Abstract 3566: Confirmed Influence Of The LPIN1 Gene On Traits Of The Metabolic Syndrome In Human
Lipin, a molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Genetic variants within the lipin gene, LPIN1, may be associated with traits of the metabolic syndrome (MetS) as we have shown previously in a sample of the general population.
Methods: 15 SNPs densely covering the LPIN1 gene region were genotyped in an age- and sex- stratified sample of the general population (MONICA study Augsburg, DNA and phenotypes of 1,416 Caucasians). Ten of these SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The MetS was defined via the sum of its core components and additionally by a factor score derived from factor analysis. Permutation based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance.
Results: Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the MetS (OR=1.6, 95% CI[1.2–2.2]), while the other two being less common (5.7% and 4.0%) are strongly associated with lower blood pressure (p<0.0001), a lower BMI and waist circumference (p<0.0001), lower HbA1c (p<0.01) as well as a lower MetS factor score (p<0.0001). Furthermore, the frequencies of arterial hypertension (p<0.0001), obesity (p<0.0001), diabetes (p<0.05), and the presence of ≥3 MetS components (p<0.0006) were significantly lower than in subjects not carrying one of these protective haplotypes. These findings could be largely confirmed in the replication sample. Specifically, the same haplotypes were significantly associated with fasting triglyceride levels (p=0.00008), HDL cholesterol levels (p=0.00012), diabetes (p=0.00007), and the MetS factor score (p=0.002).
Conclusion: These data confirm that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and highlight the importance of lipin in the pathophysiology of the MetS. Permutation-based low p-values and the consistent findings in several populations across multiple phenotypes of the MetS reflect the robustness of these results.