Meta-analyses between 18 candidate genetic markers and overweight/obesity

  • Linlin Tang1,

    Affiliated with

    • Huadan Ye1,

      Affiliated with

      • Qingxiao Hong1,

        Affiliated with

        • Fei Chen1,

          Affiliated with

          • Qinwen Wang1, 3,

            Affiliated with

            • Leiting Xu1, 3,

              Affiliated with

              • Shizhong Bu1, 3,

                Affiliated with

                • Qiong Liu1, 3,

                  Affiliated with

                  • Meng Ye2Email author,

                    Affiliated with

                    • Dao Wen Wang4Email author,

                      Affiliated with

                      • Yifeng Mai2Email author and

                        Affiliated with

                        • Shiwei Duan1, 3Email author

                          Affiliated with

                          Diagnostic Pathology20149:56

                          DOI: 10.1186/1746-1596-9-56

                          Received: 2 January 2014

                          Accepted: 4 March 2014

                          Published: 12 March 2014

                          Abstract

                          Aims

                          The goal of our study is to investigate the associations between 18 candidate genetic markers and overweight/obesity.

                          Methods

                          A total of 72 eligible articles were retrieved from literature databases including PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. Meta-analyses of 18 genetic markers among 56,738 controls and 48,148 overweight/obese persons were done by Review Manager 5.0.

                          Results

                          Our results showed that SH2B1 rs7498665 polymorphism was significantly associated with the risk of overweight/obesity (overall odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.09-1.34, P = 0.0004). Increased risk of overweight/obesity was also observed in FAIM2 rs7138803 polymorphism (overall OR = 1.11, 95% CI = 1.01-1.22, P = 0.04).

                          Conclusion

                          Our meta-analyses have shown the important role of 2 polymorphisms (SH2B1 rs7498665 and FAIM2 rs7138803) in the development of overweight/obesity. This study highlighted the importance of above two candidate genes (SH2B1 and FAIM2) in the risk of overweight/obesity.

                          Virtual slides

                          The virtual slide(s) for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​2785487401176182​.

                          Keywords

                          SH2B1 FAIM2 Polymorphism Overweight Obesity Meta-analysis

                          Introduction

                          Overweight/obesity as a metabolic disorder is closely associated with diabetes mellitus and cardiovascular disease, which are chronic diseases influencing the average life expectancy [1, 2]. In 2008, world health organization (WHO) has reported that a large portion of adults (>20 yr) were overweight (35%) and obese (12%) [3]. The overweight/obesity will become an epidemic [4] and cause a huge economic burden of society [4] in the near future.

                          The occurrence and the development of obesity are influenced by both environmental and genetic factors [5, 6]. Environmental factors, such as poor nutritional state and a lack of physical exercise, have an impact on the development of overweight/obesity [7, 8] through the epigenetic modifications such as gene methylation [9]. Genetic polymorphisms can confer the susceptibility of overweight/obesity and obesity-related morbidities [10]. Recent genome-wide association studies (GWAS) have identified a handful of candidate genetic markers to the risk of overweight/obesity [11].

