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

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LPIN2 Is Associated with Type 2 Diabetes, Glucose Metabolism and Body Composition Diabetes Publish Ahead of Print, published online September 5, 2007 LPIN2 is associated with type 2 diabetes, glucose metabolism and body composition Yurii S. Aulchenko,1,* Jan Pullen,2 Wigard P. Kloosterman,3 Mojgan Yazdanpanah,1 Albert Hofman,1 Norbert Vaessen,1 Pieter J. L. M. Snijders,1 Dmitry Zubakov,1 Ian Mackay,2,* Mark Olavesen,2 Balbinder Sidhu,2 Vicki E. Smith,2 Alisoun Carey,2 Eugene Berezikov,3 André G. Uittenlinden,4 Ronald H. A. Plasterk,3 Ben A. Oostra1, and Cornelia M. van Duijn1 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 *Present address: National Institute of Agricultural Botany, Cambridge CB3 0LE, UK *To whom correspondence should be addressed: Yurii S. Aulchenko Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, Postbus 2040, 3000 CA Rotterdam, The Netherlands e-mail: [email protected] Received for publication 11 March 2007 and accepted in revised form 26 August 2007. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2007 ABSTRACT 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. 2 The majority of type 2 diabetes (T2D) required upstream of PPARG for normal patients are obese and obesity by itself adipocyte differentiation (24). may be a cause of insulin resistance (1;2). We reported a genome-wide scan Not only total fat mass, but also fat using combined association and linkage distribution is an important determinant test in a sample of T2D patients derived of insulin resistance (3;4). Given the from a recently genetically isolated same degree of obesity, insulin sensitivity population from the Southwest of the varies largely depending on visceral Netherlands (25). Evidence for adipose tissue content (5;6). Abdominal association with T2D was found for one obesity measures and visceral fat content region at chromosome 18p11 (P=0.001 at may be better predictors of insulin marker D18S63). The locus at 18p was resistance when compared to body mass originally found to be linked to T2D in index (BMI) (see e.g. (7)). Also families from Finland and Southern abnormally decreased adipose tissue Sweden (26) and was confirmed in a mass, such as observed in lipodystrophy, second series derived from the Southwest leads to severe insulin resistance in of the Netherlands (27). In all three humans (8;9) and animal models (10-13). studies the effect of the 18p region was Several known genes for T2D are strongest in the obese sub-population. also implicated in lipodistrophy. One of the human homologues of Examples include peroxisome mouse Lpin1 gene, LPIN2, is located in proliferator-activated receptor gamma the 18p11 region. In this paper we (PPARG) (14), which plays a critical role examine the association between T2D in the differentiation of preadipocytes to and related traits and LPIN2 gene in three mature fat cells (15). A common 12Pro cohort. polymorphism in this gene is associated with increased risk of T2D in general RESEARCH DESIGN AND population (16;17) and rare deleterious METHODS variants lead to familial partial Study population lipodystrophy (9;18). Another example is Two series of patients and controls were the lamin A gene, which is implicated in studied. The first was derived from a rare Dunnigan-type familial partial young genetically isolated population lipodystrophy (8). This gene also plays a located in the Southwest of the role in T2D and related phenotypes (19- Netherlands. The characteristics of the 22). The LPIN1 gene was recently shown population regarding linkage to be associated with serum insulin levels disequilibrium (LD) and drift are and BMI in a Finnish population (23). described elsewhere (28-30). The original This gene appeared as a possible sample was formed by 79 small families candidate involved in human glucose (117 patients) which could be traced to a metabolism because it is one of the common ancestor within 13 generations. human homologues of mouse Lpin1 gene. The diagnosis of T2D was based on the Fdl mice, in which Lpin1 is deleted, have American Diabetes Association criteria diminished adipose tissue mass and (31). The details of the recruitment multiple pathologies including insulin procedure and analysis are described resistance, fatty liver and progressive elsewhere (25). The study protocol was neuropathy of peripheral nerves (11;13). approved by the medical ethics The protein encoded by Lpin1, Lipin, is committee of the Erasmus Medical 3 Centre, Rotterdam, and written consent 361 normoglycemic people, thus making was obtained from all participants. fasting glucose and insulin and postload In the present study, we used 78 glucose and insulin at 30 and 120 minutes patients, who were probands in our available. previous research, and were not or To study body fat distribution, we remotely (>10 meioses) related. The used data on 836 diabetes-free unrelated spouses of the T2D patients, individuals from the family-based together with the spouses of patients from Erasmus Rucphen Family (ERF) study. other ongoing studies, were used as The study protocol was approved by the controls (N=101). This schema justifies medical ethics board of Erasmus MC the use of the sample as independent Rotterdam. ERF consist of approximately cases and controls. 3,000 people, who are descendants of 22 There was no significant couples living in the second half of the differences in sex ratio or age between 19th century. patients and controls was observed (P>0.1). The BMI was significantly Measurements higher in patients (30.21) than in controls In the Rotterdam study, at baseline (27.53, P=0.03). examination, information concerning The second series was derived health status, and drug use was obtained from the Rotterdam Study. This is a large using a computerized questionnaire. cohort from outbred population, which is Height and weight were measured and aimed to study prevalence, incidence and BMI (kg/m2) was calculated. Blood determinants of chronic disease in the sampling and storage have been elderly (32). The medical ethics described elsewhere (34). Serum was committee of the Erasmus Medical separated by centrifugation and quickly Centre Rotterdam approved the study frozen in liquid nitrogen. Baseline protocol. Baseline examination, including measurements were performed on a detailed interview, physical nonfasting blood samples. Glucose levels examination, and blood sampling, were were measured by the glucose hexokinase conducted between 1990 and 1993. method in fasting serum and postload In the Rotterdam Study, 3506 serum samples (35). people were genotyped. Diagnosis of Glucose level was measured in T2D was made based on the use of anti- mmol/l and insulin in mU/l. As indicator diabetic medication or random glucose of insulin resistance we used HOMA-IR, level > 11.1 mmol/l, according to the as suggested by Matthews (36): previous work of Rietveld and colleagues HOMA-IR=FGLxFIL/22.5 (33). Of the investigated group, 616 were As indicator of insulin sensitivity, affected. The effect of sex was not which uses the data from the oral glucose significant. T2D people were on average tolerance test (OGTT), we used the index older (73.46 y.o. vs. 68.09 in controls, suggested by Matsuda (37): P<0.001), had higher BMI (26.76 kg/m2 ISI=10000/square_root(FGLxFILxMEA vs. 26.14 in controls, P<0.01), and WHR N_GL_IN_OGTTxMEAN_IL_IN_OGT (0.93 in cases and 0.90 in controls, T) P<0.001). In the ERF study, anthropometric Within the Rotterdam Study, oral measurements and total-body imaging glucose tolerance test was performed for (using dual-energy X-ray absorptiometry, 4 DEXA) were done with participants in denatured in 0.5M NaOH. DNA bound their underwear and without shoes. Using to the Dynabeads was transferred soft tape, with the subject in standing between solutions using the magnetic position, waist circumference was PSQ Sample Tool (Biotage, Uppsala, measured midway between the lower Sweden). After washing to remove costal margin and the iliac crest, while excess NaOH, the single-stranded hip circumference was taken at the hip’s template was hybridised to 15 nmol widest diameter.
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