ABSTRACT METHODS: We analyzed data pooled from nine studies on the human leptin receptor (_LEPR_) gene for the association of three alleles (_K109R_, _Q223R_ and _K656N_) of _LEPR_ with body

mass index (BMI; kg/m2) and waist circumference (WC). A total of 3263 related and unrelated subjects from diverse ethnic backgrounds including African-American, Caucasian, Danish, Finnish,

French Canadian and Nigerian were studied. We tested effects of individual alleles, joint effects of alleles at multiple loci, epistatic effects among alleles at different loci, effect

modification by age, sex, diabetes and ethnicity, and pleiotropic genotype effects on BMI and WC. RESULTS: We found that none of the effects were significant at the 0.05 level. Heterogeneity

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SYSTEMATIC REVIEW AND META-ANALYSIS Article 01 April 2025 REFERENCES * Chua S, Leibel RL . Obesity genes: molecular and metabolic mechanisms _Diabetes Rev_ 1997 5: 2–7. Google Scholar  *

Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, Sothern M, Udall JN, Kahle B, Leibel RL . Exonic and intronic variation in the leptin receptor (_OBR_) of obese humans _Diabetes_

1997 46: 1509–1511. Article  CAS  PubMed  Google Scholar  * Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homolog

_Nature_ 1994 372: 425–432. Article  CAS  PubMed  Google Scholar  * Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A,

Bougneres P, Lebouc Y, Froguel P, Guy-Grand B . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction _Nature_ 1998 392: 398–401. Article  CAS  PubMed  Google

Scholar  * Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF . The hypothalamic leptin receptor in humans, identification of incidental sequence polymorphisms and absence of the

_db_/_db_ mouse and _fa_/_fa_ rat mutations _Diabetes_ 1996 19: 992–994. Article  Google Scholar  * Norman RA, Leibel RL, Chung WK, Power-Kehoe L, Chua SC, Knowler WC, Thompson DB, Bogardus

C, Ravussin E . Absence of linkage of obesity and energy metabolism to markers flanking homologues of rodent obesity genes in Pima Indians _Diabetes_ 1996 45: 1229–1232. Article  CAS  PubMed

  Google Scholar  * Echwald SM, Sorensen TD, Sorensen TI, Tybaerg-Hansen A, Andersen T, Chung WK, Leibel RL, Pedersen O . Amino acid Variants in the human leptin receptor: lack of

association to juvenile onset obesity _Biochem Biophys Res Commun_ 1997 233: 248–252. Article  CAS  PubMed  Google Scholar  * Francke S, Clement K, Dina C, Inoue H, Behn P, Vatin V,

Basdevant A, Guy-Grand B, Permutt MA, Froguel P, Hager J . Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families _Hum Genet_ 1997 100: 491–496. Article  CAS

  PubMed  Google Scholar  * Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeigue PM, Scott J, Aitman TJ . Leptin Receptor Gene variation and obesity: lack of

association in a white British male population _Hum Mol Genet_ 1997 6: 869–876. Article  CAS  PubMed  Google Scholar  * Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T,

Azuma N, Natsui K, Nishimura H, Yoshimasa Y, Nishi N, Thompson DB, Nakao K . Human leptin receptor gene in obese Japanese subjects: evidence against either obesity causing mutations or

association of seauence variants with obesity _Diabetologia_ 1997 40: 1204–1210. Article  CAS  PubMed  Google Scholar  * Silver K, Walston J, Chung WK, Yao F, Parikh VV, Andersen RE, Cheskin

LJ, Elahi D, Muller D, Leibel RL, Shuldiner AR . The Gln223Arg and Lys656Asn Polymorohisms in the human leptin receptor do not associate with traits related to obesity _Diabetes_ 1997 46:

1898–1900. Article  CAS  PubMed  Google Scholar  * Hasstedt SJ, Hoffman M, Leppert MF, Elbein SC . Recessive inheritance of obesity in familial non-insulin-dependent diabetes mellitus, and

lack of linkage to nine candidate genes _Am J Hum Genet_ 1997 61: 668–677. Article  CAS  PubMed  PubMed Central  Google Scholar  * Thompson DB, Ravussin E, Bennet PH, Bogardus C . Structure

and sequence variation at the human leptin receptor gene in lean and obese Pima Indians _Hum Mol Genet_ 1997 6: 675–679. Article  CAS  PubMed  Google Scholar  * Oksanen L, Kaprio J,

Mustajoki P, Kontula K . A common pentanucleotide polymorphism of the 3′-untranslated part of the leptin receptor gene generates a putative stem-loop motif in the mRNA and is associated with

serum insulin levels in obese individuals _Int J Obes Relat Metab Disord_ 1998 22: 634–640. Article  CAS  PubMed  Google Scholar  * Rolland V, Clement K, Dugail I, Guy-Grand B, Basdevant A,

