diabetes research and clinical practice 93 (2011) 390–395

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Diabetes Research
and Clinical Practice
jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es

Transcription factor 7-like 2 (TCF7L2) gene polymorphism and

complication/comorbidity profile in type 2 diabetes patients

Monika Buraczynska *, Andrzej Swatowski, Dorota Markowska-Gosik,

Agata Kuczmaszewska, Andrzej Ksiazek
Laboratory for DNA Analysis and Molecular Diagnostics, Department of Nephrology, Medical University of Lublin, Dr K. Jaczewskiego 8,
20-954 Lublin, Poland

article info abstract

Article history: Transcription factor 7-like 2 gene (TCF7L2) has been associated with type 2 diabetes. We
Received 17 January 2011 investigated the association of the rs7903146 SNP in this gene with clinical profile of type 2
Received in revised form diabetes (T2DM) patients.
11 April 2011 The study involved 980 patients with diabetic nephropathy (44%), diabetic retinopathy
Accepted 9 May 2011 (42%), CVD (65%) and early onset of diabetes (45%) and 924 healthy controls. Subjects were
Published on line 8 June 2011 genotyped for rs7903146 by PCR-RFLP.
Genotype frequencies significantly differed between T2DM patients and controls
Keywords: ( p < 0.01, odds ratio (OR) for TT genotype 2.49 (95% confidence interval (CI) 1.84-3.39). An
Diabetic nephropathy association was observed between rs7903146 and nephropathy ( p < 0.001), with 22% of TT
Gene polymorphism homozygotes in this subgroup vs. 11% in patients without nephropathy ( p = 0.006, OR for TT
Risk alleles 2.83, 95% CI 1.94–4.13). Association was stronger in patients with early onset of diabetes (34%
TCF7L2 of TT vs. 12% in the late onset, p < 0.001). In DN group 71% of TT homozygotes had an early
Type 2 diabetes onset (OR 7.64, 95% CI 4.98–11.73 vs. controls).
Our results confirm association of rs7903146 in the TCF7L2 gene with increased risk of
type 2 diabetes. The T allele is strongly associated with nephropathy, especially in early
onset of diabetes.
# 2011 Elsevier Ireland Ltd. All rights reserved.

Transcription factor 7-like 2 (TCF7L2), a protein belonging to

1. Introduction
A combination of multiple genetic and environmental factors
contributes to the pathogenesis of type 2 diabetes (T2DM) [1].
The identification of causative genes predisposing to T2DM
could provide means to better understanding the pathogene-
sis of the disease and result in better prevention, diagnosis and
treatment. With the advent of genome-wide association
scans, numerous risk variants have been identified as
candidates for conferring susceptibility to type 2 diabetes
but most of them with only modest effects [2].
a family of TCF/lymphoid enhancer factor (LEF) transcription
factors, is a key component of the Wnt signaling pathway
involved in the regulation of pancreatic beta-cell proliferation,
differentiation and insulin secretion [3,4].
The gene encoding TCF7L2 spans a 215,863 bp region on
chromosome 10q25.3 [5].
TCF7L2 is the most significant and consistent genetic risk
factor of diabetes identified to date. It was first identified as a
diabetes risk conferring gene in 2006 [6]. Later, the common
polymorphisms in the TCF7L2 have been associated with type
2 diabetes in numerous studies in different populations. The

