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LPIN2 Is Associated With Type 2 Diabetes, Glucose Metabolism, and Body Composition

¹ Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Clinical Genetics, and Forensic Molecular Biology, Erasmus Medical Centre, Rotterdam, the Netherlands
² Oxagen, Abingdon, Oxfordshire, U.K
³ Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, the Netherlands
⁴ Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands

Address correspondence and reprint requests to Yurii S. Aulchenko, Department of Epidemiology and Biostatistics, Erasmus Medical Centre Rotterdam, Postbus 2040, 3000 CA Rotterdam, Netherlands. E-mail: i.aoultchenko{at}erasmusmc.nl

Abbreviations: DEXA, dual-energy X-ray absorptiometry; ERF, Erasmus Rucphen Family; ISI, insulin sensitivity index; OGTT, oral glucose tolerance test; PPAR, peroxisome proliferator–activated receptor; SNP, single nucleotide polymorphism; UTR, untranslated region; WHR, waist-to-hip ratio

OBJECTIVE—To identify the type 2 diabetes gene located at 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 case subjects and 101 control subjects. Two SNPs were selected and followed up in two cohorts. The first cohort came from a general Dutch population. In this cohort, association with type 2 diabetes was investigated using 616 type 2 diabetic case subjects and 2,890 control subjects; 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 type 2 diabetes (odds ratio 2.01, P = 0.03). This SNP is located at the 3' untranslated region of the LPIN2 gene, which is a plausible candidate for type 2 diabetes and obesity. In the cohort from the general Dutch population, we demonstrated that rs3745012 interacts with BMI in determination of type 2 diabetes: whereas in subjects with high BMI, the common C allele is associated with type 2 diabetes, the same allele exhibits a 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 for overall effect, P = 0.004 for interaction). In the second replication cohort, we found that the 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 type 2 diabetes and fat distribution.

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				K. Reue and J. Donkor Genetic Factors in Type 2 Diabetes: All in the (Lipin) Family Diabetes, December 1, 2007; 56(12): 2842 - 2843. [Full Text] [PDF]