Biomedical

Communication

Biosci. Biotech. Res. Comm. 9(3): 335-340 (2016)

HMGA1 variant IVS5-13insC is associated with

insulin resistance and type 2 diabetes: An updated

meta-analysis

Qinglu Wang

* Yancheng Liu

Liting Zheng

Hao Kong

and Xuewen Tian

Key Laboratory of Biomedical Engineering & Technology of Shandong High School, Qilu Medical

University, Zibo, 255213, China

S ports Science Research Center of Shandong Province, Jinan, 250102, China

ABSTRACT

High-mobility group A1 (HMGA1) polymorphism has been suspected as a gene variant associated with type 2 dia-

betes (T2D). However, con icting outcomes have been reported.This meta-analysis aimed to predict the association

between the HMGA1 variant IVS5-13insC and T2D. Statistical analyses were performed using Stata/SE 12.0 software.

A total of 11 case-control studies in 6 articles including 18,539 diabetic patients and 18,228 non-diabetic patients

were conducted in Europe, Asia and South America. Results suggested that the HMGA1 variant IVS5-13insC was

associated with an increased risk of insulin resistance (OR = 0.61, 95% CI 0.56 to 0.66, P < 0.0001), T2D (OR = 0.67,

95% CI 0.61 to 0.73, P < 0.0001), particularly for Caucasians with increased risks of T2D (OR = 0.56, 95% CI 0.49

to 0.65, P < 0.0001) compared with wild-type subjects. This meta-analysis indicated that the HMGA1 variant IVS5-

13insC can be a risk factor of T2D development, particularly among Caucasians. Signi cant risks were also found

(Asian: OR = 0.74, 95% CI: 0.63 to 0.86, P < 0.0001, Hispanic-American: OR = 0.81, 95% CI: 0.65 to 1.01, P < 0.0001)

in non-Caucasian population. However, ethnical studies should be conducted to reveal whether the HMGA1 variant

IVS5-13insC is associated with an increased risk of T2D.

KEY WORDS: HMGA1, TYPE 2 DIABETES, INSULIN RESISTANCE, VARIANT, META-ANALYSIS

335

ARTICLE INFORMATION:

*Corresponding Author: wql_zcq@126.com

Received 30

Aug, 2016

Accepted after revision 29

Sep, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2015: 3.48 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

336 HMGA1 VARIANT IVS5-13INSC IS ASSOCIATED WITH INSULIN RESISTANCE AND TYPE 2 DIABETES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Qinglu Wang et al.

INTRODUCTION

Type 2 diabetes (T2D) is one of the major and exacer-

bating health problems worldwide; T2D is predicted to

affect 490 million in 2030 (Zhang, et al., 2010). Strong

genetic in uences and many polymorphisms have been

reproducibly associated with T2D.Insulin resistance in

muscle, liver, and adipose tissues is a primary charac-

teristic of most patients with T2D; as such, these tissues

become resistant to endogenous and exogenous insulin.

The interaction of insulin with target tissues is mediated

by insulin receptor (INSR), a glycoprotein implicated

in directing insulin to target cells and initiating cell

responses to insulin, (Gold ne, 1987 Herder and Roden,

2011, Voight, et al., 2010).

High-mobility group A1 (HMGA1) is an architectural

transcription factor involved in numerous biological

functions in the nucleus, including regulation of DNA

replication, transcription, recombination, and repair;

among these functions, transcriptional regulation of

gene expression is considered as the most important.

