Inflammageing is a condition of perpetual low-grade inflammation induced by ageing. Inflammageing may be predicted by the C-reactive protein (CRP) or by a recently described biomarker which measures N Show more
Inflammageing is a condition of perpetual low-grade inflammation induced by ageing. Inflammageing may be predicted by the C-reactive protein (CRP) or by a recently described biomarker which measures N-glycosylated side chains of the carbohydrate component of several acute-phase proteins known as GlycA. The objective of this study was to examine in depth the genetic relationships between CRP and GlycA as well as between each of them and other selected cytokines, which may shed light on the mechanisms of inflammageing. Using the Olink 96 Inflammation panel, data on inflammatory mediators for 1518 twins from the TwinsUK dataset were acquired. Summary statistics for genome-wide association studies for several cytokines as well as CRP and GlycA were collected from public sources. Extensive genetic correlation analyses, colocalization and genetic enrichment analyses were carried out to detect the shared genetic architecture between GlycA and CRP. Mendelian randomization was carried out to assess potential causal relationships. GlycA predicted examined cytokines with a magnitude twice as great as that of CRP. GlycA and CRP were significantly genetically correlated (Rg = 0.4397 ± 0.0854, Show less
The association between rheumatoid arthritis (RA) and blood lipid levels has often been described as paradoxical, despite the strong association between RA and cardiovascular disease (CVD) risk. We ai Show more
The association between rheumatoid arthritis (RA) and blood lipid levels has often been described as paradoxical, despite the strong association between RA and cardiovascular disease (CVD) risk. We aimed to clarify the genetic architecture that would explain the relationship between RA and blood-lipid levels, while considering inflammation as measured by C-reactive protein (CRP). Genome-wide association study (GWAS) summary statistics were collected from the CHARGE Consortium and Global Lipids Genetics Consortium. Blood-lipid levels includes HDL-C, LDL-C, triglycerides (TG), and total cholesterol (TC). Causality was examined by assessing Mendelian Randomization (MR) analysis. Pleiotropy, the identification of shared causal variants between traits, was assessed by conducting colocalization analyses. Using the MR Egger method, RA did not appear to causally predict alterations in lipid factors, rather the MR Egger intercept revealed that the genetic relationship between RA and HDL-C, LDL-C and TC may be explained by horizontal pleiotropy (p=0.003, 0.006, and 0.018, respectively). MR was suggestive of a horizontally pleiotropic relationship between CRP and lipid factors, while a causal relationship could not be ruled out. Recurring genes arising from shared causal genetic variants between RA and varying lipid factors included NAT2/PSD3, FADS2/FADS1, SH2B3, and YDJC. Horizontal pleiotropy appears to explain the genetic relationship between RA and blood-lipid levels. In addition, blood-lipid levels appear to suggest a horizontally pleiotropic relationship to CRP, if not mediated through RA as well. Consideration of the pleiotropic genes between RA and blood lipid levels may aid in enhancing diagnostic means to predict CVD. Show less
Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce Show more
Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass. Show less