Abstract
Perilipin is a lipid droplet surface protein present in adipocytes and steroidogenic cells. We examined five common single nucleotide polymorphisms (SNPs) at the perilipin (PLIN) locus (PLIN 6209C>T, 10171A>T, 11482G>A, 13041A>G, and 14995A>T) to investigate their association with obesity risk. The study population included 4,131 subjects of three ethnic groups (Chinese, Malay, and Indian) from Singapore. The prevalence of obesity in Malays and Indians was much higher than in Chinese. Moreover, in these groups the prevalence of obesity was three times higher in women than in men. Crude analysis indicated that haplotype 11212 (CAAAT) is shared by Malays and Indians and is significantly associated with increased obesity risk as compared to the most common haplotype 21111 (TAGAA): OR 1.65 (95% CI 1.11–2.46) in Malays and 1.94 (95% CI 1.06–3.53) in Indians. No associations between PLIN haplotypes and obesity risk were found in Chinese. To simplify the haplotype analyses we used a subgroup of three SNPs (11482G>A, 13041A>G, and 14995A>T) in positive linkage disequilibrium. These analyses revealed similar associations, showing that haplotypes XX212 (XXAAT) and XX222 (XXAGT) are associated with increased obesity risk in Malays OR 2.04 (95% CI 1.28–3.25) and 2.05 (95% CI 1.35–3.12) respectively, and that haplotype XXX212 (XXAAT) is significantly associated with increased obesity risk in Indians OR 2.16 (95% CI 1.10–4.26) after adjusting for covariates including age, sex, smoking, alcohol consumption, exercise, and diabetes status. Moreover, individual SNP analyses demonstrated that the PLIN 14995A>T SNP is the most informative single genetic marker for the observed haplotype association, being significantly associated with increased obesity risk in both Malays OR 2.28 (95% CI 1.45–3.57) and Indians OR 2.04 (95% CI 1.08–3.64). These results support the role of the PLIN locus as an ethnically dependent modulator of obesity risk in humans.
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Abbreviations
- BMI :
-
Body mass index
- CI :
-
Confidence interval
- dNTP :
-
Deoxyribonucleoside triphosphate
- LD :
-
Linkage disequilibrium
- NHS 98 :
-
1998 Singapore National Health Survey
- OR :
-
Odds ratio
- PCR :
-
Polymerase chain reaction
- SNP :
-
Single nucleotide polymorphism
References
Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C (1991) Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem 266:11341–11346
Greenberg AS, Egan JJ, Wek SA, Moos Jr MC, Londos C, Kimmel AR (1993) Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes. Proc Natl Acad Sci U S A 90:12035–12039
Servetnick DA, Brasaemle DL, Gruia-Gray J, Servetnick DA, Schultz CJ, Levin DM, Kimmel AR (1995) Perilipins are associated with cholesteryl ester droplets in steroidogenic adrenal cortical and Leydig cells. J Biol Chem 270:16970–16973
Brasaemle DL, Rubin B, Harten IA, Gruia-Gray J, Kimmel A, Londos C (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J Biol Chem 275:38486–38493
Souza SC, de Vargas LM, Yamamoto MT Line P, Franciosa M, Moss L, Greenberg A (1998) Overexpression of perilipin A and B blocks the ability of tumor necrosis factor alpha to increase lipolysis in 3T3–L1 adipocytes. J Biol Chem 273:24665–24669
Martinez-Botas J, Anderson JB, Tessier D, Lapillojnne A, Hung-Junn Chang B, Quast M, Gorenstein D, Chen KH, Chan L (2000) Absence of perilipin results in leanness and reverses obesity in Lepr (db/db) mice. Nat Genet 26:474–479
Tansey JT, Sztalryd C, Gruia-Gray J, Roush D, Zeo J, Gavrilova O, Reitman M, Deng CX, Ki C, Kimmel A, Londos C (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc Natl Acad Sci U S A 98:6494–6499