                          In the present study, we performed a systematic search for eligible studies in the meta-analyses. Our results identified 18 polymorphisms among 16 genes that were all the candidate genes of obesity. Among these genes, GNB3 encodes β3-subunit protein which is involved in the process of hypertension and obesity [12]. MTHFR gene encodes methylenetetrahydrofolate reductase that is shown to be associated with increased fasting homocysteine [13]. MTHFR polymorphism is shown to be associated with lipid metabolism in the elderly women [14]. CNR1 is shown to regulate the endocannabinoid system that might stimulate the metabolism of lipogenesis through central and peripheral mechanisms [15, 16]. CNR1 is associated with low HDL dyslipidemia and a common haplotype of CNR1 could be a protective factor of obesity-related dyslipidemia [17]. BDNF is shown to play an important role in the development of several neuronal systems [18]. As an effector on energy homeostasis through MC4R signaling pathway, BDNF has an effect on the glucose and lipid metabolism in obese diabetic animals [19, 20]. FAAH gene encodes fatty acid amide hydrolase [21] and plays an important role in the development of obesity [22]. ADRB1 is shown to mediate in lipolysis and thus is important for obesity [23]. Rat study identifies that ADRB1 mediates the sympathetic nervous system (SNS) stimulation of thermogenesis in brown adipose tissue [24]. SH2B1 is able to bind leptin to its receptor, and thus increases the JAK2 activation which is involved in the insulin and leptin signaling [25, 26]. PCSK1 encodes prohormone convertase 1/3 that is a vital enzyme in the regulation of a majority of neuroendocrine body weight control [27]. A novel homozygous missense mutation in PCSK1 leads to early-onset obesity [28]. NPY2R is a presynaptic receptor [29] playing an inhibitory role in the control of appetite regulation [30], and thus influences the development of obesity [31]. FAIM2 (Fas apoptotic inhibitory molecule 2) is an anti-apoptotic gene [32]. Mutations of FAIM2 which interferes with Fas-mediated cell death confer risk for obesity [33]. SERPINE1 encodes a member of serine proteinase inhibitor which influences plasma PAI-1 activity with relation to obesity [34]. Serum paraoxonase-1 (PON1) encoded by PON1 as an enzyme associated with HDL-C could be a protector against oxidative damage in obesity [35]. CETP protein product transfers cholesterylesters from HDL to pro-atherogenic apoB-lipoproteins and thus has an impact on the lipid and HDL metabolism [36, 37]. UCP1 encodes uncoupling protein 1 that is mediated by long-chain fatty acids (LCFAs) from brown adipose tissue [38]. UCP1 expression in adipose tissue has an impact on regulating the thermogenesis and lipolysis [39, 40]. Mitochondrial uncoupling by UCP1 has demonstrated to be a target in antiobesity therapies [41]. ABCA1 gene product mediates the transport of cholesterol, phospholipids, and other metabolites [42]. Exercise has an impact on ABCA1 expression along with increased HDL levels in obese boys [43]. APOE plays a fundamental role with ligand-receptor in uptaking lipoproteins, and thus participates in the lipid metabolism [44]. In addition, APOE correlates with inflammation in adipose tissue in high-fat diet-induced obesity [45].

                          Meta-analysis is a systematic evaluation by combining the results from collected studies [46, 47]. The major advantages of meta-analysis are to improve the precision and accuracy by pooling up the data from multiple sources, and to analyze and quantify the inconsistency of results and the publish bias [48]. In the present study, we conducted comprehensive meta-analyses to identify the contribution of 18 polymorphisms to overweight/obesity.

                          Materials and methods

                          Literature search and data extraction

                          We performed the literature research using related databases such as PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. The combination of keywords in the literature search was obesity or overweight together with polymorphism or mutation or variant or single nucleotide polymorphism (SNP). The studies excluded in the meta-analysis met the following criteria: (1) the study had been included in the previous meta-analysis; (2) the study was not involved with genetic testing; (3) the study was not a case–control study. The criteria for overweight or obesity in adolescents and children were defined by WHO [49, 50]. Finally, we harvested 18 polymorphisms of 16 genes in the current meta-analysis. These included GNB3 rs5443, MTHFR rs1801133, CNR1 rs806381, BDNF rs6265, FAAH rs324420, ADRB1 rs1801253, SH2B1 rs7498665, PCSK1 rs6232 and rs6235, NPY2R rs1047214, FAIM2 rs7138803, SERPINE1rs1799768, PON1 rs854560 and rs662, CETP TaqIB, UCP1 rs1800592, ABCA1 rs2230806 and APOE ϵ2/ϵ3/ϵ4.

                          Statistical analysis

                          Meta-analysis was performed by using Statistical software Review Manager 5.0 [51]. Forest plots included the ORs with the corresponding 95% CIs, cochran’s Q and the inconsistency index (I2). If there were no significant heterogeneity (I2 < 50%, P > 0.05) of the studies in the meta-analysis, we used a fixed-effect model for the analysis. Otherwise, a random-effect model was used for the meta-analysis with large heterogeneity (I2 > 50%, P < 0.05). The weight of each involved study was calculated whatever in fixed-effect or random-effect model in forest plots by Review Manager 5.0. Two tailed P value < 0.05 was treated as significant. Power analyses were calculated by Power and Sample Size Calculation software (v3.0.43) [52].

