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LPIN2 is associated with type 2 diabetes, glucose metabolism and body composition

¹Genetic Epidemiology Unit, Department of Epidemiology & Biostatistics, Clinical Genetics, and Forensic Molecular Biology, Erasmus MC Rotterdam, 3000 CA, The Netherlands,
²Oxagen Limited, Abingdon, Oxfordshire, OX14 4RY, United Kingdom,
³Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands and
⁴Department of Internal Medicine, Erasmus MC Rotterdam, 3000 CA, The Netherlands

Objective: To identify type 2 diabetes (T2D) gene located at the chromosome 18p11.

Research design and methods: We investigated the region in a young genetically isolated population by genotyping 34 single-nucleotide polymorphisms (SNPs) in 78 cases and 101 controls. Two SNPs were selected and followed up in two cohorts. The first cohort came from general Dutch population. In this cohort, association with T2D was investigated using 616 T2D cases and 2890 controls; association with oral glucose tolerance test data was performed in 361 normoglycemic people. Association with fat distribution was studied in the second replication cohort, consisting of 836 people from the genetically isolated population.

Results: At the initial step, we found that the common C allele of SNP rs3745012 was associated with T2D (OR=2.01, P=0.03). This SNP is located at 3' UTR region of LPIN2 gene, which is a plausible candidate for T2D and obesity. In the cohort from the general Dutch population, we demonstrated that rs3745012 interacts with body mass index in determination of T2D: while in subjects with high BMI the common C allele is associated with T2D, the same allele exhibits neutral or protective effect in lean subjects (P=0.05 overall effect, P=0.02 interaction). Most remarkably, rs3745012 strongly affected composite insulin sensitivity index (P=0.006 overall effect, P=0.004 interaction). In the second replication cohort, we found that allele C of rs3745012 increases trunk to legs fat mass ratio (P=0.001) and may affect other fat-related measurements.

Conclusions: rs3745012 SNP of the LPIN2 gene is associated with T2D and fat distribution.

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