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C.S.H., O.R., and N.J.W. Gabapentin fish, Gabapentin respectively, was significantly elevated (HR 2.52 [95% CI 1.76C3.63] and 2.48 [1.79C3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16C0.72] and 0.48 [0.24C0.72]) and multiplicative (= 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (167.5 models/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70C6.72]) and an AP of 0.46 (0.12C0.80) compared with antibody-negative individuals Gabapentin with high n-3 PUFAs. CONCLUSIONS High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity. Introduction Circulating islet autoantibodies are a marker of increased risk of type 1 diabetes (1,2), but they are also associated with adult-onset diabetes with a type 2Clike phenotype (3). The most common autoantibody found in patients with autoimmune adult diabetes is usually directed against the 65-kDa isoform of GAD (GAD65) (4), whereas in children, multiple antibodies are usually present at diagnosis of type 1 diabetes (5). Several environmental risk factors have been suggested to modify progression from islet autoimmunity to clinical diabetes, but evidence about these modifying factors is limited (6). Long-chain n-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from marine food sources, have potential protective effects on diseases with an inflammatory component, such as autoimmune diabetes, owing to their anti-inflammatory, immunomodulatory, and gene expression regulatory properties (7). A Norwegian study showed that the risk of type 1 diabetes in children was diminished in those who had cod liver oil supplementation during the first year of life (8), suggesting a possible protective effect on the risk of autoimmune diabetes. In a separate study of genetically susceptible children in a U.S. cohort, total estimated dietary n-3 PUFAs as well as n-3 PUFA concentration measured in erythrocyte membranes, were inversely associated with the development of islet autoimmunity and multiple autoantibodies and type 1 diabetes, with similar hazard ratios (HRs) observed in individual analyses focused on marine n-3 PUFAs (9). Studies in adults are scarce, but we previously reported a lower risk of latent autoimmune diabetes in adults (LADA) in those who regularly consume fatty fish (10). However, the results from other studies have not confirmed these findings, and others have reported the absence of an association between serum or erythrocyte n-3 PUFAs and childhood islet MMP15 autoimmunity (11) or type 1 diabetes (12). Our aim was to investigate the potential conversation between GAD65 antibody positivity and dietary fish intake or relative plasma phospholipid concentration of n-3 PUFAs in relation to incident adult-onset diabetes using prospective data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study. Research Design and Methods Study Design and Populace The design and methods of the EPIC-InterAct case-cohort study have previously been described (13). A total of 340,234 EPIC participants, who were free of known diabetes at baseline, in 8 of the 10 EPIC study countries (26 centers in Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, and the U.K.) were followed for 3.99 million person-years (median follow-up 10.9 years). During this time (1991C2007), 12,403 incident cases of diabetes were ascertained and verified. Ascertainment of incident diabetes involved multiple sources of evidence, including self-report and linkage to primary care registers, secondary care registers, medication use (drug registers), hospital admissions, and mortality data. A minimum of two data sources were required to confirm the diagnosis. In Denmark and Sweden, cases were identified through local and national diabetes and pharmaceutical registers, and hence, all ascertained cases were considered verified. Follow-up was censored at the date of diagnosis, 31 December 2007, or the date of death, whichever occurred first. All included cases were a diagnosis of type 2 diabetes, and diagnosis of other diabetes forms (e.g., type 1 diabetes, gestational diabetes mellitus) were not included as cases. Since GAD65 antibodies were measured at baseline (described below), the antibody status at diagnosis of the cases is usually unknown. Thus, some cases will most likely meet the commonly used criteria for LADA (antibody positivity, onset 35 years, and remaining insulin secretion often indicated by absence of insulin requirement for 6C12 months following diagnosis) (14). For this reason, the studied outcome is referred to as adult-onset diabetes. A center-stratified subcohort of 16,835 (4.9% of the entire EPIC cohort) individuals was selected at random. We excluded.