                          Results

                          An initial search returned a total of 7,750 literatures from databases including PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. After a systematic filtration, 72 eligible articles, including 64 English, 6 Chinese, 1 German and 1 Spanish articles, were left for the meta-analyses (Additional file 1: Table S1). The detailed information for the retrieved studies was shown in Tables 1 and 2.
                          Table 1

                          Characteristics of 17 single nucleotide polymorphisms

                          Gene

                          SNP

                          Year

                          Author

                          Race

                          Cases/Controls (n)

                          Allele 1

                          Allele 2

                          Model selected

                          Heterogeneity

                          P value

                          Odds ratio (95% confidence interval)

                          (Case/Controls, n)

                          (Case/Controls, n)

                          (I2)%

                          GNB3

                          rs5443

                          1999

                          Siffert W

                          Caucasian

                          92/207

                          108/392

                          76/122

                          Fixed

                          42

                          0.47

                          1.04 (0.93-1.16)

                           

                          (C/T)

                          1999

                          Siffert W

                          Asian Chinese

                          186/832

                          166/886

                          206/778

                            

                          1999

                          Siffert W

                          African

                          127/607

                          34/219

                          220/995

                            

                          2000

                          Siffert W

                          Caucasian

                          207/92

                          292/108

                          122/76

                            

                          2001

                          Hinney A

                          Caucasian

                          491/330

                          695/442

                          287/218

                            

                          2001

                          Benjafield AV

                          Caucasian

                          92/188

                          133/284

                          51/92

                            

                          2001

                          Ohshiro Y

                          Asian Japanese

                          208/150

                          215/148

                          201/152

                            

                          2004

                          Suwazono Y

                          Asian Japanese

                          505/2120

                          517/2177

                          493/2063

                            

                          2008

                          Wang X

                          Asian Chinese

                          129/270

                          442/285

                          376/255

                            

                          2013

                          Hsiao TJ

                          Asian Chinese

                          467/505

                          402/441

                          532/569

                          MTHFR

                          rs1801133

                          2007

                          Terruzzi I

                          Caucasian

                          84/52

                          90/61

                          78/43

                          Fixed

                          0

                          0.59

                          1.05 (0.87-1.27)

                           

                          (C/T)

                          2010

                          Tavakkoly Bazzaz J

                          Asian Iranian

                          74/207

                          109/306

                          39/108

                            

                          2012

                          Yin RX

                          Asian Chinese

                          751/978

                          1049/1383

                          453/573

                          CNR1

                          rs806381

                          2008

                          Benzinou M

                          Caucasian

                          839/1726

                          1163/2362

                          515/1090

                          Fixed

                          0

                          0.5

                          1.04 (0.93-1.17)

                           

                          (A/G)

                          2008

                          Jaeger JP

                          Caucasian

                          430/317

                          613/464

                          247/170

                            

                          2012

                          Zhuang M

                          Asian Chinese

                          1662/1070

                          2345/1550

                          979/590

                          BDNF

                          rs6265

                          2005

                          Friedel S

                          Caucasian

                          183/283

                          342/448

                          81/118

                          Fixed

                          46

                          0.8

                          1.01 (0.92-1.11)

                           

                          (G/A)

                          2009

                          Hotta K

                          Asian Japanese

                          1127/1733

                          1367/2013

                          887/1453

                            

                          2009

                          Marti A

                          Caucasian

                          155/147

                          242/226

                          68/68

                            

                          2011

                          Xi B

                          Asian Chinese

                          1229/1619

                          1095/1554

                          1363/1684

                            

                          2011

                          Rouskas K

                          Caucasian

                          510/469

                          826/732

                          194/206

                            

