Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. This study aims to examine the causal clinical effects of blood iron and copper with Mendelian randomization (MR) analyses. Genetic instruments for the blood levels of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and a wide range of phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by MR analyses, with replication in independent data sources where possible. We found that genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.67–0.85, p = 1.90 × 10−6 for iron; OR = 0.88, 95% CI: 0.78–0.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85–0.96, p = 6.44 × 10−4; OR = 0.92, 95% CI: 0.87–0.98, p = 5.51 × 10−3) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84–0.95, p = 5.34 × 10−4; OR = 0.93, 95% CI: 0.89–0.99, p = 0.022). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the presence of pleiotropy and the robustness of causal estimates. Regardless of the approaches, consistent evidence was obtained. Moreover, the unique clinical effects of each blood mineral were identified. Notably, genetically predicated higher blood iron is associated with an enhanced risk of varicose veins (OR = 1.28, 95% CI: 1.15–1.42, p = 4.34 × 10−6), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02–1.13, p = 0.010). Sex-stratified MR analysis further revealed some degree of sex differences in their clinical effects. Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable nature of blood mineral status and the potential for clinical intervention, these findings warrant further investigation.
Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10−6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10−8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.
Circulating polyunsaturated and monounsaturated fatty acid (PUFA and MUFA) levels, whose imbalances co-occur with human metabolic diseases, have strong heritable components. We performed the largest genome-wide association study (GWAS) to-date on fourteen PUFA and MUFA phenotypes, measured by nuclear magnetic resonance in plasma. We identified 612 significant loci-phenotype associations (115 unique loci; P < 1.678*10−8) in a European cohort from UK Biobank (UKB-EUR; n=101,729). Replication of five phenotypes (omega-3, omega-6, DHA, LA, MUFAs) was conducted in two external European studies: FinMetSeq (n=8,751) and a meta-analysis by Kettunnen et al. (n=3,644-13,544). Meta-analysis of these three studies yielded 254 significant loci-phenotype associations (109 unique loci; P < 2.439*10−8); we identified 87 novel loci, 51 of which were replicated. A transcriptome-wide association study of the UKB-EUR cohort revealed an additional twelve novel loci. This study improves our understanding of the genetic architecture of unsaturated fatty acids, and can inform future gene-based dietary interventions.
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