​The inverse relationship between copy number variation burden and age of onset of metabolic syndrome in Korean middle-aged adults.

backgroundMetabolic syndrome (MetS) shows wide inter-individual variation in age at onset, yet the contribution of structural genomic variation is underexplored. We posited that copy number variation (CNV) burden—an aggregate of autosomal deletions and duplications—anticipates the timing of MetS. Our objective was to test whether higher CNV burden is associated with earlier onset of MetS and to nominate CNV regions enriched for metabolic biology, clarifying genetic architecture and guiding prevention. We leveraged a longitudinal Korean cohort to address this gap and provide evidence.

methodsA total of 546 adults from the Korean Genome and Epidemiology Study (KoGES) cohort, with baseline genotyping and up to 20 years of follow-up, were analyzed. CNV burden was quantified as the total number of autosomal CNV segments identified after quality control. For each genomic segment, log2-transformed copy number ratios outside the diploid range were classified as CNV-present (value = 1) and those within the diploid interval were set to zero. Individual CNV burden was calculated by summing all non-zero segments and log-transformed to reduce skewness prior to analysis. MetS was defined according to NCEP ATP III and Korean waist circumference reference values. Onset age of MetS was calculated by adding the elapsed follow-up time (years) until the first diagnosis of MetS to each participant’s age at baseline. Participants who did not develop MetS were excluded from the onset-age calculation. We used multivariable logistic regression, multivariable linear regression, Kaplan–Meier with log-rank tests, and Cox proportional hazards models.

resultsA total of 403 CNVs showed nominal associations with MetS based on multivariable logistic regression adjusted for demographic, lifestyle, and clinical covariates (P < 0.05). The strongest signals were located in the amylase gene clusters (AMY1A/B/C, AMY2A/B) and KDM4C, although no CNV survived multiple-testing correction. Higher CNV burden was associated with earlier MetS onset in men (β = −21.42, P = 0.0249) and women (β = −14.09, P = 0.0451). In sex-stratified Cox proportional hazards models, CNV burden was consistently associated with an increased risk of incident MetS in men across all adjustment models, with hazard ratios ranging from 1.18 to 1.21. In women, the association showed a similar positive direction, with significance observed in partially adjusted models, although attenuated after full adjustment.

conclusionsGreater CNV burden consistently was associated with earlier MetS onset in a population-based Korean cohort, positioning structural variation as a contributor to cardiometabolic trajectories. The prominence of AMY1/AMY2 and KDM4C suggests convergent pathways linking starch metabolism and epigenetic regulation to disease timing. CNV burden may serve as a biomarker to prioritize early clinical surveillance and tailored prevention, warranting mechanistic and external validation studies.