Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4- (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significansignificantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10-7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P<1.3x10-8), frontal cortex (P<1.3x10-9), and temporal cortex (P<1.2x10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10-6) and temporal cortex (P=2.6x10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Advantages of Laparoscopic Appendectomy in the Elderly

Laparoscopic appendectomy (LA) has gained in popularity in recent years. The number of elderly patients undergoing appendectomy has increased as that segment of the population has increased in number; however, the utility and benefits of LA in the elderly population are not well established. We hypothesized that LA in the elderly has distinctive advantages in perioperative outcomes over open appendectomy (OA). We queried the 1997 to 2003 North Carolina Hospital Association Patient Data System for all patients with the primary ICD-9 procedure code for OA and LA. Patients ≥65 years of age (elderly) were identified and reviewed. Outcomes including length of stay (LOS), charges, complications, discharge location, and mortality were compared between the groups. There were 29,244 appendectomies performed in adult patients (&gt;18 years old) with 2,722 of these in the elderly. The annual percentage of LA performed in the elderly increased from 1997 to 2003 (11.9–26.9%, P &lt; 0.0001). When compared with OA, elderly patients undergoing LA had a shorter LOS (4.6 vs 7.3 days, P = 0.0001), a higher rate of discharge to home (91.4 vs 78.9%, P = 0.0001) as opposed to a step-down facility, fewer complications (13.0 vs 22.4%, P = 0.0001), and a lower mortality rate (0.4 vs 2.1%, P = 0.007). When LA was compared with OA in elderly patients with perforated appendicitis, LA resulted in a shorter LOS (6.8 vs 9.0 days, P = 0.0001), a higher rate of discharge to home (86.6 vs 70.9%, P = 0.0001), but equivalent total charges ($22,334 vs$23,855, P = 0.93) and mortality (1.0 vs 2.98%, P = 0.10). When elderly patients that underwent LA were compared with adult patients (18–64 years old), they had higher total charges ($16,670 vs$11,160, P = 0.0001) but equivalent mortality (0.37 vs 0.15%, P = 0.20). The use of laparoscopy in the elderly has significantly increased in recent years. In general, the safety and efficacy of LA is demonstrated by a reduction in mortality, complications, and LOS when compared with OA. The laparoscopic approach to the perforated appendix in the elderly patient has advantages over OA in terms of decreased LOS and a higher rate of discharge to home as opposed to rehabilitation centers, nursing homes, or skilled nursing care. When compared with all younger adults, the laparoscopic approach in the elderly was associated with equal mortality rates even though hospitalization charges were higher. Laparoscopy may be the preferred approach in elderly patients who require appendectomy. </jats:p

A Clinical Prediction Model to Estimate Risk for 30-Day Adverse Events in Emergency Department Patients With Symptomatic Atrial Fibrillation

Study objective: Atrial fibrillation affects more than 2 million people in the United States and accounts for nearly 1% of emergency department (ED) visits. Physicians have little information to guide risk stratification of patients with symptomatic atrial fibrillation and admit more than 65%. Our aim is to assess whether data available in the ED management of symptomatic atrial fibrillation can estimate a patient&apos;s risk of experiencing a 30-day adverse event. Methods: We systematically reviewed the electronic medical records of all ED patients presenting with symptomatic atrial fibrillation between August 2005 and July 2008. Predefined adverse outcomes included 30-day ED return visit, unscheduled hospitalization, cardiovascular complication, or death. We performed multivariable logistic regression to identify predictors of 30-day adverse events. The model was validated with 300 bootstrap replications. Results: During the 3-year study period, 914 patients accounted for 1,228 ED visits. Eighty patients were excluded for non-atrial-fibrillation-related complaints and 2 patients had no follow-up recorded. Of 832 eligible patients, 216 (25.9%) experienced at least 1 of the 30-day adverse events. Increasing age (odds ratio [OR] 1.20 per decade; 95% confidence interval [CI] 1.06 to 1.36 per decade), complaint of dyspnea (OR 1.57; 95% CI 1.12 to 2.20), smokers (OR 2.35; 95% CI 1.47 to 3.76), inadequate ventricular rate control (OR 1.58; 95% CI 1.13 to 2.21), and patients receiving ␤-blockers (OR 1.44; 95% CI 1.02 to 2.04) were independently associated with higher risk for adverse events. C-index was 0.67. Conclusion: In ED patients with symptomatic atrial fibrillation, increased age, inadequate ED ventricular rate control, dyspnea, smoking, and ␤-blocker treatment were associated with an increased risk of a 30-day adverse event

Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

Background Neuregulin‐1β ( NRG ‐1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 ( GGF 2) isoform of NRG ‐1β improves cardiac function in rodents after myocardial infarction ( MI ), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF 2 on ventricular remodeling, cardiac function, and global transcription in post‐ MI swine, as well as potential mechanisms for anti‐remodeling effects. Methods and Results MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post‐ MI , survivors (n=13) received GGF 2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post‐ MI , fractional shortening was higher (32.8% versus 25.3%, P =0.019), and left ventricular ( LV ) end‐diastolic dimension lower (4.5 versus 5.3 cm, P =0.003) in GGF 2‐treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF 2‐treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG ‐1β reduces myoFbs, and suppresses TGF β‐induced phospho‐ SMAD 3 as well as α SMA expression. Conclusions These results suggest that GGF 2/ NRG ‐1β prevents adverse remodeling after injury in part via anti‐fibrotic effects in the heart. </jats:sec