and physical examination for VSS; vascular laboratory testing for VOO and VVI; assessment of QoL by SF36 and of ADL by pertinent sections from the Older Americans Resources and Services (OARS) and Arthritis Impact Measurement Scales (AIMS2) questionnaires. Of the 365 study participants, 232 (64%), 161 (44%), 43 (12%) and 136 (37%) had VTE, VSS, VOO and VVI, respectively. Prior VTE was associated with reduced ADL and increased pain, VSS with reduced physical QoL and increased pain, and VOO with reduced physical QoL and ADL.VVI was not associated with QoL or ADL. In conclusion,VSS and VOO are associated with worse physical QoL and increased pain. VOO and VTE are associated with impaired ADL. We hypothesize that rapid clearance of venous outflow obstruction in individuals with acute VTE will improve their QoL and ADL.

Objective— Patients with venous thromboembolism (VTE) often require temporary warfarin interruption for an invasive procedure. The incidence of thromboembolism and bleeding related to periprocedural anticoagulation management of such patients is unknown. Methods and Results— In a protocol-driven, inception cohort design study, all VTE patients (n=775) referred for periprocedural anticoagulation management (1997–2007) were followed-up to estimate the 3-month cumulative incidence of thromboembolism and bleeding. Patients were stratified by thrombus acuity (acute, <30 days; subacute, 31–90 days; or chronic ≥91 days). Decisions to provide “bridging” low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Low-molecular-weight heparin was more often administered in acute (87%) and subacute (81%) VTE compared to chronic VTE (59%; P <0.001). The 3-month cumulative incidence of thromboembolism (1.8%), major hemorrhage (1.8%), and mortality (1.7%) were low and did not differ by management strategy. Active cancer was the only independent predictor of thrombotic recurrence (HR, 4.86; 95% CI, 1.6–14.5; P =0.005), major hemorrhage (HR, 6.8; 95% CI, 2.1–21.7; P =0.001), and death (HR, 32.7; 95% CI, 4.3–251.2; P =0.0008). Conclusion— Thromboembolism, bleeding, and death among VTE patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Cancer patients require particular care given their propensity for both clotting and bleeding.

Abstract Venous stasis syndrome may complicate deep vein thrombosis (DVT; i.e. post-phlebitic syndrome), but, in most cases, venous stasis syndrome is not post-phlebitic. The objective of this study was to determine the risk factors (including prior DVT) for venous stasis syndrome, and to assess venous outflow obstruction and venous valvular incompetence as possible mechanisms for venous stasis syndrome. This was a case–control study nested within a population-based inception cohort. The study population consisted of 232 Olmsted County, MN residents with a first lifetime venous thromboembolism (VTE) and 133 residents without VTE. Measurements included a questionnaire and physical examination for venous stasis syndrome; strain gauge outflow plethysmography, venous continuous wave Doppler ultrasonography and passive venous drainage and refill testing for venous outflow obstruction and venous valvular incompetence. Altogether, 161 (44%), 43 (12%), and 136 (38%) subjects respectively, had venous stasis syndrome, venous outflow obstruction and venous valvular incompetence. Independent risk factors for venous stasis syndrome included increasing patient age and body mass index (BMI), prior DVT, longer time interval since DVT, and varicose veins. Both venous outflow obstruction ( p = 0.003) and venous valvular incompetence ( p < 0.0001) were strongly associated with venous stasis syndrome. Increasing age and prior DVT were significantly associated with venous outflow obstruction, while prior DVT, varicose veins and venous stasis syndrome diagnosed prior to the incident DVT were significantly associated with venous valvular incompetence. The risks of venous outflow obstruction, venous valvular incompetence and venous stasis syndrome were higher with left leg DVT. In conclusion, increasing patient age and BMI, prior DVT (particularly left leg DVT), longer time interval since DVT and varicose veins are independent risk factors for venous stasis syndrome. Venous stasis syndrome related to DVT is due to venous outflow obstruction and venous valvular incompetence, while venous stasis syndrome related to older age and to varicose veins is due to venous outflow obstruction and to venous valvular incompetence, respectively.

Objective— Although diabetes mellitus is reported as a risk factor for venous thromboembolism (VTE), persons with diabetes are frequently hospitalized for medical illness or surgery, or confined to a nursing home, all major VTE risk factors. Consequently, we tested diabetes for an independent association with incident VTE. Methods and Results— Using Rochester Epidemiology Project resources, we identified all Olmsted County, Minn residents who met objective criteria for incident VTE over the 25-year period, 1976 to 2000 (n=1922), and 1 to 2 resident controls per case, matched on age, gender, and length of medical history (n=2115). Complete medical histories in the community were reviewed for previously identified independent VTE risk factors and diabetes-related variables. We tested diabetes and diabetes complications (retinopathy, nephropathy or neuropathy, and ketoacidosis) as potential VTE risk factors, both alone and after adjusting for VTE risk factors. Univariately, diabetes by clinical diagnosis or by stricter criteria (fasting ambulatory blood glucose ≥140 mg/dL or antidiabetic drug therapy), and diabetes complications, were associated with overall incident VTE. However, after controlling for hospitalization for major surgery or medical illness and nursing home confinement, diabetes was no longer associated with VTE. Conclusion— Diabetes mellitus and diabetes complications are not independent risk factors for incident VTE.