👤 N Charlotte Onland-Moret

Moderate-to-vigorous physical activity (MVPA) is inversely associated with risks of cancer, cardiovascular diseases (CVD), type 2 diabetes (T2D), and their co-occurrence, defined as multimorbidity; however, the underlying biological pathways remain unclear. In 33,806 UK Biobank participants with 2911 measured blood proteins, a proteomic signature of MVPA was derived with linear and LASSO regressions. Multivariable Cox models, adjusted for MVPA, estimated prospective associations with cancer, CVD, T2D, and multimorbidity. We show that after multiple testing corrections, 220 proteins are retained in the MVPA signature. Proteins related to food intake, metabolism, and cell growth (e.g., LEP, MSTN) are inversely associated, while those involved in immune cell migration and musculoskeletal integrity (e.g., integrins, COMP) are positively associated with MVPA. Several proteins positively associated with MVPA are inversely associated with disease risk (e.g., integrins, CLEC4A for cancer; LPL, LEP for T2D), while proteins negatively associated with MVPA are positively associated with disease risk (e.g., CD38, TGFA for CVD). The proteomic signature score is inversely associated with cancer risk (hazard ratio per interquartile range: 0.87; 95% confidence interval: 0.78, 0.96) and T2D (0.66; 0.60, 0.72). For multimorbidity, proteins inversely related to MVPA align with expected risk patterns (e.g., GGT1, HR: 1.32; 95% CI: 1.12, 1.57), but the proteomic signature score is not associated. This study identifies several proteins associated with MVPA that are also associated with cancer, CVD, T2D, and the multimorbidity of these conditions. Further studies investigating the causal nature of these associations are welcome. Show less

Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. We identified 11 genomic regions associated with plasma vitamin C ( These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention. Show less

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance. Show less