Serum tryptophan metabolites are associated with erosive hand osteoarthritis and pain: results from the DIGICOD cohort.

OBJECTIVE: To investigate host and gut-microbiota related Tryptophan metabolism in hand osteoarthritis (HOA). METHODS: The baseline serum concentration of 20 Tryptophan metabolites was measured in 416 HOA patients in a cross-sectional analysis of the DIGICOD cohort. Tryptophan metabolites levels, metabolite-ratios and metabolism pathway activation were compared between erosive (N = 141) and non-erosive HOA (N = 275) by multiple logistic regressions adjusted on age, BMI and sex. The association between Tryptophan metabolite levels and HOA symptoms was investigated by a Spearman's rank correlation analysis. RESULTS: Four serum Tryptophan metabolites, eight metabolite ratios and one metabolism pathway were associated with erosive HOA. Erosive HOA was negatively associated with Tryptophan (odds ratio (OR) = 0.41, 95% confidence interval [0.24-0.70]), indole-3-aldehyde (OR = 0.67 [0.51-0.90]) and 3-OH-anthranilic acid (OR = 1.32 [1.13-1.54]) and positively with 5-OH-Tryptophan levels (OR = 1.41 [1.13-1.77]). The pro-inflammatory kynurenine-indoleamine 2,3-dioxygenase pathway was upregulated in erosive HOA (OR = 1.60 [1.11-2.29]). Eleven metabolites were correlated with HOA symptoms and were mostly pain-related. Serotonin and N-acetyl serotonin levels were negatively correlated with number of tender joints. Indole-3-aldehyde level was negatively correlated and 3-OH-anthranilic acid, 3-OH-kynurenine and 5-OH-Tryptophan levels were positively correlated with number of patients-reported painful joints. Quinolinic acid and 3-OH-kynurenine levels correlated positively with AUSCAN pain. CONCLUSIONS: Tryptophan metabolites disturbance is associated with erosive HOA and pain and emphasize the role of low-grade inflammation and gut dysbiosis in HOA.

Monogenic diabetes in adults: A multi-ancestry study reveals strong disparities in diagnosis rates and clinical presentation.

AIM: Identification of monogenic diabetes (MgD) conveys benefits for patients' care. Algorithms for selecting the patients to be genetically tested have been established in EuroCaucasians, but not in non-EuroCaucasian individuals. We assessed the diagnosis rate, the phenotype of MgD, and the relevance of selection criteria, according to ancestry in patients referred for a suspected MgD. METHODS: Seven genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11, INS) were analyzed in 1975 adult probands (42% non-EuroCaucasians), selected on the absence of diabetes autoantibodies and ≥2 of the following criteria: age ≤40 years and body mass index <30 kg/m2 at diagnosis, and a family history of diabetes in ≥2 generations. RESULTS: Pathogenic/likely pathogenic variants were identified in 6.2% of non-EuroCaucasian and 23.6% of EuroCaucasian patients (OR 0.21, [0.16-0.29]). Diagnosis rate was low in all non-EuroCaucasian subgroups (4.1-11.8%). Common causes of MgD (GCK, HNF1A, HNF4A), but not rare causes, were less frequent in non-EuroCaucasians than in EuroCaucasians (4.1%, vs. 21.1%, OR 0.16 [0.11-0.23]). Using ethnicity-specific body mass index cutoffs increased the diagnosis rate in several non-EuroCaucasian subgroups. CONCLUSION: The diagnosis rate of MgD is low in non-EuroCaucasian patients, but may be improved by tailoring selection criteria according to patients'ancestry.