Exploring the Potential Roles of SLC39A8 and POC5 Missense Variants in the Association Between Body Composition, Beverage Consumption, and Chronic Lung Diseases: A Two-Sample Mendelian Randomization Study

The study examined the association between body composition and beverage consumption and the risk of asthma and chronic obstructive pulmonary disease (COPD) and explored the single nucleotide polymorphisms (SNPs) involved in these associations by leveraging summary statistics from genome-wide association studies (GWAS) in nonoverlapping populations. The IEU OpenGWAS project was sourced for exposure datasets: body mass index, body fat percentage, fat-free mass, total body water mass, alcohol intake frequency, and coffee intake, and selected health outcome datasets: asthma and chronic obstructive pulmonary disease. Datasets were assessed and filtered using R, followed by a two-sample Mendelian randomization analysis. The MR Egger, weighted median, inverse variance weighted, simple mode, and weighted mode methods were used to examine the association between exposures and outcomes. Heterogeneity and pleiotropy analyses were used to evaluate the reliability of results. Additionally, SNPnexus was used to ascertain SNPs linked to established phenotypes, while SNP annotation was obtained from the Ensembl BioMart database via the biomaRt package. Genes belonging to overlapping groups were visualized using ComplexHeatmap. Higher body fat percentage (OR = 1.72, 95% CI: 1.23-2.41, <i>p</i> = 0.002), increased BMI (OR = 1.56, CI: 1.23-1.20, <i>p</i> = 2.53 × 10^-4), and more frequent alcohol intake (OR = 1.34, CI: 1.08-1.68, <i>p</i> = 0.009) were associated with elevated COPD risk. Asthma risk was similarly increased with higher body fat percentage (OR = 1.60, CI: 1.23-2.21, <i>p</i> = 0.001), BMI (OR = 1.54, CI: 1.29-1.84, <i>p</i> = 2.23 × 10^-6), fat-free mass (OR = 1.21, CI: 1.02-1.44, <i>p</i> = 0.032), and alcohol intake frequency (OR = 1.19, CI: 1.01-1.40, <i>p</i> = 0.039). Total body water mass and coffee intake were not associated with asthma and COPD. SNP annotation revealed that some genetic variants that influenced the association of the exposure variables with asthma and COPD were missense variants in several genes, including the evolutionarily highly conserved gene, <i>SLC39A8</i> (rs13107325; C/A/T allele), and <i>POC5</i> (rs2307111; T/A/C allele), as well as intronic variants in <i>FTO</i> (rs56094641; A/G/T allele) and <i>NRXN3</i> (rs10146997; A/G allele). The discovery of the missense variants rs13107325 and rs2307111 in <i>SLC39A8</i> and <i>POC5</i>, respectively, in addition to other intronic and synonymous SNPs suggests that these SNPs may have some roles in the development or progression of asthma and COPD. This may contribute to the identification of molecular signatures or biomarkers that forecast the risk, development, or therapeutic response of chronic lung diseases in persons with metabolic dysregulation, including obesity.