AIMS/HYPOTHESIS: It has been suggested that the gene encoding lymphotoxin-alpha (LTA) is associated with insulin resistance, and genetic association studies in the LTA region offer some support for this. However, LTA is in linkage disequilibrium with both the HLA gene cluster and the gene encoding TNF-alpha, making inferences about causality difficult. In this study, we used the galectin 2 (LGALS2) genotype, which affects LTA secretion but is located on another chromosome than the HLA gene cluster or TNF, to examine the relationship between the LTA pathway and traits of the metabolic syndrome. SUBJECTS: A cross-sectional genetic association study was carried out in 3,272 British women of European origin who were aged 60 to 79 years and were randomly selected from the community. RESULTS: Fasting plasma glucose and serum insulin were statistically significantly associated with LGALS2 rs7291467, with this association being independent of BMI and WHR. The mean difference in fasting insulin per minor allele was -4% (p=0.01 for trend by allele) and the mean per minor allele difference in fasting glucose was -2% (p=0.02 for trend by allele). When women with known diabetes were excluded from the analyses the findings did not differ from those for the whole cohort. CONCLUSIONS/INTERPRETATION: Our findings for the physically unlinked LGALS2, invite further study of LGALS2 specifically and the LTA pathway generally for their influence on glucose-insulin regulation.