After HMGA1 binds to DNA, HMGA1 can be polymerized

with other transcription factors, forming an “enhanceo-

some” to regulate gene transcription; thus, gene expres-

sions are positively or negatively regulated(Bustin and

Reeves, 1996). Studies on humans and knockout mice

have suggested that HMGA1 is involved in to T2D patho-

genesis through the regulation of INSR gene expres-

sion; INSR gene expression is decreased by functional

HMGA1 gene variants. HMGA1-de cient patients have

been biologically investigated because of their clinical

value. However, whether HMGA1 single gene deletion-

or mutation-induced insulin resistance is the underlying

cause of T2D remains unknown, (Foti, et al., 2005). Low-

frequency insertion polymorphism IVS5-13insC (c.136-

14_136-13insC) has been identi ed and associated with

insulin resistance and T2D among individuals of white

European ancestry and Chinese populations, (Chiefari,

et al., 2011 Liu, et al., 2012).

However, no similar association is observed in another

study involving Caucasians and populations of African

and Hispanic descent. Furthermore, con icting results

regarding the association of HMGA1 with T2D and

insuf cient data on diverse ethnic groups have caused

dif culty in performing clinical translation of HMGA1

IVS5-13insC genotyping, (Marquez et al., 2012, Karnes,

et al., 2013, Pullinger, et al., 2014 ).

Results regarding the functional effect of the HMGA1

IVS5-13insC variant are also contradictory. On the one

hand, HMGA1 and INSR expressions decrease in dia-

betic carriers of IVS5-13insC compared with those of

wild-type diabetic and non-diabetic patients. INSR pro-

tein expression and insulin-binding capacity are also

restored in lymphoblasts obtained from diabetic IVS5-

13insC carriers through HMGA1 DNA transfection,

(Chiefari, et al., 2011).

On the other hand, IVS5-13insC does not affect

HMGA1 or INSR expression in adipose tissues of nor-

moglycemic patients. IVS5-13insC is present at position

13 of HMGA1 exon 6; however, the direct mechanism

by which this variant affects mRNA expression or amino

acid sequence remains unclear, (Marquez, et al., 2012).

A previous meta-analysis of Caucasians focused on

this issue and arrived at a negative conclusion(Marquez,

et al., 2012). Thus, we performed a meta-analysis of eligi-

ble case-control studies worldwide to investigate whether

the HMGA1 variant IVS5-13insC is associated with an

increased risk of insulin resistance and T2D. We also con-

ducted subgroup analyses according to different ethnici-

ties to explore the presence of ethnicity-speci c effects.

MATERIAL AND METHODS

LITERATURE SEARCH STRATEGY

We searched Pubmed, EMBASE, and Web of science.

The last updated search was performed on February 12,

2015. We used any possible combinations of relevant

keywords: “HMGA1 or high-mobility group A1,” “poly-

morphism or mutation or mutant or variant,” and “insu-

lin resistance, T2D, or type 2 diabetes.”

Articles describing the relationship between T2D and

IVS5-13insC were identi ed with no language limi-

tations. The inclusion criteria were set as follows: (a)

evaluation of IVS5-13insC, insulin resistance, and T2D

risk and (b) case-control design to estimate odds ratio

(OR) with a 95% con dence interval (CI). Articles were

excluded according to the following criteria: (a) reviews,

meta-analyses, and other non-case-control studies and

(b) nonhuman studies. For studies with the same or

overlapping data by the same authors, the most suitable

studies with the largest number of cases or latest publi-

cation dates were selected.

DATA EXTRACTION

Two reviewers (Yancheng Liu and Liting Zheng) inde-

pendently extracted information from all of the eligi-

ble publications and reached consensus on all items.

An author (Hao Kong) was invited to assess articles in

cases of disagreement. The following information was

extracted from each article:  rst author, journal, year of

publication, country of origin, ethnicity, and exact data

of cases and controls.

STATISTICAL ANALYSIS

The T2D risk associated with IVS5-13insC was evaluated

using ORs with a 95% CI. Heterogeneity (I

) was evalu-

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS HMGA1 VARIANT IVS5-13INSC IS ASSOCIATED WITH INSULIN RESISTANCE AND TYPE 2 DIABETES 337

Qinglu Wang et al.

ated using a Cochran’s Q statistic to assess the degree of

inter-study variation. The pooled OR of each study was

calculated using a  xed-effects model when no statis-

tically signi cant heterogeneity was detected with a P

value < 0.10. A random-effects model was used when

signi cant heterogeneity was found.

