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1.  PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 Are Associated with Type 2 Diabetes in a Chinese Population 
PLoS ONE  2009;4(10):e7643.
Background
Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism.
Methods/Principal Findings
Twenty-one single nucleotide polymorphisms (SNPs) from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12). But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090). The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006).
Conclusions/Significance
The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively.
doi:10.1371/journal.pone.0007643
PMCID: PMC2763267  PMID: 19862325
2.  No association of multiple type 2 diabetes loci with type 1 diabetes 
Diabetologia  2009;52(10):2109-2116.
Aims/hypothesis
We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003.
Methods
The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A–CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX–IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX–IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions.
Results
Only PPARG and HHEX–IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; pcombined = 1.0 × 10−4). No SNPs showed evidence of interaction with any covariate (p > 0.05).
Conclusions/interpretation
We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-009-1391-y) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-009-1391-y
PMCID: PMC2738846  PMID: 19455305
Age-at-diagnosis; Association study; Autoantibodies; Genetics;  PPARG; SLC30A8; Type 1 diabetes; Type 2 diabetes
3.  No association of multiple type 2 diabetes loci with type 1 diabetes 
Diabetologia  2009;52(10):2109-2116.
Aims/hypothesis
We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003.
Methods
The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A–CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX–IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX–IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions.
Results
Only PPARG and HHEX–IDE showed any evidence of association with type 1 diabetes cases and controls (p=0.004 and p=0.003, respectively; p>0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p=0.003; pcombined=1.0×10-4). No SNPs showed evidence of interaction with any covariate (p>0.05).
Conclusions/interpretation
We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.
doi:10.1007/s00125-009-1391-y
PMCID: PMC2738846  PMID: 19455305
ADAMTS9; Association study; CDC123–CAMK1D; Genetics; JAZF1; NOTCH2; TSPAN8–LGR5; Type 1 diabetes; Type 2 diabetes
4.  Association study of genetic variants in eight genes/loci with type 2 diabetes in a Han Chinese population 
BMC Medical Genetics  2010;11:97.
Background
At least twenty genes/loci were shown to be associated with type 2diabetes in European original populations. Five of these genes were shown to be associated with type 2 diabetes (T2D) in Chinese populations. The purpose of this study was to replicate the association of genetic vairants in the eight diabetes-related genes/loci with type 2 diabetes in a Han Chinese cohort from western part of China. Nineteen single nucleotide polymorphisms (SNPs) from the eight genes/loci including TCF7L2, HHEX, CDKAL1, SLC30A8, PPARG, IGF2BP2, KCNJ11, and CDKN2A/CDKN2B were genotyped in 1,529 cases and 1,439 controls in a Han Chinese population using the ABI SNaPshot method. The meta-analysis of the association between rs7903146 in TCF7L2 gene and T2D in the Han Chinese was performed.
Results
Among the eight genes/loci examined, we found that four were significantly associated with T2D. Although previous studies showed that the association between the SNP rs7903146 in the TCF7L2 gene and T2D was controversial within the Han Chinese population, we have confirmed the significant association between the SNP rs7903146 in the TCF7L2 gene and T2D in both this study and the meta-analysis in the population. In addition, we also confirmed that three SNPs (rs1111875, rs7923837 and rs5015480) in HHEX , one SNP (rs10946398) in CDKAL1, and three SNPs (rs13266634, rs3802177 and rs11558471) in SLC30A8 were significantly associated with T2D in the population being studied.
Conclusions
We demonstrated that the variants in TCF7L2, CDKAL1, HHEX, and SLC30A8 genes are associated with T2D in a Han Chinese population.
doi:10.1186/1471-2350-11-97
PMCID: PMC2894791  PMID: 20550665
5.  Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes With Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5,327 Nondiabetic Finnish Men 
Diabetes  2009;58(9):2129-2136.
OBJECTIVE
We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin.
RESEARCH DESIGN AND METHODS
A total of 5,327 nondiabetic men (age 58 ± 7 years, BMI 27.0 ± 3.8 kg/m2) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium.
RESULTS
Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, and MTNR1B) were significantly (P < 6.9 × 10−4) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P < 0.05) associated with early-phase insulin release (InsAUC0–30/GluAUC0–30), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached −32% reduction in InsAUC0–30/GluAUC0–30 in carriers of ≥11 vs. ≤3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, and TCF7L2) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs (KCNJ11, HHEX, and TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC0–30/GluAUC0–30. Nine SNPs did not show any associations with examined traits.