                          2012

                          Skledar M

                          Caucasian

                          74/226

                          111/374

                          37/78

                          FAAH

                          rs324420

                          2005

                          Sipe JC

                          Caucasian

                          1094/1594

                          1777/984

                          411/204

                          Random

                          79

                          0.54

                          0.94 (0.76-1.16)

                           

                          (C/A)

                          2005

                          Sipe JC

                          African

                          507/107

                          687/161

                          327/53

                            

                          2005

                          Sipe JC

                          Asian

                          271/94

                          471/148

                          71/40

                            

                          2007

                          Jensen DP

                          Caucasian

                          4190/2507

                          6817/3991

                          1563/1023

                            

                          2008

                          Durand E

                          Caucasian

                          1517/1320

                          2473/2104

                          561/536

                            

                          2008

                          Papazoglou D

                          Caucasian

                          158/121

                          265/209

                          51/33

                            

                          2008

                          Moneletone P

                          Caucasian

                          378/110

                          614/194

                          142/26

                            

                          2010

                          Muller TD

                          Caucasian

                          2818/2818

                          3027/4607

                          689/1029

                          ADRB1

                          rs1801253

                          2001

                          Rydén M

                          Caucasian

                          141/157

                          206/214

                          76/100

                          Fixed

                          0

                          0.5

                          1.03 (0.94-1.14)

                           

                          (C/G)

                          2004

                          Tafel J

                          Caucasian

                          296/134

                          403/180

                          189/88

                            

                          2007

                          Gjesing AP

                          Caucasian

                          4575/3073

                          6781/4609

                          2369/1537

                            

                          2008

                          Ohshiro Y

                          Asian Japanese

                          180/132

                          284/215

                          76/49

                          SH2B1

                          rs7498665

                          2009

                          Hotta K

                          Asian Japanese

                          1129/1735

                          1943/3003

                          315/467

                          Fixed

                          0

                          0.0004

                          1.21 (1.09-1.34)

                           

                          (A/G)

                          2010

                          Shi J

                          Asian Chinese

                          829/1859

                          1427/3317

                          231/401

                            

                          2011

                          Beckers S

                          Caucasian

                          1045/317

                          1223/401

                          867/223

                            

                          2011

                          Rouskas K

                          Caucasian

                          510/469

                          673/675

                          347/263

                            

                          2012

                          Volckmar AL

                          Caucasian

                          3139/424

                          3728/557

                          2550/311

                          PCSK1

                          rs6232

                          2009

                          Happé F

                          Caucasian

                          3570/7933

                          6735/15028

                          405/838

                          Fixed

                          34

                          0.08

                          1.14 (0.97-1.12)

                           

                          (A/G)

                          2011

                          Rouskas K

                          Caucasian

                          510/469

                          969/882

                          51/56

                            

                          2012

                          Villalobos-Comparán M

                          South American Mexican

                          1018/1364

                          2005/2709

                          31/19

                            

                          2013

                          Choquet H

                          European American

                          263/547

                          485/1041

                          41/53

                            

                          2013

                          Dušátková L

                          Asian Czech

                          668/770

                          1255/1469

                          81/71

                          PCSK1

                          rs6235

                          2009

                          Happé F

                          Caucasian

                          3559/7793

                          5164/11432

                          1954/4154

                          Fixed

                          0

                          0.26

                          1.04 (0.97-1.12)

                           

                          (G/C)

                          2012

                          Villalobos-Comparán M

                          South America Mexican

                          994/1336

                          1575/2156

                          413/516

                            

                          2013

                          Choquet H

                          European - American

                          263/547

                          368/793

                          158/301

                            

                          2013

                          Choquet H

                          African - American

                          453/251

                          740/432

                          166/70

                            

                          2013

                          Dušátková L

                          Asian Czech

                          670/772

                          996/1130

                          344/414

                            

                          2014

                          Hsiao TJ

                          Asian Chinese

                          290/175

                          406/229

                          174/121

                          NPY2R

                          rs1047214

                          2006

                          Torekov SS

                          Caucasian

                          939/4767

                          1026/5295

                          852/4239

                          Fixed

                          0

                          0.54

                          0.97 (0.88-1.07)