Froguel P, Lavau M . Leptin receptor gene in a large cohort of massively obese subjects: no indication of the _fa_/_fa_ rat mutation. Detection of an intronic variant with no association

with obesity _Obes Res_ 1998 6: 122–127. Article  CAS  PubMed  Google Scholar  * Norman RA, Tataranni PA, Pratley R, Thompson DB, Hanson RL, Prochazka M, Baier L, Ehm MG, Sakul H, Foroud T,

Garvey WT, Burns D, Knowler WC, Bennet PH, Bogardus C, Ravussin E . Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians _Am J Hum Genet_ 1998 62: 659–668.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Roth H, Korn T, Rosenkranz K, Hinney A, Ziegler A, Kunz J, Siegfried W, Mayer H, Hebebrand J, Grzeschik K . Transmission

disequilibrium and sequence variants at the leptin receptor gene in extremely obese German children and adolescents _Hum Genet_ 1998 103: 540–546. Article  CAS  PubMed  Google Scholar  *

Chagnon YC, Chung WK, Perusse L, Chagnon M, Leibel RL, Bouchard C . Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Quebec Family Study

_Int J Obes Relat Metab Disord_ 1999 23: 278–286. Article  CAS  PubMed  Google Scholar  * De Silva AM, Walder KR, Aitman TJ, Gotoda T, Goldstone AP, Hodge AM, De Courten MP, Zimmet PZ,

Collier GR . Combination of Polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males _Int J Obes Relat Metab Disord_ 1999 23: 816–822. Article  CAS  PubMed 

Google Scholar  * Bray MS, Boerwinkle E, Hanis CL . Linkage analysis of candidate obesity genes among the Mexican-American population of Starr County, Texas _Genet Epidemiol_ 1999 16:

397–411. Article  CAS  PubMed  Google Scholar  * Chagnon YC, Wilmore JH, Borecki IB, Gagnon J, Perusse L, Chagnon M, Collier GR, Leon AS, Skinner JS, Rao DC, Bouchard C . Associations

between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE Family study _J Clin Endocrinol Metab_ 2000 85: 29–34. CAS  PubMed  Google Scholar  * Endo K,

Yanagi H, Hirano C, Hamaguchi H, Tsuchiya S, Tomura S . Association of Trp64Arg polymorphism of the beta-3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin

receptor gene in Japanese schoolchildren with obesity _Int J Obes Relat Metab Disord_ 2000 24: 443–449. Article  CAS  PubMed  Google Scholar  * Del Giudice EM, Perrone L, Forabosco P,

Devoto M, Carbone MT, Calabro C, Ditoro R . Linkage study of early-onset obesity to leptin receptor gene in Italian children _Nutr Res_ 2000 20: 1059–1063. Article  CAS  Google Scholar  *

van der Kallen CJ, Cantor RM, van Greevenbroek MM, geurts JM, Bouwman FG, Aouizerat BE, Allayee H, Buurman WA, Lusis AJ, Rotter JI, de Bruin TW . Genome scan for adiposity in Dutch

dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A _Int J Obes Relat Metab Disord_ 2000 24:

1381–1391. Article  CAS  PubMed  Google Scholar  * Draper D, Graver DP, Goel PK, Greenhouse JB, Hedges LV, Morris CN, Tucker JR, Watenaux CM . _Combining information: statistical issues and

opportunities for research_ National Academy Press: Washington, DC 1992. Google Scholar  * Rosenthal R . Meta-analytic procedures for social research Sage: Newbury Park, CA 1991. * Allison

DB, Faith M . Publication bias in obesity treatment trials? _Int J Obes Relat Metab Disord_ 1996 20: 931–937. CAS  PubMed  Google Scholar  * Heo M, Leibel RL, Boyer BB, Chung WK, Koulu M,

Karvonen MK, Pesonen U, Rissanen A, Laakso M, Uusitupa MIJ, Chagnon Y, Bouchard C, Donohoue PA, Burns TL, Shuldiner AR, Silver K, Andersen RE, Pedersen O, Echwald S, Sorensen TIA, Behn P,

Permutt MA, Jacobs KB, Elston RC, Hoffman DJ, Allison DB . Pooling analysis of genetic data: the association of leptin receptor (_LEPR_) polymorphisms with variables related to human

adiposity _Genetics_ 2001 159: 1163–1178. CAS  PubMed  PubMed Central  Google Scholar  * Allison DB, Heo M, Kaplan N, Martin ER . Development of Sibling-based Tests of Linkage in the

Presence of association for quantitative traits that do not require parental information _Am J Hum Genet_ 1999 64: 1754–1764. Article  CAS  PubMed  PubMed Central  Google Scholar  * Elston

RC, Buxbaum S, Jacobs KB, Olson JM . Haseman and Elston revisited _Genet Epidemiol_ 2000 19: 1–17. Article  CAS  PubMed  Google Scholar  * Rubin DB . Multiple imputations in sample surveys—a

phenomenological Bayesian approach to nonresponses In _Proceedings of the survey research methods section_ American Statistical Association 1978 pp 20–34. Google Scholar  * _S.A.G.E.

