The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes.

Graphical Abstract Highlights d Expanded CD8CD38 high T cells in SLE patients identify patients with infections d CD8CD38 high T cells express decreased amounts of cytotoxic molecules d CD38 decreases NAD + and SIRT1 activity and releases the activity of EZH2 d Inhibition of EZH2 restores the degranulation capacity of CD8CD38 high T cells In Brief Katsuyama et al. find that an expanded CD8CD38 high T cell population in SLE patients is linked to infections. CD8CD38 high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD + /Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE. SUMMARYPatients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38 high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38 high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38 high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

Study Design. A retrospective cohort study of a nationwide sample database. Objective. The objective of the present study was to compare the long-term incidence of reoperation for lumbar herniated intervertebral disc disease (HIVD) after major surgical techniques (open discectomy, OD; laminectomy; percutaneous endoscopic lumbar discectomy, PELD; fusion). Summary of Background Data. HIVD is a major spinal affliction; if the disease is intractable, surgery is recommended. Considering both the aging of patients and the chronicity of lumbar degenerative disease, the effect of surgical treatment for the lumbar spine should be durable for as long as possible. Methods. The National Health Insurance Service-National Sample Cohort (NHIS-NSC) of Republic of Korea was utilized to establish a cohort of adult patients (N = 1856) who underwent first surgery for lumbar HIVD during 2005 to 2007. Patients were followed for 8 to 10 years. Considering death before reoperation as a competing event, reoperation hazards were compared among surgical techniques using the Fine and Gray regression model after adjustment for age, gender, Charlson comorbidity score, osteoporosis, diabetes, the severity of disability, insurance type, and hospital type. Results. The overall cumulative incidences of reoperation were 4% at 1 year, 6% at 2 years, 8% at 3 years, 11% at 5 years, and 16% at 10 years. The cumulative incidences of reoperation were 16%, 14%, 16%, and 10% after OD, laminectomy, PELD, and fusion, respectively, at 10 years postoperation, with no difference among the surgical techniques. However, the distribution of reoperation types was significantly different according to the first surgical technique (P < 0.01). OD was selected as the reoperation surgical technique in 80% of patients after OD and in 81% of patients after PELD. Conclusion. The probability of reoperation did not differ among OD, laminectomy, PELD, and fusion during the 10-year follow-up period. However, OD was the most commonly used technique in reoperation. Level of Evidence: 4

Background: Abalones are large marine snails in the family Haliotidae and the genus Haliotis belonging to the class Gastropoda of the phylum Mollusca. The family Haliotidae contains only one genus, Haliotis, and this single genus is known to contain several species of abalone. With 18 additional subspecies, the most comprehensive treatment of Haliotidae considers 56 species valid [1]. Abalone is an economically important fishery and aquaculture animal that is considered a highly prized seafood delicacy. The total global supply of abalone has increased 5-fold since the 1970s and farm production increased explosively from 50 mt to 103 464 mt in the past 40 years. Additionally, researchers have recently focused on abalone given their reported tumor suppression effect. However, despite the valuable features of this marine animal, no genomic information is available for the Haliotidae family and related research is still limited. To construct the H. discus hannai genome, a total of 580-G base pairs using Illumina and Pacbio platforms were generated with 322-fold coverage based on the 1.8-Gb estimated genome size of H. discus hannai using flow cytometry. The final genome assembly consisted of 1.86 Gb with 35 450 scaffolds (>2 kb). GC content level was 40.51%, and the N50 length of assembled scaffolds was 211 kb. We identified 29 449 genes using Evidence Modeler based on the gene information from ab initio prediction, protein homology with known genes, and transcriptome evidence of RNA-seq. Here we present the first Haliotidae genome, H. discus hannai, with sequencing data, assembly, and gene annotation information. This will be helpful for resolving the lack of genomic information in the Haliotidae family as well as providing more opportunities for understanding gastropod evolution.