GCKR Polymorphisms Increase the Risks of Low Bone Mineral Density in Young and Non-Obese Patients With MASLD and Hyperuricemia

Abstract

Metabolic-associated steatotic liver disease (MASLD) encompasses common comorbidities including low bone mineral density (BMD) and hyperuricemia (HU), yet relevant genetic analyses are limited. This study aimed to investigate the genetic effects of risk single nucleotide polymorphisms (SNPs) on the occurrence of low BMD in patients with MASLD and HU, particularly focusing on relatively young or non-obese populations. We conducted a cross-sectional study utilizing data from the Taiwan Biobank, screening a total of 150,709 participants who were prospectively enrolled over a period of 13 years. The risk SNPs for MASLD were identified. Genotype analyses of HU and its effects on the occurrence of low BMD in the general population were evaluated, with further analyses of common SNPs focusing on patients with MASLD, including subgroup analyses on relatively young and non-obese populations. A total of 20,496 participants were eligible for analysis, including 7526 patients with MASLD. Several risk SNPs for MASLD were identified. Furthermore, MASLD patients carrying the PNPLA3-rs738409 C_C, PNPLA3-rs2896019 T_T, GCKR-rs780094 T_T, and GCKR-rs1260326 T_T genotypes exhibited an increased risk of comorbidity with HU. Trend analysis revealed that the T alleles in GCKR-rs780094 and GCKR-rs1260326 were associated with the occurrence of low BMD in MASLD individuals comorbid with HU, particularly among relatively young or non-obese populations. In relatively young, non-obese patients with MASLD and HU, genetic effects significantly increase the risk of occurrence of low BMD. Given the presence of genetic effects in these ostensibly low-risk groups, heightened awareness and close follow-up are recommended.

Keywords: hyperuricemia; low bone mineral density; metabolic‐associated steatotic liver disease; single nucleotide polymorphisms.

FIGURE 1

Flow chart of our study. In addition to dividing the subjects into MASLD and non‐MASLD groups, we further extracted a MASLD subgroup comorbid with HU for the analysis of low BMD‐associated SNPs. BMD, bone mineral density; HbA1c, hemoglobin A1c; HDL, high‐density lipoprotein cholesterol; HU, hyperuricemia; MASLD, metabolic dysfunction‐associated steatotic liver disease; SNP, single nucleotide polymorphism; TG, triglyceride.

FIGURE 2

Genetic associations with hyperuricemia and low BMD in non‐obese and relatively young general populations. PNPLA3‐rs738409 carrying risk allele C and PNPLA3‐rs2896019 carrying risk allele T, as well as GCKR‐rs780094 and GCKR‐rs1260326 with the T allele, are identified as risk factors for HU in the non‐obese population. In the young population, the GCKR‐rs780094 and GCKR‐rs1260326 variants carrying the T allele increase the risk of HU. In the general population, the PPARGC1A‐rs8192678 variant with the T allele is associated with an increased risk of low BMD. On the other hand, among non‐obese individuals, the PPARGC1A‐rs8192678 T allele also elevates the risk of low BMD. In young, non‐obese individuals with HU, the T allele in GCKR‐rs780094 and GCKR‐rs1260326 is linked to a higher risk of low BMD. BMD, bone mineral density; GCKR, glucokinase regulator; HU, hyperuricemia; MASLD, metabolic dysfunction‐associated steatotic liver disease; PNPLA3, patatin‐like phospholipase domain‐containing protein 3; PPARGC1A, peroxisome proliferator‐activated receptor γ–coactivator 1α.

FIGURE 3

Concurrent hyperuricemia and low BMD in MASLD with the cumulative effects of the T alleles in common SNPs. In patients with MASLD, the prevalence of concurrent HU and low BMD increases with the number of T alleles in GCKR‐rs780094 and GCKR‐rs1260326. BMD, bone mineral density; GCKR, glucokinase regulator; HU, hyperuricemia; MASLD, metabolic dysfunction‐associated steatotic liver disease; SNPs, single nucleotide polymorphisms.

FIGURE 4

Conclusion of risk SNPs of hyperuricemia and low BMD in MASLD patients. The T allele in APOE‐rs429358 or TM6SF2‐rs58542926 increases the risk of MASLD; meanwhile, the G allele in PNPLA3‐rs738409 or PNPLA3‐rs2896019, and the T allele in GCKR‐rs780094 or GCKR‐rs1260326 also contribute to an elevated risk of MASLD. In the MASLD population, the PNPLA3‐rs738409 variant with the C risk allele is associated with an increased risk of HU. Among MASLD individuals with fewer CMRFs, the PNPLA3‐rs2896019 variant carrying the T risk allele is linked to a higher risk of HU. In the MASLD population, the GCKR‐rs780094 and GCKR‐rs1260326 variants, both carrying the T risk allele, are associated with an elevated risk of low BMD. Among MASLD patients comorbid with HU, the T risk allele in both GCKR‐rs780094 and GCKR‐rs1260326 is similarly associated with an increased risk of low BMD. For the non‐MASLD population, there is no relationship between HU and low BMD. APOE, apolipoprotein E; BMD, bone mineral density; CMRF, cardiometabolic risk factor; GCKR, glucokinase regulator; HU, hyperuricemia; MASLD, metabolic dysfunction‐associated steatotic liver disease; PNPLA3, patatin‐like phospholipase domain containing 3; PPARGC1A, peroxisome proliferator‐activated receptor γ coactivator 1α; SNP, single nucleotide polymorphism; TM6SF2, transmembrane 6 superfamily member 2.