* Corresponding author. Tel.: +48 81 7244 716; fax: +48 81 7244 357.
E-mail addresses: monika.buraczynska@am.lublin.pl, monika.buraczynska@umlub.pl (M. Buraczynska).
0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.diabres.2011.05.017
 diabetes research and clinical practice 93 (2011) 390–395
most significant genetic association was detected for two
intronic single nucleotide polymorphisms (SNPs), rs7903146
(intron 3) and rs12255372 (intron 4) located 50 kb from each
other [6–14].
The primary site of action for the TCF7L2 gene product in
type 2 diabetes is unknown. It was suggested that TCF7L2
might be associated with beta-cell dysfunction and decreased
insulin secretion but not with insulin resistance [15].
In this study we investigated the potential association of
the rs7903146 (C/T) polymorphism in the intron 3 of the TCF7L2
gene with type 2 diabetes. We also analyzed the effect of this
SNP on different clinical phenotypes in type 2 diabetes
patients.
2. Methods
2.1. Subjects
The study population consisted of 980 unrelated type 2
diabetes mellitus (T2DM) patients, consecutively enrolled
between January 2004 and September 2008. All subjects were
Caucasians of Polish origin. The patients were stratified into
subgroups with different clinical phenotypes: diabetic ne-
phropathy (DN) (n = 432), diabetic retinopathy (DR) (n = 408),
cardiovascular disease (CVD) (n = 635), early onset of diabetes
(45 years) (n = 438), and obesity (n = 189). In the diabetic
nephropathy subgroup 199 patients (46%) had also diabetic
retinopathy. Similarly, in the diabetic retinopathy subgroup,
216 patients (53%) had also nephropathy. Diabetes was
diagnosed according to American Diabetes Association crite-
ria. One or more of the following conditions were met: the
classic symptoms of hyperglycemia (polyuria, polydipsia, and
weight loss), fasting plasma glucose 126 mg/dl or random
plasma glucose 200 mg/dl, the use of insulin or oral
hypoglycemic agents. The mean duration of diabetes was
12.6 years (range 6–27). It was estimated from time of the first
symptoms attributable to the disease or time of first detection
of glycosuria. Diabetic nephropathy was diagnosed clinically
when the patient had persistent albuminuria 300 mg/24 h in
at least two consecutive determinations in the absence of
hematuria or infection. The patients without diabetic ne-
phropathy were normoalbuminuric, those with microalbumi-
nuria were excluded. Diabetic retinopathy was diagnosed by
independent ophthalmologists. All patients underwent a
complete ophthalmological examination, including corrected
visual acuity, fundoscopic examination and fundus photogra-
phy (three 458 fields per eye) at least every year. Fundoscopic
findings were determined by retinal specialists. Retinopathy
was diagnosed according to the Early Treatment Diabetic
Retinopathy Study (ETDRS) criteria: the presence of micro-
aneurysms, hemorrhages, cotton wool spots, intraretinal
microvascular abnormalities, hard exudates, venous beading
and new vessels. Cardiovascular disease was diagnosed and
documented as one or the combination of several pathological
states: congestive heart failure, left ventricular hypertrophy,
angina pectoris, ischemic heart disease, myocardial infarc-
tion, ischemic cerebral stroke, vascular calcifications or
atheromatous lesions. Each clinical manifestation of CVD
was confirmed by appropriate biochemical, radiographic,
391
echocardiographic and vascular diagnostic criteria. There
was a substantial overlap between categories. No gender
differences between the clinical phenotypes of CVD were
observed. Arrhythmia was more prevalent in male patients
but the difference did not reach statistical significance. At the
beginning of the study 642 individuals (65.5%) in the patient
group were hypertensives. Hypertension was defined accord-
ing to WHO criteria (World Health Organization, 1999). All
patients had persistent systolic blood pressure > 140 mm Hg
and diastolic blood pressure > 90 mm Hg and/or were receiv-
ing anti-hypertensive treatment. Secondary hypertension was
excluded by clinical and laboratory examination. Obesity was
defined as BMI  30 kg/m2. A positive family history of
diabetes in first-degree relatives was reported by 224 patients
(23%).
Glycemic control was evaluated by measuring glycated
HbA1c levels by turbidimetric inhibition immunoassay TINIA
using Tina-quant hemoglobin A1cII (Roche-Hitachi 747). All
other biochemical parameters were measured by standard
laboratory procedures.
Control subjects (n = 924) were healthy normotensive
volunteers (mostly blood donors and hospital staff members),
with no history of diabetes or hypertension. Written informed
consent was obtained from all subjects in accordance with
principles of the Declaration of Helsinki. The study protocol
was approved by the institutional ethics committee.
2.2. Genotyping
Genomic DNA was extracted from peripheral blood leukocytes
(obtained from EDTA anticoagulated blood) using a standard
technique. All subjects were genotyped for the rs7903146
single nucleotide polymorphism (SNP) by polymerase chain
reaction (PCR) and subsequent cleavage of amplified fragment
with Rsa I restriction endonuclease (Fermentas GmbH, St
Leon-Rot, Germany). DNA fragments were visualized on 3%
agarose gels. The quality of genotyping was controlled by
using blind DNA duplicates for some samples (96). Also, 30
samples were randomly selected for each genotype (CC, CT
and TT) and the PCR products were sequenced by automated
sequencing in CEQ 8000 Genetic Analysis System (Beckman
Coulter, High Wycombe, England). Observed concordance
between genotyping assays was 100%.
2.3. Statistical analysis
Statistical calculations were performed using SPSS 11.0 for
Windows (SPSS, Inc., Chicago, IL, USA). For baseline char-
acteristics the normally distributed continuous variables are
presented as means  SD. The Hardy–Weinberg equilibrium
was tested with the x2 test. Genotype distribution and allele
frequencies were compared between groups using a x2 test of
independence with 2  2 contingency and z statistics. Stu-
dent’s t-test and ANOVA were used for statistical significance
between variables/groups. Where appropriate, the odds ratios
(ORs) with corresponding 95% confidence intervals (CIs) were
calculated. A Bonferroni correction was applied for multiple
testing (4 comparisons: subgroups/nephropathy, retinopathy,
CVD, early onset of diabetes). Multivariate logistic regression
was performed for analysis of independent risk factor for
392 diabetes research and clinical practice 93 (2011) 390–395

