We narrowed chromosome 15q21–23 linkage to plasma high‐density lipoprotein cholesterol (HDL‐C) levels in Turkish families by fine mapping, then focused on glucuronic acid epimerase (GLCE), a heparan sulfate proteoglycan (HSPG) biosynthesis enzyme. HSPGs participate in lipid metabolism along with apolipoprotein (apo) E. Of 31 SNPs in the GLCE locus, nine analyzed by haplotype were associated with HDL‐C and triglyceride levels (permuted p = 0.006 and 0.013, respectively) in families. Of five tagging GLCE SNPs in two cohorts of unrelated subjects, three (rs16952868, rs11631403, and rs3865014) were associated with triglyceride and HDL‐C levels in males (nonpermuted p < 0.05). The association was stronger in APOE 2/3 subjects (apoE2 has reduced binding to HSPGs) and reached multiple‐testing significance (p < 0.05) in both males and females (n= 2612). Similar results were obtained in the second cohort (n= 1164). Interestingly, at the GLCE locus, bounded by recombination hotspots, Turks had a minor allele frequency of SNPs resembling Chinese more than European ancestry; adjoining regions resembled the European pattern. Studies of glce^+/−apoe^−/− mice fed a chow or high‐fat diet supported a role for GLCE in lipid metabolism. Thus, SNPs in GLCE are associated with triglyceride and HDL‐C levels in Turks, and mouse studies support a role for glce in lipid metabolism.