CONCLUSIONS
Eight type 2 diabetes–related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity.
doi:10.2337/db09-0117
PMCID: PMC2731523  PMID: 19502414
6.  Contribution of Common Genetic Variation to the Risk of Type 2 Diabetes in the Mexican Mestizo Population 
Diabetes  2012;61(12):3314-3321.
Several studies have identified nearly 40 different type 2 diabetes susceptibility loci, mainly in European populations, but few of them have been evaluated in the Mexican population. The aim of this study was to examine the extent to which 24 common genetic variants previously associated with type 2 diabetes are associated in Mexican Mestizos. Twenty-four single nucleotide polymorphisms (SNPs) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZF1, CDC123/CAMK1D, FTO, TSPAN8/LGR5, KCNQ1, THADA, ADAMTS9, NOTCH2, NXPH1, RORA, UBQLNL, and RALGPS2) were genotyped in Mexican Mestizos. A case-control association study comprising 1,027 type 2 diabetic individuals and 990 control individuals was conducted. To account for population stratification, a panel of 104 ancestry-informative markers was analyzed. Association to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs4402960 (IGF2BP2), rs12779790 (CDC123/CAMK1D), and rs2237892 (KCNQ1). In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. Lack of association for the rest of the variants may have resulted from insufficient power to detect smaller allele effects.
doi:10.2337/db11-0550
PMCID: PMC3501881  PMID: 22923468
7.  Lack of Association of Type 2 Diabetes Susceptibility Genotypes and Body Weight on the Development of Islet Autoimmunity and Type 1 Diabetes 
PLoS ONE  2012;7(4):e35410.
Aim
To investigate whether type 2 diabetes susceptibility genes and body weight influence the development of islet autoantibodies and the rate of progression to type 1 diabetes.
Methods
Genotyping for single nucleotide polymorphisms (SNP) of the type 2 diabetes susceptibility genes CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG, SLC30A8 and TCF7L2 was obtained in 1350 children from parents with type 1 diabetes participating in the BABYDIAB study. Children were prospectively followed from birth for islet autoantibodies and type 1 diabetes. Data on weight and height were obtained at 9 months, 2, 5, 8, 11, and 14 years of age.
Results
None of type 2 diabetes risk alleles at the CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG and SLC30A8 loci were associated with the development of islet autoantibodies or diabetes. The type 2 diabetes susceptible genotype of TCF7L2 was associated with a lower risk of islet autoantibodies (7% vs. 12% by age of 10 years, P = 0.015, Pcorrected = 0.18). Overweight children at seroconversion did not progress to diabetes faster than non-overweight children (HR: 1.08; 95% CI: 0.48–2.45, P>0.05).
Conclusions
These findings do not support an association of type 2 diabetes risk factors with islet autoimmunity or acceleration of diabetes in children with a family history of type 1 diabetes.
doi:10.1371/journal.pone.0035410
PMCID: PMC3338842  PMID: 22558147
8.  Examination of Type 2 Diabetes Loci Implicates CDKAL1 as a Birth Weight Gene 
Diabetes  2009;58(10):2414-2418.
OBJECTIVE
A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 and HHEX-IDE loci, regions that were previously implicated in the pathogenesis of type 2 diabetes. In order to investigate whether type 2 diabetes risk–conferring alleles associate with low birth weight in our Caucasian childhood cohort, we examined the effects of 20 such loci on this trait.
RESEARCH DESIGN AND METHODS
Using data from an ongoing genome-wide association study in our cohort of 5,465 Caucasian children with recorded birth weights, we investigated the association of the previously reported type 2 diabetes–associated variation at 20 loci including TCF7L2, HHEX-IDE, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B, and JAZF1 with birth weight.
RESULTS
Our data show that the minor allele of rs7756992 (P = 8 × 10−5) at the CDKAL1 locus is strongly associated with lower birth weight, whereas a perfect surrogate for variation previously implicated for the trait at the same locus only yielded nominally significant association (P = 0.01; r2 rs7756992 = 0.677). However, association was not detected with any of the other type 2 diabetes loci studied.