                           

                          (T/C)

                          2007

                          Siddiq A

                          Caucasian

                          953/1042

                          1048/1132

                          858/952

                            

                          2007

                          Wang HJ

                          Caucasian

                          184/183

                          189/169

                          179/197

                            

                          2009

                          Zhang J

                          Asian Chinese

                          705/1325

                          1171/2133

                          239/517

                          FAIM2

                          rs7138803

                          2009

                          Hotta K

                          Asian Japanese

                          1125/1726

                          1408/2251

                          842/1201

                          Fixed

                          0

                          0.04

                          1.11 (1.01-1.22)

                           

                          (G/A)

                          2011

                          Xi B

                          Asian Chinese

                          1229/1619

                          1711/2332

                          747/906

                            

                          2011

                          Rouskas K

                          Caucasian

                          510/469

                          643/610

                          377/328

                            

                          2013

                          Li C

                          Asian Chinese

                          242/469

                          331/663

                          153/275

                            

                          2013

                          Zhao XY

                          Asian Chinese

                          371/393

                          534/565

                          208/221

                          SERPINE1

                          rs1799768

                          2001

                          Sartori MT

                          Caucasian

                          93/79

                          95/84

                          91/74

                          Fixed

                          39

                          0.07

                          0.83 (0.67-1.02)

                           

                          (4G/5G)

                          2002

                          Hoffstedt J

                          Caucasian

                          317/188

                          305/141

                          329/235

                            

                          2006

                          Berberoğlu M

                          Asian Turk

                          126/133

                          151/133

                          101/133

                            

                          2008

                          Solá E

                          Caucasian

                          67/67

                          70/65

                          64/69

                            

                          2008

                          Kinik ST

                          Asian Turk

                          39/38

                          52/36

                          26/40

                            

                          2011

                          Espino A

                          South American Chilean

                          50/71

                          32/51

                          44/52

                            

                          2012

                          Wingeyer SD

                          South American Argentine

                          110/111

                          92/109

                          128/113

                          PON1

                          rs854560

                          2011

                          Veiga L

                          Caucasian

                          81/74

                          101/90

                          61/58

                          Fixed

                          31

                          0.4

                          0.87 (0.62-1.21)

                           

                          (A/T)

                          2011

                          Martínez-Salazar MF

                          South American Mexican

                          63/64

                          114/101

                          12/27

                            

                          2013

                          Rupérez AI

                          Caucasian

                          177/81

                          210/219

                          137/143

                          PON1

                          rs662

                          2011

                          Veiga L

                          Caucasian

                          81/74

                          68/44

                          94/104

                          Fixed

                          18

                          0.6

                          1.09 (0.79-1.51)

                           

                          (G/A)

                          2011

                          Martínez-Salazar MF

                          South American Mexican

                          63/64

                          66/65

                          60/63

                            

                          2013

                          Rupérez AI

                          Caucasian

                          177/81

                          252/249

                          102/111

                          CETP

                          TaqIB

                          2006

                          Huang ZY

                          Asian Chinese

                          199/141

                          243/162

                          155/120

                          Fixed

                          0

                          0.23

                          0.91 (0.79-1.06)

                           

                          (B1/B2)

                          2008

                          Srivastava N

                          Asian Indian

                          159/278

                          153/263

                          165/293

                            

                          2010

                          Ruan X

                          Asian Chinese

                          934/924

                          1104/1028

                          764/820

                            

                          2011

                          Huang Y

                          Asian Chinese

                          206/132

                          250/155

                          162/109

                          UCP1

                          rs1800592

                          1998

                          Gagnon J

                          Caucasian

                          674/311

                          1013/473

                          335/149

                          Random

                          60

                          0.23

                          1.19 (0.90-1.57)

                           

                          (A/G)

                          2000

                          Proenza AM

                          Asian Turk

                          136/94

                          189/131

                          83/57

                            

                          2002

                          Kieć-Wilk B

                          Caucasian

                          12/106

                          18/146

                          6/66

                            