The statistical signi cance of the pooled ORs was

determined using a Z test. P value < 0.05 was consid-

ered signi cant. A strati ed analysis of ethnicity and

continent was also performed: (1) Caucasian and non-

Caucasian and (2) Asian and European. E gger’s plot was

used to evaluate the probability of publication bias. Sta-

tistical analyses were carried out using Stata/SE 12.0 for

Windows.

RESULTS

CHARACTERISTICS OF THE STUDIES

Figure 1 demonstrates the progress of the article selec-

tion. After initially searching PubMed, EMBASE, and

Web of science, we identi ed 52 publications. Of these

52 publications, 34 were excluded after titles and

abstracts were scanned to determine whether or not

these articles are relevant to T2D and HMGA1 polymor-

phism; as a result, 18 articles were considered for fur-

ther assessment. Of these 18 articles, 11 were not related

to the HMGA1 variant IVS5-13insC; thus, these articles

were removed from the list. After reading the full text

of the 7 remaining studies, we excluded 1 article that

did not compare between T2D patients and healthy con-

trols.

As a result, 18,539 diabetic patients and 1 8,228

non-diabetic patients were enrolled to determine the

HMGA1 variant IVS5-13insC. (5 articles about T2D(Liu,

et al., 2012, Chiefari, et al., 2011, Pullinger, et al., 2014,

Karnes, et al., 2013, Marquez, et al., 2012) and 1 article

about MetS(Chiefari, et al., 2013).

The 6 studies included 13,719 diabetic patients and

13,572 non-diabetic patients were came from Europe,

4 studies included 2,112 diabetic patients and 2,081

non-diabetic patients were came from South America,

and 1 study included 2,712 diabetic patients and 2,575

non-diabetic patients were came out of Asia. Thus, 11

case-control studies from 6 articles were included in

our meta-analysis. Reports from other areas were lim-

ited. The detailed information of each study is shown in

Table 1. We estimated the risk between T2D and control

groups by comparing gene frequencies of the HMGA1

variant IVS5-13insC (del/ins, ins/ins) and the wild type

(del/del).

OVERALL META-ANALYSIS AND SUBGROUP

ANALYSIS

A summary of the meta-analysis of the HMGA1 variant

IVS5-13insC and T2D is shown in Figure 2. The HMGA1

FIGURE 1. Flow diagram of included/excluded studies

338 HMGA1 VARIANT IVS5-13INSC IS ASSOCIATED WITH INSULIN RESISTANCE AND TYPE 2 DIABETES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Qinglu Wang et al.

Table 1: Characteristics of the 11 case-controls included in the meta-analysis

First author

(years)

Disease Country Ethnicity Non-diabetic patients

genotype

Diabetic patients genotype

Mutant type

(c/c or c/-)

Wild type

(-/-)

Mutant type

(c/c or c/-)

Wild type

(-/-)

Pullinger (2014) T2D America Hispanic-American 293 531 135 185

Karnes (2013) T2D America Hispanic-American 45 597 69 868

African-American 6 147 6 210

Caucasian 18 475 17 591

Chiefari (2013) MetS Italian Caucasian 195 4821 299 3106

Chiefari (2013) MetS Turkish Caucasian 57 703 72 587

Liu (2012) T2D China Asian 354 2358 436 2139

Marquez (2012) T2D France Caucasian 228 4159 267 4639

Chiefari (2011) T2D Italy Caucasian 11 2533 237 3041

Chiefari (2011) T2D America Caucasian 45 913 75 895

Chiefari (2011) T2D France Caucasian 0 50 27 327

MetS: The metabolic syndrome is a common multicomponent disorder where insulin resistance is associated with an increased risk

for type 2 diabetes (T2D), hypertension, dyslipidemia, and cardiovascular disease (CVD).