CONCLUSIONS
We observe association between lower birth weight and type 2 diabetes risk–conferring alleles at the CDKAL1 locus. Our data show that the same genetic locus that has been identified as a marker for type 2 diabetes in previous studies also influences birth weight.
doi:10.2337/db09-0506
PMCID: PMC2750235  PMID: 19592620
9.  Replication Study of Candidate Genes Associated With Type 2 Diabetes Based On Genome-Wide Screening 
Diabetes  2009;58(2):493-498.
OBJECTIVE—The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single-nucleotide polymorphisms (SNPs) from the TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2A/B, SLC30A8, and KCNJ11 genes were analyzed.
RESEARCH DESIGN AND METHODS—Candidate SNPs were genotyped in 506 type 2 diabetic patients and 402 control subjects and meta-analyzed with six previous association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population sample (n = 1,963, 61 ± 13 years).
RESULTS—In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 [1.298–2.263]). Odds ratio of other polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in type 2 diabetic patients after adjustment for other confounding factors.
CONCLUSIONS—Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type 2 diabetes was independent of ethnic background.
doi:10.2337/db07-1785
PMCID: PMC2628625  PMID: 19033397
10.  Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk 
BMC Medical Genetics  2008;9:59.
Background
Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (PPARG2; rs 1801282); insulin-like growth factor two binding protein 2 (IGF2BP2; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (CDK5; rs7754840); a zinc transporter and member of solute carrier family 30 (SLC30A8; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (CDKN2A; rs10811661); hematopoietically expressed homeobox (HHEX; rs 1111875); transcription factor-7-like 2 (TCF7L2; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(KCNJ11; rs 5219); and fat mass obesity-associated gene (FTO; rs 9939609)].
Methods
We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis.
Results
Four of the nine SNPs revealed a significant association with T2D; PPARG2 (Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03–0.52); p = 0.005], IGF2BP2 [OR 1.37; 95% CI (1.04–1.82); p = 0.027], TCF7L2 [OR 1.64; 95% CI (1.20–2.24); p = 0.001] and FTO [OR 1.46; 95% CI (1.11–1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of CDK5 (rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of TCF7L2 (rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort.
Conclusion
To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.
doi:10.1186/1471-2350-9-59
PMCID: PMC2481250  PMID: 18598350
11.  Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in Type 2 Diabetes in a Chinese population 
BMC Medical Genetics  2010;11:81.
Background
Recently, several genome-wide and candidate gene association studies have identified many novel genetic loci for type 2 diabetes (T2D); among these genes, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 are the most important. We aimed to determine the effects of these genetic loci associated with T2D in the Chinese Han population of China.
Methods
Single-nucleotide polymorphisms (SNPs) in or near CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 genes were genotyped in a case-control Chinese Han sample living in Beijing, China involving 1024 patients with T2D and 1005 control subjects.
Results
In Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs) as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008) for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003) for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009) for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005) for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03) for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 × 10-4) for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046) for FTO-rs8050136 after adjustment for age, gender, and body mass index. Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis. Moreover, the relationship between FTO-rs8050136 and body mass index, together with the effect of CDKAL1-rs10946398 on beta cell function, was also observed in the control individuals.
Conclusions
Our findings support the important contribution of these genetic loci to susceptibility for T2D in the Chinese Han population in Beijing of China.
doi:10.1186/1471-2350-11-81
PMCID: PMC2896346  PMID: 20509872
12.  Common Variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE Genes Are Associated With Type 2 Diabetes and Impaired Fasting Glucose in a Chinese Han Population 
Diabetes  2008;57(10):2834-2842.
OBJECTIVE— Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.
RESEARCH DESIGN AND METHODS— We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.
RESULTS— We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27–1.75]; P = 8.91 × 10−7) and CDKN2A/B (1.31 [1.12–1.54]; P = 1.0 × 10−3). We observed significant association of SNPs in IGF2BP2 (1.17 [1.03–1.32]; P = 0.014) and SLC30A8 (1.12 [1.01–1.25]; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2, and SLC30A8 were also associated with impaired β-cell function estimated by homeostasis model assessment of β-cell function. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) or for combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 × 10−11). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013) but not in those from Beijing (P > 0.33).
