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Evaluating the Role of LPIN1 Variation in Insulin Resistance, Body Weight, and Human Lipodystrophy in U.K

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Evaluating the Role of LPIN1 Variation in Insulin Resistance, Body Weight, and Human Lipodystrophy in U.K ORIGINAL ARTICLE Evaluating the Role of LPIN1 Variation in Insulin Resistance, Body Weight, and Human Lipodystrophy in U.K. Populations Katherine A. Fawcett,1 Neil Grimsey,2 Ruth J.F. Loos,3 Eleanor Wheeler,1 Allan Daly,1 Maria Soos,4 Robert Semple,4 Holly Syddall,5 Cyrus Cooper,5 Symeon Siniossoglou,2 Stephen O’Rahilly,4 Nicholas J. Wareham,3 and Ineˆs Barroso1 OBJECTIVE—Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence ipin 1, a multifunctional protein highly expressed adiposity and insulin sensitivity in humans. We aimed to conduct in mouse and human adipose tissue, has been a comprehensive association study to clarify the influence of shown to influence adipose tissue development common LPIN1 variation on adiposity and insulin sensitivity in Land function. Null mutations in the murine lipin 1 U.K. populations and to examine the role of LPIN1 mutations in gene (Lpin1) result in impaired adipocyte differentiation insulin resistance syndromes. leading to a severe reduction in adipose tissue mass, RESEARCH DESIGN AND METHOD—Twenty-two single nu- insulin resistance, and progressive peripheral neuropathy 2J cleotide polymorphisms tagging common LPIN1 variation were in the fld and fld mouse models (1). In contrast, trans- genotyped in Medical Research Council (MRC) Ely (n ϭ 1,709) genic mice with adipose tissue–specific overexpression of and Hertfordshire (n ϭ 2,901) population-based cohorts. LPIN1 Lpin1 exhibit diet-induced obesity and enhanced insulin exons, exon/intron boundaries, and 3Ј untranslated region were sensitivity compared with those seen in wild-type litter- sequenced in 158 patients with idiopathic severe insulin resis- mates (2). In humans, LPIN1 expression in adipose tissue tance (including 23 lipodystrophic patients) and 48 control appears to be inversely correlated with measures of adi- subjects. posity such as BMI and positively correlated with insulin RESULTS—We found no association between LPIN1 single sensitivity (3–6). nucleotide polymorphisms and fasting insulin but report a nom- The mechanism through which lipin 1 influences adipos- inal association between rs13412852 and BMI (P ϭ 0.042) in a ity and insulin sensitivity in mice and humans is not meta-analysis of 8,504 samples from in-house and publicly avail- entirely known. However, recent data indicate that lipin 1 able studies. Three rare nonsynonymous variants (A353T, R552K, is a magnesium-dependent phospatidate phosphatase re- and G582R) were detected in severely insulin-resistant patients. sponsible for catalyzing the penultimate step in triacyl- However, these did not cosegregate with disease in affected glyceride synthesis, explaining why Lpin1-deficient fld families, and Lipin1 protein expression and phosphorylation in mice cannot accumulate fat in mature adipocytes (7). patients with variants were indistinguishable from those in Lipin 1 is also thought to regulate transcription of genes control subjects. involved in adipocyte differentiation (PPAR␥ and CONCLUSIONS—Our data do not support a major effect of C/EBP␣), fat synthesis and storage (DGAT, ACC-1, common LPIN1 variation on metabolic traits and suggest that PEPCK, FAS, and SCD1), and fatty acid oxidation mutations in LPIN1 are not a common cause of lipodystrophy in (CPT-1, AOX, and PPAR␣) (2,6–10). humans. The nominal associations with BMI and other metabolic There has only been one study sequencing LPIN1 in traits in U.K. cohorts require replication in larger cohorts. lipodystrophic patients (n ϭ 15), with no pathogenic Diabetes 57:2527–2533, 2008 mutation reported (11). Furthermore, although a number of studies have evaluated the role of common variation in LPIN1 and metabolic quantitative phenotypes (12–14), the results have been inconsistent across studies and some- times within the same study. For example, rs2716610 and From the 1Metabolic Disease