Statistical analysis for genetic epidemiology, release 3.1_ Computer program package available from the Department of Epidemiology and Biostatistics, Rammelkamp Center for Education and

Research, MetroHealth Campus, Case Western University, Cleveland 1997. * Hedges LV, Olkin I . _Statistical methods for meta-analysis_ Academic Press: New York 1985. Google Scholar  * Begg

CB, Mazumdar M . Operating characteristics of a rank correlation test for publication bias _Biometrics_ 1994 50: 1088–1101. Article  CAS  PubMed  Google Scholar  * Lynch M, Walsh B .

_Genetics and analysis of quantitative traits_ Sinauer Associates: Sunderland, MA 1985. Google Scholar  * Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH,

Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E,

Hanis CL, Bell GI . Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus _Nature Genet_ 2000 26: 163–175. Article  CAS  PubMed  Google Scholar  *

Tanizawa YA, Riggs C, Dagog-Jack S . Isolation of the human LIM/homeodomain gene islet-1 and identification of a sample sequence repeat polymorphism _Diabetes_ 1994 43: 935–941 [Published

erratum appears in _Diabetes_ 1994; 43: 1171.] Article  CAS  PubMed  Google Scholar  * Donohoue PA, Burns TL, Mendoza MCB . Lys656Asn variant of the leptin receptor gene (LEPR) and the β-3

adrenergic receptor (β3AR) gene linked to body mass index in humans: the Muscatine study _Pediatr Res_ 2000 47: 127A. Article  Google Scholar  Download references ACKNOWLEDGEMENTS This study

was supported in part by the NIH grants R01DK51716, R01DK52431, R01ES09912, F33DK09919, P30DK26687, DK25295 and P41RR03655. We thank Drs Jose Fernandez and Gary Gadbury for their valuable

input. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * New York Obesity Research Center, St Luke's-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York,

NY, USA M Heo & E Gropp * Division of Molecular Genetics, Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA RL Leibel & WK Chung *

Department of Rheumatology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA KR Fontaine * Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA

BB Boyer * Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland M Koulu, MK Karvonen & U Pesonen * Eating Disorder Unit, University of Helsinki,

Helsinki, Finland A Rissanen * Department of Medicine, University of Kuopio, Kuopio, Finland M Laakso & MIJ Uusitupa * Kinesiologie, Physical Activity Sciences Lab, Laval University,

Ste-Foy, Quebec, Canada Y Chagnon * Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA C Bouchard * Department of Pediatrics, Division of Endocrinology,

University of Iowa College of Medicine, Iowa City, IA, USA PA Donohoue & TL Burns * Department of Preventive Medicine, University of Iowa College of Public Health, Iowa City, IA, USA TL

Burns * Division of Endocrinology, Diabetes & Nutrition, University of Maryland at Baltimore, Baltimore, MD, USA AR Shuldiner & K Silver * Department of Geriatrics, Johns Hopkins

Bayview Medical Center, Johns Hopkins University, Baltimore, MD, USA RE Andersen * Steno Diabetes Center, Hagedorn Research Institute, Gentofte, Denmark BB Boyer, O Pedersen & S Echwald

* Danish Epidemiology Science Center, Institute of Preventive Medicine, Copenhagen Health Services, Copenhagen, Denmark TIA Sørensen * Internal Medicine Associates, Bloomington, IN, USA P

Behn * Department of Internal Medicine, Metabolism Division, Washington University School of Medicine, St Louis, MO, USA MA Permutt * Department of Epidemiology and Biostatistics, Case

Western Reserve University, Cleveland, OH, USA KB Jacobs & RC Elston * Department of Nutritional Science, Rutgers University, New Brunswick, NJ, USA DJ Hoffman * Department of

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Fontaine, K. _et al._ A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference. _Int J Obes_ 26,

640–646 (2002). https://doi.org/10.1038/sj.ijo.0801990 Download citation * Received: 10 May 2001 * Revised: 25 October 2001 * Accepted: 18 December 2001 * Published: 17 May 2002 * Issue

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circumference * meta-analysis * leptin receptor polymorphism * linkage * association