FIGURE 2. Meta-analysis of the HMGA1 variant IVS5-13insC and T2D

variant IVS5-13insC was signi cantly associated with

an increased risk of insulin resistance and T2D com-

pared with that of healthy controls in overall popula-

tions (insulin resistance: OR = 0.61, 95% CI 0.56 to 0.66,

P < 0.0001; T2D: OR = 0.67, 95% CI 0.61 to 0.73, P <

0.0001).

Subgroup analysis was performed according to dif-

ferent ethnic groups in this meta-analysis. Signi cant

associations were found in Figure 3 (OR = 0.56, 95% CI:

0.49 to 0.65, P < 0.0001) in the Caucasian population;

an increasing pattern was observed in non-Caucasian

populations (Asian: OR = 0.74, 95% CI: 0.63 to 0.86, P <

0.0001, Hispanic-American: OR = 0.81, 95% CI: 0.65 to

1.01, P < 0.0001).

Publication bias: Egger’s test revealed a consistent out-

come. Egger’s plot indicated a lack of publication bias.

DISCUSSION

RETROSPECTIVE

This meta-analysis is the  rst to identify the increased

T2D vulnerability of the HMGA1 variant IVS5-13insC

variant carriers; our result suggested that the HMGA1

variant IVS5-13insC variant is likely involved in T2D

pathogenesis. However, a previous meta-analysis of

Caucasians revealed that the HMGA1 variant IVS5-

13insC is not associated with T2D. However, our meta-

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS HMGA1 VARIANT IVS5-13INSC IS ASSOCIATED WITH INSULIN RESISTANCE AND TYPE 2 DIABETES 339

Qinglu Wang et al.

analysis of Caucasians and other populations showed

that the HMGA1 variant IVS5-13insC may increase

the prevalence of T2D. Furthermore, the HMGA1 vari-

ant IVS5-13insC may increase the prevalence of T2D in

other ethnic groups.

Genome-wide association studies (GWAS) on patients

with T2D have identi ed associations between polymor-

phisms and mutations in some genes(Hale, et al., 2012).

These genes have been regarded as potential T2D risk

factors. However, current GWAS fail to detect an associ-

ation between the HMGA1 variant IVS5-13insC and the

presence of T2D. To the best of our knowledge, future

meta-analyses that include GWAS datasets will help

determine whether the IVS5-13insC shows a consistent

association with T2D.

LIMITATIONS

The limitations of our study are as follows. First, only

published studies in English were included in our data

analysis; other languages or unpublished materials could

be overlooked. Second, majority of the studies involved

Caucasian populations, whereas four studies focused

on non-Caucasian populations. Thus, further studies on

other populations should be conducted to investigate

such association among non-Caucasian populations.

Third, the ORs obtained using comparison models were

unadjusted; a precise analysis should be conducted if

individual raw data were available. Finally, two meta-

analyses indicated signi cant heterogeneity. Despite

these restrictions, our study provided a comprehensive

understanding of the association between the HMGA1

variant IVS5-13insC and risk of T2D.

CROSS SECTIONAL

In conclusion, the HMGA1 variant IVS5-13insC can

be regarded as a new risk factor of the development of

insulin resistance and T2D, particularly among Cauca-

sians. Furthermore, Asian and Hispanic-American eth-

nic groups fail to indicate ethnic diversity of disease

susceptibility. In the future, case-control investigations

of many ethnic groups and communities should be per-

formed to reveal whether the HMGA1 variant IVS5-

13insC is associated with an increased risk of T2D and

to determine ethnicity-speci c effects.

