Introduction Carriage of the HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADAs) to antitumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease. However, ADA is not uniformly associated with treatment failure. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of biologic therapy evaluated by drug persistence. Methods A multicenter, retrospective study of 877 patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy with HLA-DQA1*05 genotypes were generated by imputation from whole genome sequence using the HIBAG package, in R. Primary end point was anti-TNF therapy persistence, (time to therapy failure), segregated by HLA-DQA1*05 allele genotype and development of a risk score to predict anti-TNF therapy failure, incorporating HLA-DQA1*05 allele genotype status (LORisk score). Results In all, 877 patients receiving anti-TNF therapy were included in our study; 543 (62%) had no copy, 281 (32%) one copy, and 53 (6%) 2 copies of HLA-DQA1*05 allele. Mean time to anti-TNF therapy failure in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared with patients with 0 or 1 copy at 700 days' follow-up: 418 vs 541 vs 513 days, respectively (P = .012). Factors independently associated with time to anti-TNF therapy failure included carriage of HLA-DQA1*05 allele (hazard ratio [HR], 1.2, P = .02; female gender HR, 1.6, P < .001; UC phenotype HR, 1.4, P = .009; and anti-TNF therapy type [infliximab], HR, 1.5, P = .002). The LORisk score was significantly associated with shorter time to anti-TNF therapy failure (P < .001). Conclusions Carriage of 2 HLA-DQA1*05 alleles is associated with less favorable outcomes for patients receiving anti-TNF therapy with shorter time to therapy failure. HLA-DQA1*05 genotype status in conjunction with clinical factors may aid in therapy selection in patients with IBD.

Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether genes encoding agrin (AGRN) and neurotrypsin (PRSS12) were associated with sarcopenia phenotypes: muscle mass, strength and plasma C-terminal agrin fragment (CAF). PhenoScanner was used to determine if AGRN and/or PRSS12 variants had previously been implicated with sarcopenia phenotypes. For replication, we combined genotype from whole genome sequencing with phenotypic data from 6715 GenoFit participants aged 18–83 years. Dual energy X-ray absorptiometry assessed whole body lean mass (WBLM) and appendicular lean mass (ALM), hand dynamometry determined grip strength and ELISA measured plasma CAF in a subgroup (n = 260). Follow-up analyses included eQTL analyses, carrier analyses, single-variant and gene-burden tests. rs2710873 (AGRN) and rs71608359 (PRSS12) associate with muscle mass and strength phenotypes, respectively, in the UKBB (p = 8.9 × 10−6 and p = 8.4 × 10−6) and GenoFit cohort (p = 0.019 and p = 0.014). rs2710873 and rs71608359 are eQTLs for AGRN and PRSS12, respectively, in ≥ three tissues. Compared to non-carriers, carriers of rs2710873 had 4.0% higher WBLM and ALM (both p < 0.001), and 9.5% lower CAF concentrations (p < 0.001), while carriers of rs71608359 had 2.3% lower grip strength (p = 0.034). AGRN and PRSS12 are associated with muscle strength and mass in single-variant analyses, while PRSS12 has further associations with muscle strength in gene-burden tests. Our findings provide novel evidence of the relevance of AGRN and PRSS12 to sarcopenia phenotypes and support existing physiological data illustrating the importance of the NMJ in maintaining muscle health during ageing.

