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Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans

¹Clinic for Internal Medicine II, University of Regensburg, Regensburg, Germany
²GSF-National Research Center for Environment and Health, Institute for Epidemiology, Neuherberg, Germany
³Clinic for Internal Medicine 2, University of Schleswig-Holstein, Lübeck, Germany

Objective: Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Thus, we hypothesized that genetic variants within LPIN1 are associated with traits of the metabolic syndrome (MetS).

Research Design and Methods: 15 SNPs 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 levels (systolic BP: 127±18 vs. 135±20 mmHg, p=0.0001), a lower BMI (24.6±3.6 vs. 26.9±4.1 kg/m², p=3.7*10^–7) and waist circumference (82±12 vs. 90±12, p=3.2*10^–8), lower HbA1c levels (5.1±0.7 vs. 5.3±0.9, p=0.0002) as well as a lower MetS factor score (–0.67±1.00 vs. 0.04±1.24, p=1.4*10^–7). Furthermore, the frequencies of arterial hypertension (23.7 vs. 46.4%, p=0.00001), obesity (12.9 vs. 30.8%, p=0.0003), diabetes (2.2 vs. 8.2%, p=0.041), and the presence of 3 MetS components (3.3 vs. 13.7%, p=0.002) were significantly lower than in subjects not carrying one of these protective haplotypes. Strong associations were also observed in the replication sample using the same haplotypes, but with effects in the opposite direction.

Conclusions: These data suggest that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and thus implicate lipin in the pathophysiology of the metabolic syndrome.

Correspondence: andrea.baessler{at}klinik.uni-regensburg.de

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