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Published online October 16, 2007
Diabetes 57:209-217, 2008
DOI: 10.2337/db07-0083
© 2008 by the American Diabetes Association
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Genetic Variants Within the LPIN1 Gene, Encoding Lipin, Are Influencing Phenotypes of the Metabolic Syndrome in Humans

Silke Wiedmann1, Marcus Fischer1, Martina Koehler1, Katharina Neureuther1, Guenter Riegger1, Angela Doering2, Heribert Schunkert3, Christian Hengstenberg1, and Andrea Baessler1

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

Address correspondence and reprint requests to Andrea Baessler, MD, or Christian Hengstenberg, MD, Clinic for Internal Medicine 2, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. E-mail: andrea.baessler{at}klinik.uni-regensburg.de; or christian.hengstenberg{at}klinik.uni-regensburg.de

Key Words: LD, linkage disequilibrium • MI, myocardial infarction • MONICA, Monitoring Trends and Determinants on Cardiovascular Diseases • SNP, single nucleotide polymorphism

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.

RESEARCH DESIGN AND METHODS— A total of 15 single nucleotide polymorphisms (SNPs) covering the LPIN1 gene region were genotyped in an age- and sex-stratified sample of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Study Augsburg; DNA and phenotypes of 1,416 Caucasians). Ten SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The metabolic syndrome 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 metabolic syndrome (odds ratio 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 blood pressure 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 x 10–7) and waist circumference (82 ± 12 vs. 90 ± 12 cm; P = 3.2 x 10–8), lower A1C levels (5.1 ± 0.7 vs. 5.3 ± 0.9%; P = 0.0002), as well as a lower metabolic syndrome factor score (–0.67 ± 1.00 vs. 0.04 ± 1.24; P = 1.4 x 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 three or more metabolic syndrome 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.


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