                          2002

                          Nieters A

                          Caucasian

                          154/153

                          232/231

                          76/75

                            

                          2003

                          Forga Ll

                          Caucasian

                          159/154

                          258/244

                          60/64

                            

                          2004

                          Ramis JM

                          Caucasian

                          82/170

                          259/433

                          49/81

                            

                          2008

                          Mottagui-Tabar S

                          Caucasian

                          91/479

                          433/736

                          149/222

                            

                          2009

                          Shen ZN

                          Asian Chinese

                          127/257

                          129/240

                          125/274

                          ABCA1

                          rs2230806

                          2006

                          Porchay I

                          Caucasian

                          2097/2947

                          2992/4238

                          1202/1656

                          Fixed

                          0

                          0.87

                          1.01 (0.90-1.13)

                           

                          (G/A)

                          2007

                          Kitjaroentham A

                          Asian Thai

                          112/117

                          143/143

                          81/91

                            

                          2011

                          Huang Y

                          Asian Chinese

                          206/132

                          233/141

                          179/123

                          Table 2

                          Characteristics of APOE ϵ2/ϵ3/ϵ4 polymorphism

                          Year

                          Author

                          Race

                          Case/Controls (n)

                          Genotypes (case/controls, n)

                          Alleles (case/controls, n)

                              

                          ϵ2/ϵ2

                          ϵ2/ϵ3

                          ϵ2/ϵ4

                          ϵ3/ϵ3

                          ϵ3/ϵ4

                          ϵ4/ϵ4

                          ϵ2

                          ϵ3

                          ϵ4

                          2003

                          Guerra A

                          Caucasian

                          31/81

                          0/0

                          6/4

                          0/0

                          63/20

                          13/7

                          0/0

                          6/4

                          145/51

                          13/7

                          2008

                          Srivastava N

                          Asian Indian

                          159/278

                          0/1

                          17/18

                          2/6

                          90/198

                          41/55

                          9/0

                          19/30

                          238/469

                          61/61

                          2010

                          Ergun MA

                          Asian Chinese

                          38/42

                          0/2

                          2/0

                          12/4

                          8/9

                          16/26

                          0/1

                          14/8

                          34/44

                          28/32

                          2012

                          Zhang J

                          Asian Chinese

                          282/172

                          1/3

                          46/16

                          7/2

                          186/123

                          40/27

                          2/1

                          55/24

                          458/289

                          51/31

                          2012

                          Zarkesh M

                          Asian Iran

                          463/370

                          1/1

                          48/38

                          6/7

                          348/268

                          63/53

                          3/3

                          56/47

                          807/627

                          75/66

                          Module

                          Case/Controls (n)

                          Model selected

                          Heterogeneity (I2)%

                          P value

                          OR (95% CI)

                                 

                          ϵ2/ϵ2/ϵ3/ϵ3

                          954/813

                          Fixed

                          0

                          0.12

                          0.35 (0.09-1.32)

                                 

                          ϵ2/ϵ3ϵ3/ϵ3

                          814/694

                          Fixed

                          48

                          0.07

                          1.33 (0.98-1.82)

                                 

                          ϵ2/ϵ4/ϵ3/ϵ3

                          695/618

                          Fixed

                          0

                          0.92

                          0.96 (0.45-2.05)

                                 

                          ϵ3/ϵ4/ϵ3/ϵ3

                          868/786

                          Fixed

                          28

                          0.7

                          1.05 (0.82-1.35)

                                 

                          ϵ4/ϵ4/ϵ3/ϵ3

                          695/618

                          Random

                          63

                          0.54

                          1.89 (0.25-14.46)

                                 

                          ϵ2/ϵ3

                          1832/1593

                          Fixed

                          23

                          0.26

                          1.16 (0.90-1.51)

                                 