CONCLUSIONS— Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through β-cell dysfunction.
doi:10.2337/db08-0047
PMCID: PMC2551696  PMID: 18633108
13.  Investigation of Type 2 Diabetes Risk Alleles Support CDKN2A/B, CDKAL1, and TCF7L2 As Susceptibility Genes in a Han Chinese Cohort 
PLoS ONE  2010;5(2):e9153.
Background
Recent genome-wide association studies (GWASs) have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort.
Methodology/Principal Findings
Selected type 2 diabetes–associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P≤0.05), of whom the three first would stand correction for multiple testing: CDKN2A/B rs10811661, OR: 1.26 (1.12–1.43) P = 1.8*10−4; CDKAL1 rs10946398, OR: 1.23 (1.09–1.39); P = 7.1*10−4, and TCF7L2 rs7903146, OR: 1.61 (1.19–2.18) P = 2.3 * 10−3. Only nominal phenotype associations were observed, notably for rs8050136 in FTO and fasting plasma glucose (P = 0.002), postprandial plasma glucose (P = 0.002), and fasting C-peptide levels (P = 0.006) in the diabetic patients, and with BMI in controls (P = 0.033).
Conclusions/Significance
We have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities.
doi:10.1371/journal.pone.0009153
PMCID: PMC2818850  PMID: 20161779
14.  Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population 
Diabetes  2009;58(7):1690-1699.
OBJECTIVE
To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population.
RESEARCH DESIGN AND METHODS
In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10–5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population.
RESULTS
Four loci—1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 × 10–5) and three previously reported—were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10–19). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population.
CONCLUSIONS
The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.
doi:10.2337/db08-1494
PMCID: PMC2699880  PMID: 19401414
15.  Genetic Risk Score Constructed Using 14 Susceptibility Alleles for Type 2 Diabetes Is Associated With the Early Onset of Diabetes and May Predict the Future Requirement of Insulin Injections Among Japanese Individuals 
Diabetes Care  2012;35(8):1763-1770.
OBJECTIVE
We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes.
RESEARCH DESIGN AND METHODS
We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features.
RESULTS
Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10−21). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = −0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = −0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = −0.031, SE = 0.012, P = 0.0125).
CONCLUSIONS
Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell–preserving therapy.
doi:10.2337/dc11-2006
PMCID: PMC3402252  PMID: 22688542
16.  Prioritizing genes for follow-up from genome wide association studies using information on gene expression in tissues relevant for type 2 diabetes mellitus 
BMC Medical Genomics  2009;2:72.
Background
Genome-wide association studies (GWAS) have emerged as a powerful approach for identifying susceptibility loci associated with polygenetic diseases such as type 2 diabetes mellitus (T2DM). However, it is still a daunting task to prioritize single nucleotide polymorphisms (SNPs) from GWAS for further replication in different population. Several recent studies have shown that genetic variation often affects gene-expression at proximal (cis) as well as distal (trans) genomic locations by different mechanisms such as altering rate of transcription or splicing or transcript stability.
Methods
To prioritize SNPs from GWAS, we combined results from two GWAS related to T2DM, the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC), with genome-wide expression data from pancreas, adipose tissue, liver and skeletal muscle of individuals with or without T2DM or animal models thereof to identify T2DM susceptibility loci.
Results
We identified 1,170 SNPs associated with T2DM with P < 0.05 in both GWAS and 243 genes that were located in the vicinity of these SNPs. Out of these 243 genes, we identified 115 differentially expressed in publicly available gene expression profiling data. Notably five of them, IGF2BP2, KCNJ11, NOTCH2, TCF7L2 and TSPAN8, have subsequently been shown to be associated with T2DM in different populations. To provide further validation of our approach, we reversed the approach and started with 26 known SNPs associated with T2DM and related traits. We could show that 12 (57%) (HHEX, HNF1B, IGF2BP2, IRS1, KCNJ11, KCNQ1, NOTCH2, PPARG, TCF7L2, THADA, TSPAN8 and WFS1) out of 21 genes located in vicinity of these SNPs were showing aberrant expression in T2DM from the gene expression profiling studies.
Conclusions
Utilizing of gene expression profiling data from different tissues of individuals with or without T2DM or animal models thereof is a powerful tool for prioritizing SNPs from WGAS for further replication studies.
doi:10.1186/1755-8794-2-72
PMCID: PMC2815699  PMID: 20043853
17.  Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets 
Diabetologia  2013;56(5):1036-1046.
