Joshua P. Slusser

A Major Lung Cancer Susceptibility Locus Maps to Chromosome 6q23–25

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Two Common Chromosome 8q24 Variants Are Associated with Increased Risk for Prostate Cancer

Two variants (rs1447295/DG8S737) of chromosome 8q24 were recently reported to be associated with increased risk of prostate cancer (PC). To confirm this finding, we genotyped and compared the frequencies of these polymorphisms among 1,121 Caucasian men with PC (435 men with familial PC, 491 men with sporadic PC, and 195 men with aggressive PC) to 545 population-based controls. For the single nucleotide polymorphism marker rs1447295, frequencies of the minor allele (A) were 10.3% in controls, 11.9% in sporadic cases, 16.7% in familial cases, and 17.2% in aggressive cases. Compared with controls, the A allele was significantly more common in both familial PC [odds ratios (OR), 1.93; 95% confidence intervals (95% CI), 1.37-2.72; P = 0.0004] and aggressive PC (OR, 1.87; 95% CI, 1.28-2.74; P = 0.0005) but not for sporadic PC (OR, 1.16; 95% CI, 0.85-1.58; P = 0.25). Although the A allele was more frequent in aggressive PC cases when compared with controls, the allele frequencies were similar among cases with high- and low-grade PC (Gleason grades <7 and >/=7, respectively). For the microsatellite marker DG8S737, the -8 allele was significantly more frequent in familial PC (OR, 1.68; 95% CI, 1.09-2.60; P = 0.031), whereas the -10 allele was more frequent in aggressive PC (OR, 2.85; 95% CI, 1.52-5.36; P = 0.0004). Haplotype analysis showed significant differences in haplotype frequencies between the familial PC (P = 0.006) and aggressive PC (P = 0.005) cases versus controls. The -8/A haplotype showed the strongest association with familial PC (P = 0.008), whereas the -10/A haplotype was most strongly associated with aggressive PC (P = 0.00005). These results further confirm the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PC. However, the mechanism explaining this increased risk has not yet been established.

Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis†

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disorder that can progress to cirrhosis, shortening life expectancy. PBC patients are often asymptomatic, present with biochemical cholestasis, and test positive (≥90%) for antimitochondrial antibodies (AMAs) in serum. Although AMA positivity without biochemical cholestasis may indicate increased risk of future PBC development, the contribution of these antibodies to pathogenesis remains enigmatic. Environmental risks and genetic determinants are likely implicated in PBC etiology. Given the familial aggregation of PBC, we hypothesized that AMAs also aggregate among relatives of PBC probands. We investigated the prevalence of AMAs in first‐degree relatives (FDRs) of PBC probands to examine whether AMAs aggregate in such pedigrees. Using a PBC family registry, we prospectively screened for AMAs in the serum of 306 FDRs in 145 pedigrees, 350 PBC probands, and 196 controls who were age‐matched, sex‐matched, race‐matched, and residence‐matched to probands. The prevalence of AMA in FDRs and controls was 13.1% and 1%, respectively. Greater prevalence of AMA was found in female FDRs of PBC probands [sisters (20.7%), mothers (15.1%), and daughters (9.8%)] than in male FDRs [brothers (7.8%), fathers (3.7%), and sons (0%)]. Conclusions: AMAs aggregate among FDRs of PBC probands. Our data have clinical implications for FDRs of PBC probands because AMA positivity may suggest susceptibility to PBC. Thus, the identification and follow‐up of these relatives may lead to earlier disease diagnosis and treatment. Furthermore, if AMA development is heritable, this trait will provide a basis to dissect the genetic predisposition to PBC. (HEPATOLOGY 2007.)

Familial segregation of venous thromboembolism

Background: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. Objective: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. Patients and methods: In a family‐based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age‐specific, non‐gender‐ and gender‐specific liability classes under Mendelian and non‐Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non‐Mendelian. Results: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first‐degree relatives. The sporadic model was rejected in both non‐gender‐ and gender‐specific liability class analyses. Among the remaining gender‐specific models, the unrestricted (non‐Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. Conclusion: A multifactorial non‐Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