                          ϵ4/ϵ3

                          1910/1681

                          Random

                          65

                          0.54

                          1.13 (0.77-1.66

                                 
                          Heterogeneity is an important indicator to identify if there is difference in the collected studies. According to the extent of heterogeneity, we categorized the meta-analyses into three groups that have minimal (I2 = 0), moderate (I2 < 50%), and significant heterogeneity (I2 ≥ 50%), respectively. As shown in Figure 1, minimal heterogeneity (I2 = 0) was found for the meta-analyses of 10 polymorphisms that included MTHFR rs1801133, CNR1 rs806381, ADRB1 rs1801253, SH2B1 rs7498665, PCSK1 rs6235, NPY2R rs1047214, FAIM2 rs7138803, CETP TaqIB and ABCA1 rs2230806. Moderate heterogeneity was found for 5 polymorphisms, including BDNF rs6265 (I2 = 46%), PCSK1 rs6232 (I2 = 34%), GNB3 rs5443 (I2 = 42%), PON1 rs854560 (I2 = 31%), PON1 rs662 (I2 = 18%), and SERPINE1 rs1799768 (I2 = 39%). Significant heterogeneity was found for UCP1 rs1800592 (I2 = 60%) and FAAH rs324420 (I2 = 79%). Moreover, As shown in Figure 2, various heterogeneities were shown in the meta-analyses of APOE ϵ2/ϵ3/ϵ4 polymorphism under the seven genetic models (ϵ2/ϵ3 versus ϵ3/ϵ3: I2 = 48%; ϵ2/ϵ4 versus ϵ3/ϵ3: I2 = 0%; ϵ3/ϵ4 versus ϵ3/ϵ3: I2 = 28%; ϵ4/ϵ4 versus ϵ3/ϵ3: I2 = 63%; ϵ2/ϵ3 versus ϵ3/ϵ3: I2 = 0%; ϵ2 versus ϵ3: I2 = 23%; ϵ4 versus ϵ3: I2 = 65%). No obvious publication bias was observed based on their funnel plots (Figures 3 and 4).
                          http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-9-56/MediaObjects/13000_2014_1106_Fig1_HTML.jpg
                          Figure 1

                          Forest plots of the association studies between 17 SNPs and overweight/obesity.

                          http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-9-56/MediaObjects/13000_2014_1106_Fig2_HTML.jpg
                          Figure 2

                          Forest plots of the association studies between APOE ϵ2/ϵ3/ϵ4 polymorphism and overweight/obesity.

                          http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-9-56/MediaObjects/13000_2014_1106_Fig3_HTML.jpg
                          Figure 3

                          Funnel plots of the studies of 17 SNPs involved in meta-analysis.

                          http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-9-56/MediaObjects/13000_2014_1106_Fig4_HTML.jpg
                          Figure 4

                          Funnel plots of the studies of APOE ϵ2/ϵ3/ϵ4 involved in meta-analysis.

                          Our results showed that SH2B1 rs7498665 was significantly associated with the risk of overweight/obesity among 6,142 cases and 4,345 controls from four studies (overall OR = 1.21, 95% CI = 1.09-1.34, P = 0.0004, Figure 1). Increased risk of overweight/obesity was also observed in rs7138803 of FAIM2 among 3,477 cases and 4,676 controls from five studies (overall OR = 1.11, 95% CI = 1.01-1.22, P = 0.04, Figure 1). No evidence of association was observed for the meta-analyses of the rest 16 variants (Figures 1 and 3). For the meta-analyses with large heterogeneity, we further performed subgroup meta-analyses by ethnicity. No significant association of UCP1 rs1800592 with overweight/obesity was observed in Caucasian (P = 0.13, I2 = 62%), and Asian (P = 0.59, I2 = 0%, Additional file 2: Figure S1). And the subgroup meta-analysis of APOE ϵ2/ϵ3/ϵ4 polymorphism by excluding the study of Srivastava et al. [53] didn’t produce any significant association of APOE ϵ2/ϵ3/ϵ4 with overweight/obesity (Additional file 3: Figure S2). There was no visual publication bias in all the above meta-analyses (Additional file 4: Figure S3).

