Clinical laboratory tests play a pivotal role in medical decision making, but little is known about their genetic variability between populations. We report a genome-wide association study with 45 clinically relevant traits from the population of Qatar using a whole genome sequencing approach in a discovery set of 6218 individuals and replication in 7768 subjects. Trait heritability is more similar between Qatari and European populations (r = 0.81) than with Africans (r = 0.44). We identify 281 distinct variant-trait-associations at genome wide significance that replicate known associations. Allele frequencies for replicated loci show higher correlations with European (r = 0.94) than with African (r = 0.85) or Japanese (r = 0.80) populations. We find differences in linkage disequilibrium patterns and in effect sizes of the replicated loci compared to previous reports. We also report 17 novel and Qatari-predominate signals providing insights into the biological pathways regulating these traits. We observe that European-derived polygenic scores (PGS) have reduced predictive performance in the Qatari population which could have implications for the translation of PGS between populations and their future application in precision medicine.

IntroductionPatients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration—a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP).Research design and methodsHuman PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function—binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored.ResultsIn high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP.ConclusionsIncreased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease.

Recent research has identified glycation as a non-enzymatic post-translational modification of proteins in plants with a potential contributory role to the functional impairment of the plant proteome. Reducing sugars with a free aldehyde or ketone group such as glucose, fructose and galactose react with the N-terminal and lysine side chain amino groups of proteins. A common early-stage glycation adduct formed from glucose is Nε-fructosyl-lysine (FL). Saccharide-derived reactive dicarbonyls are arginine residue-directed glycating agents, forming advanced glycation endproducts (AGEs). A dominant dicarbonyl is methylglyoxal—formed mainly by the trace-level degradation of triosephosphates, including through the Calvin cycle of photosynthesis. Methylglyoxal forms the major quantitative AGE, hydroimidazolone MG-H1. Glucose and methylglyoxal concentrations in plants change with the developmental stage, senescence, light and dark cycles and also likely biotic and abiotic stresses. Proteomics analysis indicates that there is an enrichment of the amino acid residue targets of glycation, arginine and lysine residues, in predicted functional sites of the plant proteome, suggesting the susceptibility of proteins to functional inactivation by glycation. In this review, we give a brief introduction to glycation, glycating agents and glycation adducts in plants. We consider dicarbonyl stress, the functional vulnerability of the plant proteome to arginine-directed glycation and the likely role of methylglyoxal-mediated glycation in the activation of the unfolded protein response in plants. The latter is linked to the recent suggestion of protein glycation in sugar signaling in plant metabolism. The overexpression of glyoxalase 1, which suppresses glycation by methylglyoxal and glyoxal, produced plants resistant to high salinity, drought, extreme temperature and other stresses. Further research to decrease protein glycation in plants may lead to improved plant growth and assist the breeding of plant varieties resistant to environmental stress and senescence—including plants of commercial ornamental and crop cultivation value.