Table 1 – Demographic and clinical profile of studied subjects.

Variable T2DM patients Controls p value
N 980 924
Male/female 512/468 492/432 NS
Age at study (years) 57  18 54  17 <0.001
Diabetes duration (years) 12.6  8a NA
Diabetic retinopathy (%) 408 (42) 0
Diabetic nephropathy (%) 432 (44) 0
Hypertension (%) 642 (65.5) 0
HbA1c (%) 8.2  3.8 ND
Total cholesterol (mmol/l) 5.1  1.51 3.9  1.71 <0.001
HDL cholesterol (mmol/l) 1.2  0.65 1.82  0.86 <0.001
Triglycerides (mmol/l) 2.3  1.78 1.17  0.93 <0.001
BMI (kg/m2) 27.4  3.6 26.2  3.4 <0.001
T2DM: type 2 diabetes mellitus. Values are presented as mean  SD or numbers (%). NA: not applicable and ND: not determined.
a
Mean diabetes duration was 14.0  9.2 for patients with DN and 11.2  6.8 for patients without DN.

diabetic nephropathy. A two-tailed type I error rate of 5% was
considered statistically significant. Power calculations were
done using on-line available power calculator (http://calcula-
tors.stat.ucla.edu).
3. Results
The genotype of the rs7903146 polymorphism in the TCF7L2
gene was determined in 980 patients with type 2 diabetes and
924 healthy individuals. The demographic and clinical profile
of studied subjects has been presented in Table 1.
The frequencies of the genotypes and alleles in the control
group were similar to those reported for other European
populations [16,17]. The genotype distribution among the
controls was in Hardy–Weinberg equilibrium. Table 2 shows
the genotypes of rs7903146 SNP in diabetes patients and
controls. The genotype distribution and allele frequencies
were significantly different between the entire diabetes group
and healthy individuals ( p < 0.01). The odds ratio (OR) for the
TT genotype vs. CC was 2.49 (95% CI 1.84–3.39).
Genotype and allele frequencies were compared in sub-
groups of diabetes patients with diabetic nephropathy,
diabetic retinopathy, CVD, early onset of diabetes and obesity.
The results are presented in Table 3. The frequency of the TT
genotype was higher in patients with CVD than in those
without cardiovascular comorbidity although the difference
did not reach a statistical significance ( p = 0.061). The same
tendency was observed for diabetic retinopathy and early
onset of diabetes, with no statistical significance after
adjusting for confounding factors. The T allele was associated
with an earlier age at diagnosis (54.3 years for CC, 54.1 years for
CT and 52.7 years for TT genotype, p < 0.01). There were no
statistically significant differences in the allele/genotype
distribution between obese and non-obese subjects (data
not shown).
After the Bonferroni correction for multiple comparisons a
strong association was observed between the rs7903146 SNP
and diabetic nephropathy (Table 4). The frequency of the TT
homozygous genotype in the diabetic nephropathy subgroup
was 22% compared to 9% in patients with no microvascular
complications after 10 years of T2DM duration. The OR for TT
genotype in DN patients, after adjusting for multiple testing,
was 3.71 (95% CI 1.99–6.93) vs. no complications subgroup.
After adjusting for age, sex, blood pressure, BMI and diabetes
duration, the odds ratio was 2.98 (95% CI 1.16–6.87).
The observed association of the rs7903146 SNP with
diabetic nephropathy was even stronger in patients with an
early onset of diabetes. The minor allele frequency was 0.52 vs.
0.28 in patients with no complications. The frequency of the
TT homozygotes in T2DM patients with early onset of diabetes
was 34% compared to 12% in patients with nephropathy and
late onset of diabetes ( p < 0.001). Of all TT homozygotes in
diabetic nephropathy group 71% were among patients with an
early onset of diabetes. After adjusting for multiple testing, OR
for TT genotype was 6.60 (95% CI 3.38–12.87) vs. no complica-
tions subgroup.
Logistic regression analysis revealed that the association of
minor allele of rs7903146 polymorphism with type 2 diabetes
and diabetic nephropathy remained significant after adjusting
for other covariates potentially associated with T2DM risk,
age, gender, hypertension, BMI, HbA1c and also diabetes
duration (OR 2.36, 95% CI 2.11–3.66 for T2DM and OR 2.73, 95%
CI 2.29–3.42 for diabetic nephropathy).