Predictors of major bleeding in peri-procedural anticoagulation management

Summary.  Background: Appropriate periprocedural management for chronically anticoagulated patients requires assessment of patient‐specific thrombosis and bleeding risks. However, predictors of post‐procedure bleeding are unknown. Objectives: To determine the 3‐month cumulative incidence and independent predictors of peri‐procedural bleeding in chronically anticoagulated patients requiring temporary warfarin interruption for an invasive procedure. Methods: In a protocol driven, cohort study design, all patients referred to the Mayo Clinic Thrombophilia Center for peri‐procedural anticoagulation management (1997–2007; n = 2182), were followed forward in time to determine the 3‐month cumulative incidence of peri‐procedural bleeding (Kaplan–Meier product limit) and potential predictors of bleeding (Cox proportional hazards). Decisions to ‘bridge’ with low‐molecular‐weight heparin were based on estimated thromboembolism and bleeding risk. Results: Indications for chronic anticoagulation included venous thromboembolism (38%), atrial fibrillation (30%) and mechanical heart valves (27%). Of these, 1496 (69%) patients received bridging therapy. The 3‐month cumulative incidence rates of major and overall bleeding were 2.1% and 5.1%, respectively. Major bleeding occurred more frequently in patients receiving bridging therapy (3% vs. 1%; P = 0.017). Independent predictors (hazard ratio; 95% confidence interval) of major bleeding included mitral mechanical heart valve (2.2; 1.1–4.3), active cancer (1.8; 1.0–3.1), prior bleeding history (2.6; 1.5–4.5) and re‐initiation of heparin therapy within 24 h after the procedure (1.9; 1.1–3.4). Conclusion: Factors predisposing to peri‐procedural bleeding are primarily patient‐specific. Premature heparin re‐initiation is an avoidable provider‐specific variable to consider.

Factors Associated With 30-Day Readmission Rates After Percutaneous Coronary Intervention

BACKGROUND Thirty-day readmission rates have become a publicly reported quality performance measure for congestive heart failure, acute myocardial infarction, and percutaneous coronary intervention (PCI). However, little is known regarding the factors associated with 30-day readmission after PCI. METHODS To assess the demographic, clinical, and procedural factors associated with 30-day readmission rates after PCI, we identified 15, 498 PCI hospitalizations (elective or for acute coronary syndromes) from January 1998 through June 2008 at Saint Marys Hospital, Rochester, Minnesota. All were included in this analysis. Multivariate logistic regression models were used to estimate the adjusted association between demographic, clinical, and procedural variables and 30-day readmission. The association between 30-day readmission and 1-year mortality was estimated using Cox proportional hazards models with readmission as a time-dependent covariate and by using landmark analysis. The main outcome measures were all-cause 30-day readmission to any hospital following PCI and 1-year mortality. RESULTS Overall, 9.4% of PCIs (n = 1459) were readmitted, and 0.68% of PCIs (n = 106) resulted in death within 30 days after discharge. After multivariate analysis, female sex, Medicare insurance, having less than a high school education, unstable angina, cerebrovascular accident or transient ischemic attack, moderate to severe renal disease, chronic obstructive pulmonary disease, peptic ulcer disease, metastatic cancer, and a length of stay of more than 3 days were associated with an increased risk of 30-day readmission after PCI. Thirty-day readmission after PCI was associated with a higher risk of 1-year mortality (adjusted hazard ratio, 1.38; 95% CI, 1.08-1.75; P = .009). CONCLUSIONS Nearly 1 in 10 patients undergoing PCI were readmitted within 30 days. Thirty-day readmission after PCI was associated with a higher risk of 1-year mortality.