P ERSPECTIVES

HMGAl plays a crucial role in blood sugar balance as a

structural transcription factor. We believe that an indi-

vidual with the HMGA1 variant IVS5-13insC has clini-

cal implications. First, the presence of these variants

can serve as an early predictive marker of both insu-

lin resistance and T2D, especially for individuals with

family histories of T2D and related conditions. Second,

the presence of these variants may predict responses to

therapy(Smith, et al., 2010). T2D treatment is largely

empirical and the prediction of speci c responses to a

therapeutic agent in any patient is dif cult

. Patients

with T2D and variants may respond differently to spe-

ci c therapies, such as an insulin sensitizer, because

HMGA1 variant IVS5-13insC de nes a speci c defect

that decreases insulin receptor concentrations and insu-

lin resistance. Third, individuals possessing functional

HMGA1 variant IVS5-13insC and T2D may have dif-

ferent clinical courses from other patients with T2D,

including differences in the development of compli-

cations. Fourth, the search for new therapies for T2D

can include agents that upregulate HMGA1 expression.

Finally, this conclusion provides some theoretical basis

for HMGA1 single gene deletion- or mutation-induced

insulin resistance as the underlying cause of T2D. Fur-

thermore, IVS5-13insC can be regarded as a novel target

of gene therapy for T2D and insulin resistance.

FIGURE 3. Subgroup meta-analysis of different ethnic groups

340 HMGA1 VARIANT IVS5-13INSC IS ASSOCIATED WITH INSULIN RESISTANCE AND TYPE 2 DIABETES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

The exact biological mechanism underlying the

association between the HMGA1 gene and risk of T2D

remains uncertain. Functional studies and succeeding

replications of these associations are necessary to de ne

the potential role of the HMGA1 variant IVS5-13insC

in predicting T2D developments. Although the cur-

rent study provides this conclusion, further studies on

HMGA1 are warranted to clarify the role of this gene in

diabetes pathogenesis.

HMGA1 has been extensively investigated. HMGA1

is highly expressed in tumor cells; furthermore, HMGA1

is implicated in tumor initiation and progression by

disrupting the stability of mitochondrial genome or

by participating in the transcriptional regulation of

gene expression related to tumors(Mao, et al., 2009).

Thus, accurate physiological characteristics of HMGA1

polymorphism should be determined through several

approaches.

DECLARATION OF INTEREST

We declare that there no any  nancial or other potential

con ict of interest, and there is no con ict of interest

that could be perceived as prejudicing the impartiality

of the research reported.

ACKNOWLEDGMENTS

This work was supported by grants from the Natural

Scienti c Foundation of Shandong Province, China

(ZR2014CM046, ZR2010CQ031 and ZR2015CL019) and

Collaborative Innovation Center of Chinese medicine

antivirus in Shandong University of Tranditional Chi-

nese Medicine (XTCX2014B01-07).

REFERENCES

Bustin M and R. Reeves (1996): High-mobility-group chromo-

somal proteins: architectural components that facilitate chro-

matin function. Prog Nucleic Acid Res Mol Biol, 54, 35-100

Chiefari E, S. Tanyolac, S. Iiritano, A. Sciacqua, C. Capula, B.

Arcidiacono, A. Nocera, K. Possidente, F. Baudi, V. Ventura, G.

Brunetti, F. S. Brunetti, R. Vero, R. Maio, M. Greco, M. Pavia,

U. Hodoglugil, V. Durlach, C. R. Pullinger, I. D. Gold ne, F.

Perticone, D. Foti and A. Brunetti (2013): A polymorphism of

HMGA1 is associated with increased risk of metabolic syn-

drome and related components. Sci Rep, 3, 1491

Chiefari, E., S. Tanyolac, F. Paonessa, C. R. Pullinger, C. Capula,

S. Iiritano, T. Mazza, M. Forlin, A. Fusco, V. Durlach, A. Dur-

lach, M. J. Malloy, J. P. Kane, S. W. Heiner, M. Filocamo, D. P.

