Abstract 4112: Genetic Variants within the LPIN1 Gene, Encoding Lipin, Are Influencing Phenotypes of the Metabolic Syndrome in Human
Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass and insulin sensitivity. Specifically, lipin deficiency results in lipodystrophy and insulin resistance, whereas excess lipin levels promote fat accumulation and insulin sensitivity. Moreover, the gene encoding lipin, LPIN1, is localized on chr2p25, a genomic region that has been linked to fat mass and leptin levels. Thus, we hypothesised that genetic variants within LPIN1 are associated with traits of the metabolic syndrome.
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 1,418 Caucasians). We performed a comprehensive analysis of linkage disequilibrium (LD) and haplotype structure. Factor analysis was applied to define the metabolic syndrome and its components. Permutation based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance.
Results: LD analysis revealed three LD blocks (69 kb) encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for metabolic syndrome (OR=1.31 [1.01–1.70]), while the other two being less common (5.7% and 4.0%) are strongly associated with lower blood pressure levels (mean arterial BP 93±18 vs. 100±21, p<0.0001), lower BMI (25.0±3.8 vs. 27.0±4.1, p<0.0001) and smaller waist circumference (84±12 vs. 90±12, p<0.0001), log[triglycerides/HDL cholesterol] (0.93±0.83 vs. 1.08±0.80, p=0.011) and, thus, with a markedly lower risk for metabolic syndrome (OR=0.27[0.18–0.39]).
Conclusion: These data imply 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 metabolic syndrome. Permutation-based low p-values and the consistent findings across multiple phenotypes of the metabolic syndrome reflect the robustness of these results.