                          Discussion

                          Current meta-analyses were performed among 48,148 cases and 56,738 controls from 72 studies, covering a total of 6 populations, including Caucasian, Asian, Japanese-American, European-American, African-American, South American, and African. Among the tested 18 polymorphisms, there were two (SH2B1 rs7498665 and FAIM2 rs7138803) with significant association results (P < 0.05). Power analysis also showed large power existed in our meta-analyses of two significant polymorphisms including SH2B1 rs7498665 (100%) and FAIM2 rs7138803 (100%).

                          SH2B1 encodes an adaptor protein associated with leptin and insulin signaling in the lipid metabolism [54]. SH2B1 is an enhancer that may influence the phenotype of obesity through JAK-STAT pathway [55], which is important in the development and function of adipocytes [56]. SH2B1 acts as a mediator through PI3-kinase pathway which is correlated with the biological actions of leptin [26]. Many animal studies have shown that SH2B1 is involved in the development of obesity. SH2B1 through its participation in the regulation of leptin sensitivity, energy metabolism and body weight [57]. SH2B1 has been identified to be related to obesity through genome-wide association studies (GWAS) [55]. Our meta-analysis of SH2B1 rs7498665 was performed among 6,652 cases and 4,814 controls with four studies. Among the tested populations, no heterogeneity was observed (I2 = 0). Our results confirmed the relationship between SH2B1 and the risk of overweight/obesity (overall OR = 1.21, 95% CI = 1.09-1.34, P = 0.0004, Figure 1).

                          FAIM2 is an anti-apoptotic gene that provides protection from Fas-mediated cell death [32] that is associated with extreme overweight by GWAS [58]. FAIM2 rs7138803 polymorphism is associated with increased risk of obesity in Japanese [59]. But there is no relationship between FAIM2 rs7138803 and obesity in Chinese [60]. Minor allele frequency of rs7138803 in Chinese populations ranges from 0.28 to 0.29, while FAIM2 rs7138803 is monomorphic in Japanese and Caucasian populations. Our meta-analysis among 3477 cases and 4676 controls demonstrated that FAIM2 rs7138803 was associated with the risk of overweight/obesity (overall OR = 1.11, 95% CI = 1.01-1.22, P = 0.04, Figure 1).

                          Although meta-analysis is an important method to improve the precision and accuracy, to analyze and quantify the published results [6163], some disadvantages exist in the meta-analysis. For the current meta-analyses, several limitations need to be taken with cautions. Firstly, obesity is always accompanied by other complications such as coronary artery diseases and hypertension. These confounding factors needed to be adjusted in the original case–control studies. We were unable to obtain the related information. Therefore we can’t exclude a chance of the positive findings confounded by these obesity-related factors. Secondly, the significant result of FAIM2 rs7138803 needs to be validated in the future. However, after Bonferroni’s correction by the number of testing, the association of FAIM2 rs7138803 was unable to retain significant. Thirdly, power analysis suggested moderate power in the meta-analyses of MTHFR rs1801133 (power = 78.2%) and SERPINE1 rs1799768 (power = 69.4%) The negative results of them might be caused by a lack of power in our meta-analyses. Future studies with larger samples may help clarify the contribution of these biomarkers to the risk of overweight/obesity.

                          Our results identified significant associations between 2 polymorphisms (SH2B1 rs7498665 and FAIM2 rs7138803) and overweight/obesity. Moreover, overweight/obesity is a complicated disease influenced by both genetic and environmental factors. The potential mechanism of interaction between gene and environment could be taken into consideration in the future study. Well-designed studies with large samples could help elucidate the contribution of above polymorphisms to overweight/obesity.

                          Authors’ information

                          Linlin Tang and Huadan Ye: co-first authors of this work.

                          Declarations

                          Acknowledgments

                          The research was supported by the grants from: National Natural Science Foundation of China (31100919 and 81371469), Natural Science Foundation of Zhejiang Province (LR13H020003), K. C. Wong Magna Fund in Ningbo University, and Ningbo Social Development Research Projects (2012C50032).

                          Authors’ Affiliations

                          (1)
                          Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University
                          (2)
                          The Affiliated Hospital, Ningbo University
                          (3)
                          Diabetes Center, School of Medicine, Ningbo University
                          (4)
                          Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

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