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Evaluating the Role of LPIN1 Variation on Insulin Resistance, Body Weight and Human Lipodystrophy in UK Populations

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Evaluating the Role of LPIN1 Variation on Insulin Resistance, Body Weight and Human Lipodystrophy in UK Populations Diabetes Publish Ahead of Print, published online June 30, 2008 Evaluating the role of LPIN1 variation on insulin resistance, body weight and human lipodystrophy in UK populations Katherine A. Fawcett BSc1, Neil Grimsey BSc2, Ruth J.F. Loos PhD3, Eleanor Wheeler PhD1, Allan Daly BSc1, Maria Soos PhD4, Robert Semple MD PhD4, Holly Syddall MSc5, Cyrus Cooper DM5, Symeon Siniossoglou PhD2, Stephen O’Rahilly MD4, Nicholas J. Wareham PhD3, Inês Barroso PhD1 1Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK 2Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council (MRC) Building, Hills Road, Cambridge CB2 2XY, UK 3MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK 4Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK 5MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK Inês Barroso Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA E-mail: [email protected] Received 27 March 2008 and accepted 17 June 2008. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org This is an uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association, publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2008 LPIN1, insulin resistance and adiposity OBJECTIVE: Loss of Lpin1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of LPIN1 common variation on adiposity and insulin sensitivity in UK populations, and to examine the role of LPIN1 mutations in insulin resistance syndromes. RESEARCH DESIGN AND METHOD: Twenty-two SNPs tagging LPIN1 common variation were genotyped in MRC Ely (N = 1709) and Hertfordshire (N = 2901) population-based cohorts. LPIN1 exons, exon/intron boundaries and 3’UTR were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients), and 48 controls. RESULTS: We found no association between LPIN1 SNPs and fasting insulin, but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K and G582R) were detected in severely insulin resistant patients. However, these did not co-segregate with disease in affected families and Lipin1 protein expression and phosphorylation in patients with variants was indistinguishable from controls. CONCLUSIONS: Our data do not support a major effect of LPIN1 common variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in UK cohorts require replication in larger cohorts. 2 LPIN1, insulin resistance and adiposity ipin 1, a multi-functional protein associated with BMI in a Finnish obesity highly expressed in mouse and human case-control and in the Quebec Family Study L adipose tissue, has been shown to (12; 14) but not in a German population-based influence adipose tissue development and cohort (the MONICA study) (13). Moreover, function. Null mutations in the murine lipin 1 LPIN1 haplotypes were strongly associated gene (Lpin1) result in impaired adipocyte with traits underlying metabolic syndrome in differentiation leading to a severe reduction in the MONICA study but these haplotypes adipose tissue mass, insulin resistance, and often had the opposite effect on the same progressive peripheral neuropathy in the fld traits in a replication cohort (13). This and fld2J mouse models (1). In contrast, inconsistency suggests that further studies are transgenic mice with adipose tissue-specific needed to clarify the role of LPIN1 variation overexpression of Lpin1 exhibit diet-induced on human metabolic traits. In this study we obesity and enhanced insulin sensitivity have taken complementary approaches to compared to wild-type littermates (2). In study the role of LPIN1 variation in human humans, LPIN1 expression in adipose tissue metabolic traits in UK populations: appears to be inversely correlated with measures of adiposity such as Body Mass a. We genotyped 22 SNPs that tag Index (BMI), and positively correlated with common LPIN1 variation (Minor Allele insulin sensitivity (3-6). Frequency (MAF) >0.01) in two white UK population-based cohorts (N = 4610) and The mechanism through which lipin 1 tested for association with fasting serum influences adiposity and insulin sensitivity in insulin levels, BMI, and a number of mice and humans is not