AbstractBackgroundEfforts to enhance diagnostic measures for sarcopenia have led to an increased focus on the screening utility of blood‐based biomarkers. In this regard, circulating neurofilament light chain (NfL) levels are a potent indicator of axonal damage and have been linked with several neurological disorders. However, despite the strong neurogenic contribution to skeletal muscle health, no studies have explored the relevance of NfL concentrations to sarcopenia. With that in mind, this study aimed to examine the association between plasma NfL concentration and sarcopenic domains.MethodsThree hundred adults aged between 50 and 83 years participated to this study (male participants, n = 150; mean age: 64.2 ± 8.7 years and female participants, n = 150; mean age: 63.9 ± 8.3 years). Body composition was assessed using dual‐energy X‐ray absorptiometry, and a skeletal muscle index (SMI) was calculated. Muscle strength was assessed with hand dynamometry. Sarcopenia was classified using the European Working Group on Sarcopenia in Older People criteria. Plasma NfL concentration was determined using a highly sensitive, enzyme‐linked immunosorbent assay.ResultsNeurofilament light chain levels were associated with grip strength and SMI (P = 0.005 and P = 0.045, respectively) and were significantly elevated in sarcopenic individuals, compared with non‐sarcopenic participants (P < 0.001). Individuals with pre‐sarcopenia (either low grip strength or low SMI) had significantly higher NfL levels, compared with healthy controls (P = 0.001 and P = 0.006, respectively). Male participants with either low grip strength or low SMI had significantly raised NfL levels (P = 0.006 and P = 0.002, respectively), while in female participants, NfL concentrations were significantly elevated only in those with low grip strength (P = 0.049). NfL concentration displayed acceptable diagnostic accuracy for sarcopenia (area under the curve = 0.726, P < 0.001).ConclusionsOur study clearly demonstrates the indicative pertinence of circulating NfL levels to sarcopenic domains, supporting its potential use as a biomarker of sarcopenia. More studies are needed, however, to further illuminate the diagnostic value of circulating NfL. Future research should explore whether NfL levels are more powerfully linked with muscle strength than mass and whether sex mediates the relevance of NfL concentrations to sarcopenic phenotypes.

Weak grip strength is a strong predictor of multiple adverse health outcomes and an integral diagnostic component of sarcopenia. However, the limited availability of normative data for certain populations impedes the interpretation of grip performance across adulthood. This study aimed to establish normative data and low grip strength thresholds in a large adult population, and to examine associations between grip strength and clinically relevant health variables. A total of 9431 adults aged between 18 and 92 years participated in this study (mean age: 44.8 ± 13.4 years; 57% females). Grip strength, body composition, and cardiorespiratory (CR) fitness were assessed using hand dynamometry, dual-energy x-ray absorptiometry and physical work capacity tests, respectively. Low grip strength was established according to criteria of the European Working Group on Sarcopenia in Older People. Normative data and t-scores, stratified by sex and age groups, are presented. Grip performance was associated with lean mass, skeletal muscle index (SMI), fat mass, CR fitness, bone mineral density (BMD), android/gynoid ratio, disease prevalence and physical activity levels (all p < 0.001) after controlling for multiple potential confounders. Individuals with weak grip strength had lower lean mass, SMI, CR fitness (all p < 0.001) and BMD (p = 0.001), and higher disease prevalence (p < 0.001), compared to healthy controls, although sex-specific differences were observed. Grip strength has practical screening utility across a range of health domains. The normative data and grip strength thresholds established in this study can guide the clinical interpretation of grip performance and facilitate timely therapeutic strategies targeting sarcopenia.

Barriers associated with direct muscle quantification have prevented a consistent implementation of therapeutic measures for sarcopenia. Recently, the relevance of circulating C-terminal agrin fragment (CAF) as an accessible screening method alternative for sarcopenia has gained credence. Accordingly, this study aimed to verify the pertinence of plasma CAF as a biomarker for sarcopenia. Three hundred healthy adults aged between 50 and 83 years took part in this study. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older People criteria. Body composition was assessed using dual-energy x-ray absorptiometry, while muscle strength was examined using hand dynamometry. Plasma CAF concentrations were determined using a commercially available ELISA kit. CAF concentrations were significantly associated with appendicular lean mass (ALM), but not grip strength (p = .028, p = .575, respectively). Plasma CAF concentrations were significantly elevated in sarcopenic individuals compared to nonsarcopenic (p < .001). Overall, individuals with low grip strength or low ALM displayed significantly higher CAF levels compared to healthy controls, after adjusting for age and body mass index (p = .027, p = .003, respectively). In males, those with low grip strength or low ALM had significantly elevated CAF levels (p = .039, p = .027, respectively), while in females, only those with low ALM had significantly raised CAF concentrations, compared to healthy controls (p = .035). Our findings illuminate the potential relevance of CAF as an accessible biomarker for skeletal muscle health. CAF determination may enhance clinical practice by facilitating more widespread treatment strategies for sarcopenia. Nevertheless, future research is needed to confirm the diagnostic pertinence of CAF concentrations in screening for sarcopenia.