Group, Wellcome Trust Sanger Institute, Well- come Trust Genome Campus, Hinxton, Cambridgeshire, U.K.; the 2Cam- a SNP in high linkage disequilibrium, rs2716609, were bridge Institute for Medical Research, University of Cambridge, Wellcome associated with BMI in a Finnish obesity case-control Trust, Cambridge, U.K.; the 3Medical Research Council Epidemiology Unit, study and in the Quebec Family Study (12,14) but not in a Institute of Metabolic Science, Cambridge, U.K.; the 4Department of Clinical Biochemistry, Addenbrooke’s Hospital, University of Cambridge, Cam- German population-based cohort (the the MONItoring of bridge, U.K.; and the 5Medical Research Council Epidemiology Resource trends and determinants in CArdiovascular disease Centre, University of Southampton, Southampton, U.K. [MONICA] study) (13). Moreover, LPIN1 haplotypes were Corresponding author: Ineˆs Barroso, [email protected]. Received 27 March 2008 and accepted 17 June 2008. strongly associated with traits underlying the metabolic Published ahead of print at http://diabetes.diabetesjournals.org on 30 June syndrome in the MONICA study, but these haplotypes 2008. DOI: 10.2337/db08-0422. often had the opposite effect on the same traits in a © 2008 by the American Diabetes Association. Readers may use this article as replication cohort (13). This inconsistency suggests that long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by further studies are needed to clarify the role of LPIN1 -nc-nd/3.0/ for details. variation on human metabolic traits. In this study, we have The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance taken complementary approaches to study the role of with 18 U.S.C. Section 1734 solely to indicate this fact. LPIN1 variation in human metabolic traits in U.K. popu- DIABETES, VOL. 57, SEPTEMBER 2008 2527 LPIN1, INSULIN RESISTANCE, AND ADIPOSITY TABLE 1 Mean fasting insulin levels and mean BMI of study participants by LPIN1 tagSNP genotype in the MRC Ely cohort and the Hertfordshire cohort studies Ely Insulin (pmol/l) BMI (kg/m2) SNP 012P 012P rs893346 49.18 Ϯ 1.02 47.65 Ϯ 1.05 57.57 Ϯ 1.08 0.609 27.23 Ϯ 0.13 27.5 Ϯ 0.39 26.3 Ϯ 1.7 0.303 rs4669778 49.99 Ϯ 1.03 48.88 Ϯ 1.02 47.23 Ϯ 1.03 0.216 27.42 Ϯ 0.24 27.41 Ϯ 0.16 27.11 Ϯ 0.27 0.109 rs893345 48.17 Ϯ 1.03 48.69 Ϯ 1.02 49.76 Ϯ 1.03 0.424 27.27 Ϯ 0.28 27.75 Ϯ 0.32 25.87 Ϯ 1.57 0.967 rs7595221 47.75 Ϯ 1.03 50.08 Ϯ 1.02 48.59 Ϯ 1.04 0.55 27.11 Ϯ 0.22 26.99 Ϯ 0.24 26.09 Ϯ 0.92 0.815 Novel1 48.46 Ϯ 1.02 49.79 Ϯ 1.03 49.67 Ϯ 1.08 0.409 27.15 Ϯ 0.15 27.49 Ϯ 0.21 27.01 Ϯ 0.64 0.393 rs16857866 49.1 Ϯ 1.01 53.35 Ϯ 1.08 47.7 Ϯ 0 0.398 27.23 Ϯ 0.12 28.02 Ϯ 0.64 29.65 Ϯ 0 0.215 rs13412852 50.18 Ϯ 1.02 48.63 Ϯ 1.02 45.1 Ϯ 1.05 0.042 27.42 Ϯ 0.18 27.36 Ϯ 0.18 26.44 Ϯ 0.35 0.054 rs2278513 47.41 Ϯ 1.03 49.45 Ϯ 1.02 48.82 Ϯ 1.04 0.37 27.06 Ϯ 0.22 27.28 Ϯ 0.16 27.45 Ϯ 0.26 0.467 rs3795974 48.59 Ϯ 1.02 49.57 Ϯ 1.02 49.93 Ϯ 1.04 0.441 27.21 Ϯ 0.19 27.76 Ϯ 0.96 27.86 Ϯ 3.19 0.844 rs33997857 48.95 Ϯ 1.01 46.11 Ϯ 1.1 56.18 Ϯ 1.9 0.627 27.24 Ϯ 0.12 27.7 Ϯ 0.67 28.76 Ϯ 0.57 0.401 rs17603350 48.99 Ϯ 1.02 47.89 Ϯ 1.05 99.5 Ϯ 1.37 0.986 27.34 Ϯ 0.13 26.3 Ϯ 0.36 27.52 Ϯ 1.28 0.031 rs17603420 50.63 Ϯ 1.03 47.75 Ϯ 1.02 49.14 Ϯ 1.03 0.271 27.33 Ϯ 0.2 27.39 Ϯ 0.18 26.9 Ϯ 0.25 0.269 rs6729430 48.95 Ϯ 1.02 45.77 Ϯ 1.1 49.99 Ϯ 1.47 0.61 27.24 Ϯ 0.12 27.39 Ϯ 0.34 29.79 Ϯ 1.28 0.508 rs2577264 48.61 Ϯ 1.02 48.91 Ϯ 1.02 50.6 Ϯ 1.04 0.368 27.19 Ϯ 0.2 27.37 Ϯ 0.18 27.21 Ϯ 0.3 0.733 rs2577262 49.25 Ϯ 1.02 48.96 Ϯ 1.02 48.72 Ϯ 1.05 0.639 27.24 Ϯ 0.17 27.61 Ϯ 0.28 27.99 Ϯ 0.86 0.857 rs2577261 49.52 Ϯ 1.02 46.67 Ϯ 1.03 48.09 Ϯ 1.12 0.15 27.18 Ϯ 0.12 27.38 Ϯ 0.18 27.23 Ϯ 0.3 0.256 rs4669781 48.91 Ϯ 1.02 49.56 Ϯ 1.04 43.59 Ϯ 1.21 0.844 27.22 Ϯ 0.12 27.19 Ϯ 0.18 27.25 Ϯ 0.29 0.780 rs2716609 48.99 Ϯ 1.02 48.25 Ϯ 1.05 44.85 Ϯ 1.2 0.61 27.13 Ϯ 0.15 27.34 Ϯ 0.17 26.82 Ϯ 0.24 0.073 Novel2 48.11 Ϯ 1.02 50.44 Ϯ 1.04 52.4 Ϯ 1.17 0.117 27.25 Ϯ 0.12 27.25 Ϯ 1.26 0 Ϯ 0 0.987 rs1050800 49.01 Ϯ 1.01 47.15 Ϯ 1.19 0 Ϯ 0 0.728 27.21 Ϯ 0.14 27.34 Ϯ 0.23 26.55 Ϯ 0.62 0.993 rs2577256 48.81 Ϯ 1.02 49.32 Ϯ 1.03 49.09 Ϯ 1.09 0.862 27.02 Ϯ 0.24 27.41 Ϯ 0.19 26.94 Ϯ 0.38 0.208 Data are means Ϯ SE.
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