Mottagui-Tabar S, Ryden M, Lofgren P, Faulds G, Hoffstedt J, Brookes AJ, Andersson I, Arner P (2003) Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia 46:789–797
Qi L, Corella D, Sorli JV, Portoles O, Shen H, Coltell O, Godoy D, Greenberg AS, Ordovas JM (2004) Genetic variation at the perlipin (PLIN) locus is associated with obesity-related phenotypes in White women. Clin Genet 66:299–310
Qi L, Shen H, Larson I, Schaefer EJ, Greenberg ES, Tregouet DA, Corella D, Ordovas JM (2004) Gender-specific association of a perilipin gene haplotype with obesity risk in a white population. Obes Res 12:1758–1765
Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H (2001) Genetic versus environmental aetiology of the metabolic syndrome among male and female twins. Diabetologia 44:537–543
Hughes K, Aw TC, Kuperan P (1997) Central obesity, insulin resistance, syndrome X, lipoprotein (a), and cardiovascular risk in Indians, Malays, and Chinese in Singapore. J Epidemiol Community Health 51:394–399
Cutter J, Tan BY, Chew SK (2001) Levels of cardiovascular disease risk factors in Singapore following a national intervention programme. Bull World Health Organ 79:908–915
Deurenberg-Yap M, Li T, Tan WL, van Staveren WA, Chew SK, Deurenberg P (2001) Can dietary factors explain differences in serum cholesterol profiles among different ethnic groups (Chinese, Malays and Indians) in Singapore? Asia Pac J Clin Nutr 10:39–45
Tregouet DA, Barbaux S, Escolano S, Tahri N, Golmard JL, Tiret L, Cambien F (2002) Specific haplotypes of the P-selectin gene are associated with myocardial infarction. Hum Mol Genet 11:2015–2023
Nishiu J, Tanaka T, Nakamura Y (1998) Isolation and chromosomal mapping of the human homolog of perilipin (PLIN), a rat adipose tissue-specific gene, by differential display method. Genomics 48:254–257
Sztalryd C, Xu G, Dorward H, Tansey J, Contreras J, Kimmel A, Londos C (2003) Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation. J Cell Biol 161:1093–1103
Chang CJ, Wu CH, Chang CS, Yao WJ, Yang YC, Wu JS, Lu FH (2003) Low body mass index but high percent body fat in Taiwanese subjects: implications of obesity cutoffs. Int J Obes Relat Metab Disord 27:253–259
WHO Expert Consultation (2004) Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363:157–163
Lu X, Gruia-Gray J, Copeland NG, Gilbert D, Jenkins N, Londos C, Kimmel A (2001) The murine perilipin gene: the lipid droplet-associated perilipins derive from tissue-specific, mRNA splice variants and define a gene family of ancient origin. Mamm Genome 12:741–749
Tansey JJ, Huml AM, Vogt R, Davis KE, Jones JM, Fraser KA, Brasaemle DL, Kimmel AR, Londos C (2003) Functional studies on native and mutated forms of perilipins: a role in protein kinase A-mediated lipolysis of triacylglycerols in CHO cells. J Biol Chem 278:8401–8406
Acknowledgements
This study was supported by grants from the United States Department of Agriculture, Foreign Agricultural Service, International Cooperation and Development, Research and Scientific Exchanges Division, Scientific Cooperation Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute grant HL-54776, contracts 53-K06-5-10 and 58-1950-9-001 from the United States Department of Agriculture Agricultural Research Service, National Medical Research Council of Singapore grant 0462/2000, and grants PR2004-0054 (to D.C.) from the Ministerio de Educación, Spain.
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Qi, L., Tai, E.S., Tan, C.E. et al. Intragenic linkage disequilibrium structure of the human perilipin gene (PLIN) and haplotype association with increased obesity risk in a multiethnic Asian population. J Mol Med 83, 448–456 (2005). https://doi.org/10.1007/s00109-004-0630-4
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DOI: https://doi.org/10.1007/s00109-004-0630-4