Abstract
MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46–MUC1–THBS3–MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46–MUC1–THBS3–MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.
Highlights
The results revealed that gout and microalbuminuria were significantly associated with Mucin 1 (MUC1) gene variants (Figure 1 and Table S1)
MUC1 functional single-nucleotide polymorphism (SNP) with multiple clinical and laboratory parameters by using both candidate gene and regional plot association approaches. We observed that both MUC1 variants were associated with renal functional parameters (BUN, serum creatinine level, and estimated glomerular filtration rate (eGFR)), albuminuria, and serum uric acid levels; this finding is in accordance with that of previous studies
We provide the first evidence of the possibility that the previously reported association between rs4072037 and the total or alternative spliced form of gene expression may be secondary to MUC1 gene-body methylation status
Summary
Mucin 1 (MUC1), named polymorphic epithelial mucin and encoded as MUC1 in humans, is a single-pass type I transmembrane phosphoprotein with substantial O-linked glycosylation. In terms of its functions, MUC1 was initially assumed to only protect from the external environment and lubricate the epithelium, whereas MUC1 is currently considered to play a crucial role as a multifunctional protein in cell signal transduction and cell–cell interaction [1,3]. MUC1 is normally expressed in the glandular or luminal epithelial cells of the mammary gland, esophagus, stomach, duodenum, pancreas, uterus, prostate, and lungs, and to a lesser extent, in hematopoietic cells [5,6,7]. MUC1 is overexpressed in breast, ovarian, lung, pancreatic, and prostate cancers and is a marker of poor prognosis in gastric cancer [8,9]. A recent proteomic analysis of urine revealed that the urinary excretion of five proteins including
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