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Background Proprotein convertase subtilisin/kexin type 9 ( PCSK9) is a key regulator of low-density lipoprotein cholesterol and cardiovascular disease risk, and is an emerging therapeutic target. Objective We compared serum PCSK9 levels in young adults, with and without type 2 diabetes. Subjects and methods Cross-sectional analysis was conducted in a cohort, aged 15 to 26 years, in Cincinnati, OH, from 2005 to 2010. Serum PCSK9 levels were measured in 94 youth with type 2 diabetes, 93 obese control subjects, and 99 lean control subjects. Correlative analyses were conducted to determine significant covariates of PCSK9 by group and sex, and multivariate linear regression models were used to study the independent determinants of PCSK9. Results In females, PCSK9 levels were significantly increased in the obese and type 2 diabetes subjects relative to the lean controls ( P < .01). Moreover, PCSK9 was positively correlated with multiple metabolic parameters in females: body mass index, systolic blood pressure, fasting glucose, fasting insulin, and C-reactive protein levels ( P ≤ .02). In males, PCSK9 levels were decreased overall compared with females ( P = .03), and did not differ between the lean, obese, or type 2 diabetes groups. Conclusions Obesity and type 2 diabetes were associated with significantly higher levels of PCSK9 in young women, but not in young men. These data suggest that sex could modify the effects of obesity and diabetes on PCSK9 in young adults. [ABSTRACT FROM AUTHOR]