Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

Background

Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span.

Methods

We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate ≥80%, minor allele frequency ≥10%, Hardy-Weinberg test p ≥ 0.001).

Results

In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10^-5). The two sets of SNPs were in high linkage disequilibrium (minimum r² = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

     

Single-cell approaches to investigate B cells and antibodies in autoimmune neurological disorders

Autoimmune neurological disorders, including neuromyelitis optica spectrum disorder, anti-N-methyl-D-aspartate receptor encephalitis, anti-MOG antibody-associated disorders, and myasthenia gravis, are clearly defined by the presence of autoantibodies against neurological antigens. Although these autoantibodies have been heavily studied for their biological activities, given the heterogeneity of polyclonal patient samples, the characteristics of a single antibody cannot be definitively assigned. This review details the findings of polyclonal serum and CSF studies and then explores the advances made by single-cell technologies to the field of antibody-mediated neurological disorders. High-resolution single-cell methods have revealed abnormalities in the tolerance mechanisms of several disorders and provided further insight into the B cells responsible for autoantibody production. Ultimately, several factors, including epitope specificity and binding affinity, finely regulate the pathogenic potential of an autoantibody, and a deeper appreciation of these factors may progress the development of targeted immunotherapies for patients.     

Pre-Hospital Diagnosis in Mobile Stroke Unit

ObjectivesMobile stroke unit (MSU) has been shown to rapidly provide pre-hospital thrombolysis in acute ischemic stroke (AIS). MSU encounters neurological disorders other than AIS that require emergent treatment.Methods/MaterialsWe obtained pre-hospital diagnosis and treatment data from the prospectively collected dataset on 221 consecutive MSU encounters. Based on initial clinical evaluation and neuroimaging obtained on MSU, the diagnosis of AIS (definite, probable, and possible AIS, transient ischemic attack), intracranial hemorrhage, and likely stroke mimics was made.ResultsFrom July 2014 to April 2015, 221 patients were treated on MSU. 78 (35%) patients had initial clinical diagnosis of definite/probable AIS or TIA, 69 (31%) were diagnosed as possible AIS or TIA, 15 (7%) had intracranial hemorrhage while 59 patients (27%) were diagnosed as likely stroke mimics. Stroke mimics encountered included 13 (6%) metabolic encephalopathy, 11 (5%) seizures, 9 (4%) migraines, 3 (1%) substance abuse, 2 (1%) CNS tumor, 3 (1%) infectious etiology and 3 (1%) hypoglycemia. Fifty-four (24%) patients received non-thrombolytic treatments on MSUConclusionAbout one third of MSU encounters were not AIS initially, including intracranial hemorrhage and stroke mimics. MSU can be utilized to provide pre-hospital treatments in emergent neurological conditions other than AIS.     

Laparoscopic sleeve gastrectomy as an initial weight-loss procedure for high-risk patients with morbid obesity

Background The surgical treatment of obesity in the high-risk, high-body-mass-index (BMI) (>60) patient remains a challenge. Major morbidity and mortality in these patients can approach 38% and 6%, respectively. In an effort to achieve more favorable outcomes, we have employed a two-stage approach to such high-risk patients. This study evaluates our initial outcomes with this technique. Methods In this study, patients underwent laparoscopic sleeve gastrectomy (LSG) as a first stage during the period January 2002–February 2004. After achieving significant weight loss and reduction in co-morbidities, these patients then proceeded with the second stage, laparoscopic Roux-en-Y gastric bypass (LRYGBP). Results During this time, 126 patients underwent LSG (53% female). The mean age was 49.5 ± 0.9 years, and the mean BMI was 65.3 ± 0.8 (range 45–91). Operative risk assessment determined that 42% were American Society of Anesthesiologists physical status score (ASA) III and 52% were ASA IV. The mean number of co-morbid conditions per patient was 9.3 ± 0.3 with a median of 10 (range 3–17). There was one distant mortality and the incidence of major complications was 13%. Mean excess weight after LSG at 1 year was 46%. Thirty-six patients with a mean BMI of 49.1 ± 1.3 (excess weight loss, EWL, 38%) had the second-stage LRYGBP. The mean number of co-morbidities in this group was 6.4 ± 0.1 (reduced from 9). The ASA class of the majority of patients had been downstaged at the time of LRYGB. The mean time interval between the first and second stages was 12.6 ± 0.8 months. The mean and median hospital stays were 3 ± 1.7 and 2.5 (range 2–7) days, respectively. There were no deaths, and the incidence of major complications was 8%. Conclusion The staging concept of LSG followed by LRYGBP is a safe and effective surgical approach for high-risk patients seeking bariatric surgery.