Progression of preclinical diastolic dysfunction to the development of symptoms

Background Preclinical diastolic dysfunction (PDD) has been defined as subjects with normal systolic function, diastolic dysfunction but no symptoms of heart failure (HF). The clinical phenotype and natural history of the syndrome remains poorly defined. This studys objective was to determine the clinical phenotype and progression to HF in a group of patients with normal systolic function and moderate or severe diastolic dysfunction as determinate by Doppler criteria without any clinical diagnosis of HF according to the Framingham criteria or any symptoms of HF, specifically dyspnoea, oedema or fatigue at the time of echocardiography. Methods The authors used resources of the Mayo Clinic echocardiography database to consecutively select among patients who had an echocardiogram in 2005, a cohort with moderate or severe diastolic dysfunction by Doppler criteria and EF ≥50%. Patients could not have a diagnosis of HF, or any HF symptoms—specifically dyspnoea, oedema or fatigue—at the time of echocardiography; nor grade 3 or greater valvular dysfunction (except tricuspid valve). A total of 82 patients had their medical chart reviewed. Primary endpoint was the time to the development of (1) HF according to the Framingham criteria or (2) any symptoms of dyspnoea, oedema or fatigue. Results The mean age of the cohort of PDD subjects was 69±10 years with a female (67%) preponderance. Presence of hypertension was 76%, coronary artery disease was 29%, paroxysmal atrial fibrillation was 26%, estimated creatinine clearance <60 ml/min was 51%. The 2-year cumulative probability of development of HF according to the Framingham criteria was 1.9%; however, the 2-year cumulative probability of development of any symptoms was 31.1%. The 2-year cumulative probability for cardiac hospitalisation was 21.2%. Peripheral vascular disease and hypertension were independently associated with increased likelihood for the development of symptoms. Conclusion The study demonstrates that hypertension, hyperlipidaemia, CAD and renal dysfunction are prevalent in patients with PDD. More importantly, although the progression to the development of clinical HF over 2 years was low, there was a moderate degree of progression to development of symptoms and cardiac hospitalisations over 2 years. Based on the finding that only PVD and hypertension were independently associated with the progression to the development of symptoms in subject with PDD, the authors speculate that ventricular-arterial interaction may be important to the progression of diastolic dysfunction to the development of symptoms.

A genetic association study of 5-HTT LPR and GNβ3 C825T polymorphisms with irritable bowel syndrome

Abstract  A pharmacogenetic study suggests the 5‐HTT LPR polymorphism predicts response to alosetron, and another study describes a possible association of the GNβ3 C825T polymorphism with IBS in patients with dyspepsia. We performed a case–control association study to determine whether these polymorphisms are associated with irritable bowel syndrome (IBS). The study aim was to compare allele and genotype frequencies between cases and controls for the 5‐HTT LPR and the GNβ3 C825T polymorphism. Cases were 50 GI outpatients; controls were 53 General Medicine outpatients matched to cases for age, gender and race at a major medical centre. Participants completed a questionnaire and donated blood. DNA was genotyped using polymerase chain reaction based assays. Eighty‐two per cent of cases met Rome II criteria for IBS: 12% constipation‐, 46% diarrhoea‐, and 42% mixed‐IBS. Genotype and allele frequencies for both polymorphisms did not differ between cases and controls. However, the allele frequency of the short (S) allele of the 5‐HTT LPR polymorphism was greater in those with mixed‐IBS compared with controls (68%vs 45%, P < 0.05). This study suggests that the 5‐HTT LPR polymorphism may be associated with mixed‐IBS, but not IBS overall. No association was observed for the GNβ3 C825T polymorphism with IBS overall or subtypes.

Periprocedural Anticoagulation Management of Patients With Venous Thromboembolism

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.

Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: A single-center retrospective study

BACKGROUND It is unknown whether radiofrequency ablation (RFA) or antiarrhythmic therapy is superior when treating patients with symptomatic premature ventricular contractions (PVCs). OBJECTIVE To determine the relative efficacy of RFA and antiarrhythmic drugs (AADs) on PVC burden reduction and increasing left ventricular systolic function. METHODS Patients with frequent PVCs (>1000/24 h) were treated either by RFA or with AADs from January 2005 through December 2010. Data from 24-hour Holter monitoring and echocardiography before and 6-12 months after treatment were compared between the 2 groups. RESULTS Of 510 patients identified, 215 (40%) underwent RFA and 295 (60%) received AADs. The reduction in PVC frequency was greater by RFA than with AADs (-21,799/24 h vs -8,376/24 h; P < .001). The left ventricular ejection fraction (LVEF) was increased significantly after RFA (53%-56%; P < .001) but not after AAD (52%- 52%; P = .6) therapy. Of 121 (24%) patients with reduced LVEF, 39 (32%) had LVEF normalization to 50% or greater. LVEF was restored in 25 of 53 (47%) patients in the RFA group compared with 14 of 68 (21%) patients in the AAD group (P = .003). PVC coupling interval less than 450 ms, less impaired left ventricular function, and RFA were independent predictors of LVEF normalization performed by using multivariate analysis. CONCLUSION RFA appears to be more effective than AADs in PVC reduction and LVEF normalization.