Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

66 / 244

rapid decline in renal function (10% decline of eGFR, area
Under ROC Curve 0.86).
Conclusions: Higher baseline DN_Score is associated with a
significantly decline of renal function in patients with T2DM
over a period of 2.5 years. Further investigations with a larger
study population and longer follow-up period will be neces-
sary for better validations of the predictive role of DN_Score on
the progression of DKD.
Genetics and Epidemiology
OL04-3
The association of GIPR variants with fat accumulation in
Chinese Han populations
Bo XU1, Rong ZHANG1, Feng JIANG1 , Cheng HU1, Weiping JIA1*.
1 Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,
China
Objectives: Obesity, particularly central obesity which is
considered as the culprit of obesity-associated complications
such as type 2 diabetes, metabolic syndrome and cardiovas-
cular disease, imposes seriousmedical and economic burdens.
Compared with body mass index (BMI), waist circumference
and waist to hip ratio, visceral fat area (VFA) and subcutaneous
fat area (SFA) is more precise as a measurement of obesity.
Genetic variants of glucose-dependent insulinotropic poly-
peptide receptor (GIPR) relevant to BMI and glucose metabol-
ism have been uncovered using genome-wide association
studies (GWAS). We aimed to test the association of GIPR with
fat distribution in Chinese Han populations.
Methods: A total of 2884 community-based individuals with
Chinese Han ancestry were genotyped for four tag single-
nucleotide polymorphisms (SNPs) of GIPR. Linear analysis was
applied to test the associations of these variants with VFA and
SFA quantified by Magnetic Resonance Imaging (MRI) as well
as glucose related traits.
Results: We replicated the effects of several loci of GIPR on BMI,
waist circumference as well as glucose related traits in Chinese
Han populations (P range from 9.46 × 10−5 to 0.028). In the
search for fat distribution variants, we found rs11671664 in
GIPR was associated with VFA and SFA in total subjects
(p = 0.018 and 0.020, respectively). In a subgroup analysis
stratified by gender, rs11671664 showed the association with
VFA in males (p = 0.030), whereas displayed the borderline
association with SFA in females (p = 0.049). However, after
adjusting for BMI, the association disappeared. Analysis of
linkage disequilibrium (LD) revealed no association between
the GIPR haplotype block (rs2334255 and rs2287019) and fat
distribution, while we observed that the GT and GC haplotypes
of rs2334255 and rs2287019 were associated with higher
glucose and insulin level as well as higher insulin sensitivity
assessed with Gutt index (P range from 1.90 × 10−5 to 0.045).
Conclusion: Our results suggest that the association between
rs11671664 and visceral fat distribution might be mediated by
BMI in Chinese Han populations.
OL04-4
Impaired pancreatic beta cell compensatory function is the
main cause of type 2 diabetes in individuals with high genetic
risk
Jing YAN 1 , Danfeng PENG1, Feng JIANG1, Cheng HU 1,2,
Weiping JIA 1*. 1Shanghai Diabetes Institute, Shanghai Key
Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for
Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s
Hospital, 2Institute for Metabolic Diseases, Shanghai Jiao Tong
University Affiliated Sixth People ’s Hospital South Campus, China
Aims/hypothesis: We aimed to evaluate the combined effects
of type 2 diabetes risk variants on predicting deterioration of
blood glucose and progression of beta cell function and insulin
sensitivity in a 9-year prospective cohort from the Chinese
population.
Methods: We constructed a weighted genetic risk score (GRS)
model based on 40 variants associated with type 2 diabetes
validated in an established cross-sectional Chinese population
(n = 6,822). The weighted scores were categorised into tertiles
to assess the predictive capacity for incidence of type 2
diabetes and impaired glucose regulation (IGR), as well as for
changes in Stumvoll first- and second-phase insulin secretion
indices and Gutt’s insulin sensitivity index (ISI) in a commu-
nity-based 9-year prospective cohort (n = 2,495), including
2192 individuals with normal glucose tolerance and 303 with
IGR at baseline, through logistic and multiple linear regression
tests.
Results: Weighted GRS predicted the incidence of type 2
diabetes and IGR in logistic regression (OR 1.236, 95% CI 1.100,
1.389, p = 0.0004) after adjusting for age, sex, BMI, smoking and
alcohol status at baseline.Moreover,weobserved thatweighted
GRS was able to predict deterioration in beta cell function (β =
–0.0480, p = 9.66 × 10−5 and β = − 0.0303, p = 3.32×10−5 for first-
and second-phase insulin secretion, respectively), but not
insulin sensitivity (p = 0.3815), during the 9-year follow-up
period.
Conclusions/interpretation: The weighted GRS predicted blood
glucose deterioration arising from change in beta cell function
in the Chinese population. Individuals in the intermediate- or
high-weighted GRS group exhibited progressive deterioration
of beta cell function.
OL04-5
Computational analysis of type 2 diabetes associated SNPs
and genes identified by GWASs
Mengrong CHENG1*, Xinhong LIU1, Mei YANG1, Lanchun HAN 1,
Aimin XU2, Qingyang HUANG1. 1College of Life Sciences, Central
China Normal University, 2The University of Hong Kong, China
Type 2 diabetes (T2D) is characterized by chronic hypergly-
cemia due to insulin resistance of peripheral tissues and
insufficient compensatory insulin secretion by pancreatic beta
cells. Until 2007, genetic study of T2D was mainly achieved by
genome-wide familial linkage analyses and candidate gene
association studies with limited success. Progress in identify-
ing common variants associated with T2D has since been
accelerated primarily by Genome-wide association studies
(GWASs). By the end of 2014, 43 GWASs and 13 meta-analyses
reported 116 genes and 161 SNPs (Lead SNP) that were
associated with T2D at the stringent threshold of 5 × 10−8 for
genome-wide significance. Functional characterization and
mechanistic elucidation of these SNPs and genes action are the
next major challenge. We conducted multiple computational
analyses to explore function and mechanisms of T2D GWAS-
associated SNPs and genes, including SNP conservation
analysis and functional annotation (influence of SNPs on
protein phosphorylation and miRNA binding, eQTLs), gene
ontology analysis, pathway enrichment analysis and protein-
protein interaction analysis.
Functional annotations using GWAS3D and RegulomeDB show
that most of the SNPs were located in the non-coding region
withmultiple regulatory functions. Thirty-eight lead SNPs had
the long-range regulatory signals. Comparative genomic
analyses showed that 9 SNPs are highly conserved. A total of
1174 proxy SNPs (r2≥ 0.80) were identified by SNAP based on
genotype data from the International HapMap Project(v3) and
the 1000 Genomes Pilot 1 Project with the CEU population
panel. Some T2D GWAS associated SNPs were located at
protein binding sites (identified through CHIP-seq), including
CTCF, EP300, HNF4A, TCF7L2, FOXA1 and FOXA2, which are
required for normal pancreatic development and maintaining
β-cell function. Two T2D GWAS lead SNPs and 29 proxy SNPs
were identified as miRNA related SNPs (miR-SNPs) that might
Oral Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S40–S64 S48