Table 2 – Genotype and allele distribution of rs7903146 SNP in the TCF7L2 gene in type 2 diabetes patients and controls.
Subjects CC CT TT MAF OR (95% CI)

For T allele For TT genotype

T2 DM (n = 980) 416 (42) 407 (42) 157 (16) 0.37 1.53 (1.33–1.76) 2.49 (1.84–3.39)
Controls (n = 924) 490 (53) 360 (39) 74 (8) 0.27 1.0 (ref.) 1.0 (ref.)
T2DM: type 2 diabetes mellitus and MAF: minor allele frequency. Data are n (%). HWE test: T2DM x2 = 11.22, p = 0.000809; Controls x2 = 0.48,
p = 0.488422. Statistical power for T2DM vs. controls = 99.1%.
 diabetes research and clinical practice 93 (2011) 390–395 393

Table 3 – The rs7903146 SNP and different clinical profiles in T2DM patient group.
Subjects CC CT TT MAF T allele carriers OR (95% CI)a
for T allele
CVD (n = 635) 261 (41) 254 (40) 120 (19) 0.39 374 (59) 1.29 (1.06–1.57)
No CVD (n = 345) 155 (45) 153 (44) 37 (11) 0.33 190 (55) 1.0 (ref.)
DR (n = 408) 162 (40) 167 (41) 79 (19) 0.40 246 (60) 1.25 (1.03–1.50)
No DR (n = 572) 254 (44) 240 (42) 78 (14) 0.35 318 (56) 1.0 (ref.)
Early onset of T2DM (n = 438) 178 (41) 172 (39) 88 (20) 0.40 260 (59) 1.25 (1.04–1.51)
Late onset of T2DM (n = 542) 238 (44) 235 (43) 69 (13) 0.34 304 (56) 1.0 (ref.)
T2DM: type 2 diabetes mellitus; CVD: cardiovascular disease; DR: diabetic retinopathy; and MAF: minor allele frequency.
a
Odds ratios were calculated: CVD vs. no CVD, DR vs. no DR, early onset vs. late onset, and adjusted for age, sex, blood pressure, BMI, HbA1c
and diabetes duration.

