Systematic genetic investigation on relative macronutrient intake, circulating metabolic biomarkers and the risk of autoimmune diseases

The effects of specific macronutrients on autoimmune diseases (ADs) independent of total calorie intake have rarely been studied. The study aims to decipher the associations of relative macronutrient intake with risk of ADs and identify potential circulating metabolic mediators. We performed a mendelian randomization (MR) study in Europe, using genetic variants associated with relative macronutrient intake among 268,992 participants, and genetic variants with 17 ADs outcomes from two large-scale biobanks including up to 951,301 participants. Eight potential causal associations were identified and further classified into three levels, according to the robustness of MR results. Tier 1 evidence included associations of relative protein and carbohydrate intake with risk of psoriasis, which was demonstrated by the fact that the association remained significant in the meta-analysis of two biobanks. For each 4.8% increment in relative protein intake and each 16.1% increment in relative carbohydrate intake, the odds ratios and 95% confidence intervals for the association with psoriasis risk were 0.84 (0.71-0.99) and 1.20 (1.02-1.41), respectively, as determined by the MR meta-analysis. To explain above associations, a two-step MR framework was further to identify five potential mediated metabolic biomarkers, using the genetic variants for 233 metabolic traits in up to 136,016 participants. This study provides insights into the clinical significance of dietary macronutrient intake and circulating metabolic biomarkers in the context of ADs.