entirely known. additional metabolic traits with previously However, recent data indicates that lipin 1 is a reported association with LPIN1. magnesium-dependent phospatidate phosphatase responsible for catalysing the b. We sequenced LPIN1 in a cohort of penultimate step in triacylglyceride synthesis, patients with syndromes of severe insulin explaining why Lpin1 deficient fld mice resistance (N=135) and lipodystrophy (N=23) cannot accumulate fat in mature adipocytes to identify potentially pathogenic mutations. (7). Lipin 1 is also thought to regulate RESEARCH DESIGN AND METHODS transcription of genes involved in adipocyte differentiation (PPARγ, C/EBPα), fat Definition of cohorts synthesis and storage (DGAT, ACC-1, PEPCK, FAS, SCD1), and fatty acid oxidation ELY Cohort. The Medical Research Council (CPT-1, AOX, PPARα) (2; 6-10). (MRC) Ely Study is a population-based cohort study of the aetiology and There has only been one study pathogenesis of type 2 diabetes and related sequencing LPIN1 in lipodystrophic patients metabolic disorders in the UK (15). It (N=15), with no pathogenic mutation being comprises white men and women aged 35-79 reported (11). Furthermore, although a years without diagnosed diabetes. number of studies have evaluated the role of Measurements of anthropometric and common variation in LPIN1 and metabolic metabolic data analysed in this study have quantitative phenotypes (12-14), the results been described previously (16). Informed have been inconsistent across studies, and consent was obtained from all participants sometimes within the same study. For and ethical approval for the study was granted example, rs2716610 and a SNP in high by the Cambridge Local Research Ethics linkage disequilibrium, rs2716609, were Committee. 3 LPIN1, insulin resistance and adiposity Hertfordshire Cohort. The Hertfordshire informed consent with approval of the local Cohort Study was recruited from the cohort of research ethics committee in Cambridge, U.K. people born in Hertfordshire between 1931 and 1939. The cohort details and Selection of SNPs to tag LPIN1 common measurements of metabolic traits analysed in variation. TagSNPs were selected to cover this study have been described previously variation with MAF greater than 1% present (17). in LPIN1 and its flanking 4 kb regions (Chromosome 2, coordinates 11800212- EPIC-Obesity Study. The EPIC-Obesity 11889941 (NCBI B36 assembly)). The study is nested within the EPIC-Norfolk International HapMap (Rel 20, PhaseII) study, a population based cohort study of reports 61 SNPs for CEU samples in this 25663 white European men and women aged chromosomal region, while we identified 5 39-79 recruited in Norfolk, UK between 1993 novel SNPs during resequencing of 48 CEPH and 1997 (18). Height and weight were individuals (Supplementary Table 1). measured using standard anthropometric Twenty-five tagSNPs were selected to cover techniques (18). All samples were genotyped all 66 novel and known HapMap using the Affymetrix GeneChip Human polymorphisms with a pairwise r2 ≥ 0.8 using Mapping 500K Array Set that contained Tagger (21) as a stand-alone program in genotype information for 5 of our LPIN1 Haploview (22) (Supplementary Figure 1). tagSNPs, each of which had a call rate >90%. Twenty-two of these tagSNPs passed assay In total, 2415 individuals with height and design and pre-screening (Supplementary weight measures and quality-controlled Table 2). The three failed SNPs tagged only genotype data were available for analyses. five intronic SNPs. We calculated that we have >80% power to detect a per allele effect HGDP-CEPH. The HGDP-CEPH Human on BMI of >1.33 kg/m2 with MAF=0.01, and Genome Diversity Cell Line Panel is a >0.27kg/m2 with MAF=0.5. For logged resource of 1064 DNA samples from fasting insulin data this range is >1.04 to individuals distributed around the world and >1.22. has been described previously (19). Genotyping. Genotyping was performed by CEPH. 48 unrelated individuals from CEPH the genotyping facility within the Genetics of families supplied by Coriell Cell Repositories Complex Traits in Humans team at the (20) are control individuals of North and West Wellcome Trust Sanger Institute. LPIN1 European origin. mutations A353T, R552K, and G582R were genotyped on the CEPH human diversity Severe Insulin Resistance Cohort. All
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