for nephropathy. However, this study did not distinguish

4. Discussion
Several recent studies have investigated the effect of SNPs in
TCF7L2 on type 2 diabetes development. So far TCF7L2 is the
most reproducible susceptibility gene for type 2 diabetes in
various ethnic groups [4,6,12,13,15,18,19]. Recently, in the
study of African American population, rs7903146 SNP in the
TCF7L2 gene was implicated as a causal variant in type 2
diabetes [20]. Functional studies also point to a functional role
of this SNP. Gaulton et al. [21] found that rs7903146 is located in
islet-selective open chromatin and shows allele-specific islet
enhancer activity.
In the present study we investigated the potential
association between type 2 diabetes and rs7903146 SNP in
the intron 3 of TCF7L2 gene in a large group of Polish patients
with type 2 diabetes. The results successfully replicated the
previously found association between this SNP and type 2
diabetes. In addition, after stratification it was apparent that
there is a strong association of this SNP with diabetic
nephropathy, especially in patients with an early onset of
diabetes. This could indicate to the higher risk of microvascu-
lar complications of T2DM for the T allele carriers. Previously
published papers suggested a possible association of the
rs7903146 variant with renal dysfunction in diabetic patients
[22–24]. In the older population of Italian subjects the T allele
carriers were more likely to have the key microvascular
complication of poor renal function [22]. Another study
investigated association of the TCF7L2 rs7903146 variant with
type 2 diabetes in an African-American population enriched
whether observed associations were with type 2 diabetes or
diabetic nephropathy [23]. Wu et al. investigated association of
diabetes related genes with diabetic nephropathy in Taiwa-
nese population. In a single locus analysis they found the
marginally significant association of rs7903146 variant with
DN [24]. In the study of French population there was no
evidence of association of the rs7903146 variant with type 2
diabetes complications such as CHD, severe nephropathy or
retinopathy (exact data were not reported) [18]. In our study
there was a trend towards association of TT genotype with
CVD in diabetes patients ( p = 0.061). Similar trend was
observed for CHD in the ARIC study [25]. In contrast, Sousa
et al. found a significant association between TCF7L2 rs7903146
genotypes and coronary artery disease in non-diabetic
subjects but were not able to demonstrate this association
in diabetic patients [26]. We found that the T allele of rs7903146
was associated with an earlier age at diagnosis. It is in
agreement with earlier studies [18,27,28].
A gene dosage effect has been observed. The risk of type 2
diabetes in TT homozygotes was increased by 2.49, similar to
the result obtained in another study performed in a group of
290 Polish patients with T2DM [29].
It is not clear how rs7903146 variant, located approximately
9 kb downstream of exon 4 of TCF7L2 gene, might affect its
expression or the function of the protein product. Functional
studies are required to elucidate this.
Our results should be viewed with caution since there is a
deviation from HWE estimates in cases. The genotyping errors
can be excluded since the quality of genotyping in our study

Table 4 – Genotype and allele distribution of rs7903146 SNP in diabetes patients with and without diabetic nephropathy.
Subjects CC CT TT MAF OR (95% CI)a
for T allele
DN (n = 432) 146 (34) 191 (44) 95 (22) 0.44 1.97 (1.49–2.61)
No DN (n = 548) 270 (50) 216 (39) 62 (11) 0.31 –
No complicationsb (n = 154) 80 (52) 60 (39) 14 (9) 0.28 1.0 (ref.)
Early onset with DN (n = 198) 58 (29) 73 (37) 67 (34) 0.52 2.74 (1.99–3.75)
Late onset with DN (n = 234) 88 (38) 118 (50) 28 (12) 0.37 1.47 (1.08–2.01)
DN: diabetic nephropathy and MAF: minor allele frequency.
a
After adjusting for multiple testing. Data are n (%). The OR for TT genotype: DN patients vs. no complications 3.71 (1.99–6.93) and adjusted for
age, sex, blood pressure, BMI and diabetes duration 2.98 (1.16–6.87), early onset with DN vs. no complications 6.60 (3.38–12.87) and adjusted 5.93
(2.96–11.04). Statistical power for DN vs. no complications = 97.4%.
b
No microvascular complications after 10 years of T2DM duration.
394 diabetes research and clinical practice 93 (2011) 390–395
was carefully controlled with using blind sample duplicates
and direct sequencing. The likely reason for deviation from
HWE may be selection bias.
As most of the association studies, ours has some
limitations. Since it is a retrospective case-control study, a
selection bias cannot be excluded. To limit this bias we
included consecutive patients in the study and tried to adjust
for known confounding risk factors. All normoglycemic
individuals with traits related to type 2 diabetes, like obesity,
hypertension or hyperlipidemia, were excluded from the
study.
The strength of our study is that all patients and controls
are of the same ethnic origin. Furthermore all subjects were
examined employing well defined diagnostic criteria and
genotyping was performed blind with respect to case-control
status. The sample size in our study had 97.4% power to detect
the genetic effect of TCF7L2 allele at a p value of 0.05.
In conclusion, the findings of our study confirm that the
risk allele of the rs7903146 SNP in the TCF7L2 gene is strongly
associated with type 2 diabetes, even after correcting for
traditional risk factors. The T allele of this polymorphism also
conferred the risk of developing diabetic nephropathy.
Acknowledgements
This study was supported by the grants DS 379/09 and DS 383/
09 from Medical University of Lublin.
Conflict of interest
The authors declare no conflict of interest.
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