Foti, I. D. Gold ne and A. Brunetti (2011): Functional variants

of the HMGA1 gene and type 2 diabetes mellitus. JAMA, 305,

903-912

Foti, D., E. Chiefari, M. Fedele, R. Iuliano, L. Brunetti, F. Paon-

essa, G. Man oletti, F. Barbetti, A. Brunetti, C. M. Croce and A.

Fusco (2005): Lack of the architectural factor HMGA1 causes

insulin resistance and diabetes in humans and mice. Nat Med,

11, 765-773

Gold ne ID (1987): The insulin receptor: molecular biology

and transmembrane signaling. Endocr Rev, 8, 235-255

Hale PJ , A. M. Lopez-Yunez and J. Y. Chen (2012): Genome-

wide meta-analysis of genetic susceptible genes for Type 2

Diabetes. BMC Syst Biol, 6 Suppl 3, S16

Herder H., and M. Roden (2011): Genetics of type 2 diabetes:

pathophysiologic and clinical relevance. Eur J Clin Invest, 41,

679-692

Karnes JH, T. Y. Langaee, C. W. McDonough, S. W. Chang, M.

Ramos, J. R. Catlin, Jr., O. E. Casanova, Y. Gong, C. J. Pepine, J.

A. Johnson and R. M. Cooper-Dehoff (2013): Lack of associa-

tion of the HMGA1 IVS5-13insC variant with type 2 diabetes

in an ethnically diverse hypertensive case control cohort. J

Transl Med, 11, 12

Liu, L., H. Ding, H. R. Wang, Y. J. Xu, G. L. Cui, P. H. Wang,

G. Yuan, X. F. Yu and D. W. Wang (2012): Polymorphism of

HMGA1 is associated with increased risk of type 2 diabetes

among Chinese individuals. Diabetologia, 55, 1685-1688

Mao M, K. J. Wertzler, S. C. Maloney, Z. Wang, N. S. Magnuson

and R. Reeves (2009): HMGA1 levels in uence mitochondrial

function and mitochondrial DNA repair ef ciency. Mol Cell

Biol, 29, 5426-5440

Marquez M, M. Huyvaert, J. R. Perry, R. D. Pearson, M. Fal-

chi, A. P. Morris, S. Vivequin, S. Lobbens, L. Yengo, S. Gaget,

F. Pattou, O. Poulain-Godefroy, G. Charpentier, L. M. Carls-

son, P. Jacobson, L. Sjostrom, O. Lantieri, B. Heude, A. Walley,

B. Balkau, M. Marre, P. Froguel and S. Cauchi (2012): Low-

frequency variants in HMGA1 are not associated with type 2

diabetes risk. Diabetes, 61, 524-530

Pullinger CR, I. D. Gold ne, S. Tanyolac, I. Movsesyan, M.

Faynboym, V. Durlach, E. Chiefari, D. P. Foti, P. H. Frost, M.

J. Malloy, A. Brunetti and J. P. Kane (2014): Evidence that an

HMGA1 gene variant associates with type 2 diabetes, body

mass index, and high-density lipoprotein cholesterol in a

Hispanic-American population. Metab Syndr Relat Disord, 12,

25-30

Smith RJ, D. M. Nathan, S. A. Arslanian, L. Groop, R. A. Rizza

and J. I. Rotter (2010): Individualizing therapies in type 2 dia-

betes mellitus based on patient characteristics: what we know

and what we need to know. J Clin Endocrinol Metab, 95, 1566-

1574

Voight BF., L. J. Scott, V. Steinthorsdottir, A. P. Morris, et al.,

(2010): Twelve type 2 diabetes susceptibility loci identi ed

through large-scale association analysis. Nat Genet, 42, 579-

589

Zhang,P X. Zhang, J. Brown, D. Vistisen, R. Sicree, J. Shaw

and G. Nichols (2010): Global healthcare expenditure on dia-

betes for 2010 and 2030. Diabetes Res Clin Pract, 87, 293-301

Qinglu Wang et al.