Aims/hypothesis
To date, the molecular function of most of the reported type 2 diabetes-associated loci remains unknown. The introduction or removal of cytosine–phosphate–guanine (CpG) dinucleotides, which are possible sites of DNA methylation, has been suggested as a potential mechanism through which single-nucleotide polymorphisms (SNPs) can affect gene function via epigenetics. The aim of this study was to examine if any of 40 SNPs previously associated with type 2 diabetes introduce or remove a CpG site and if these CpG-SNPs are associated with differential DNA methylation in pancreatic islets of 84 human donors.
Methods
DNA methylation was analysed using pyrosequencing.
Results
We found that 19 of 40 (48%) type 2 diabetes-associated SNPs introduce or remove a CpG site. Successful DNA methylation data were generated for 16 of these 19 CpG-SNP loci, representing the candidate genes TCF7L2, KCNQ1, PPARG, HHEX, CDKN2A, SLC30A8, DUSP9, CDKAL1, ADCY5, SRR, WFS1, IRS1, DUSP8, HMGA2, TSPAN8 and CHCHD9. All analysed CpG-SNPs were associated with differential DNA methylation of the CpG-SNP site in human islets. Moreover, six CpG-SNPs, representing TCF7L2, KCNQ1, CDKN2A, ADCY5, WFS1 and HMGA2, were also associated with DNA methylation of surrounding CpG sites. Some of the type 2 diabetes CpG-SNP sites that exhibit differential DNA methylation were further associated with gene expression, alternative splicing events determined by splice index, and hormone secretion in the human islets. The 19 type 2 diabetes-associated CpG-SNPs are in strong linkage disequilibrium (r2 > 0.8) with a total of 295 SNPs, including 91 CpG-SNPs.
Conclusions/interpretation
Our results suggest that the introduction or removal of a CpG site may be a molecular mechanism through which some of the type 2 diabetes SNPs affect gene function via differential DNA methylation and consequently contributes to the phenotype of the disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2815-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-012-2815-7
PMCID: PMC3622750  PMID: 23462794
Alternative splicing; CpG-SNP; DNA methylation; Epigenetics; Glucagon; Human pancreatic islets; Insulin secretion; SNP; Splice index; Type 2 diabetes
18.  Examination of All Type 2 Diabetes GWAS Loci Reveals HHEX-IDE as a Locus Influencing Pediatric BMI 
Diabetes  2009;59(3):751-755.
OBJECTIVE
A number of studies have found that BMI in early life influences the risk of developing type 2 diabetes later in life. Our goal was to investigate if any type 2 diabetes variants uncovered through genome-wide association studies (GWAS) impact BMI in childhood.
RESEARCH DESIGN AND METHODS
Using data from an ongoing GWAS of pediatric BMI in our cohort, we investigated the association of pediatric BMI with 20 single nucleotide polymorphisms at 18 type 2 diabetes loci uncovered through GWAS, consisting of ADAMTS9, CDC123-CAMK1D, CDKAL1, CDKN2A/B, EXT2, FTO, HHEX-IDE, IGF2BP2, the intragenic region on 11p12, JAZF1, KCNQ1, LOC387761, MTNR1B, NOTCH2, SLC30A8, TCF7L2, THADA, and TSPAN8-LGR5. We randomly partitioned our cohort exactly in half in order to have a discovery cohort (n = 3,592) and a replication cohort (n = 3,592).
RESULTS
Our data show that the major type 2 diabetes risk–conferring G allele of rs7923837 at the HHEX-IDE locus was associated with higher pediatric BMI in both the discovery (P = 0.0013 and survived correction for 20 tests) and replication (P = 0.023) sets (combined P = 1.01 × 10−4). Association was not detected with any other known type 2 diabetes loci uncovered to date through GWAS except for the well-established FTO.
CONCLUSIONS
Our data show that the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric BMI.
doi:10.2337/db09-0972
PMCID: PMC2828649  PMID: 19933996
19.  Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples 
Science (New York, N.Y.)  2007;316(5829):1336-1341.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
doi:10.1126/science.1142364
PMCID: PMC3772310  PMID: 17463249
20.  The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI 
BMC Medical Genetics  2010;11:140.
Background
Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI).
Methods
The study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.
Results
In cross-sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the A allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood.
Conclusions
There was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time.
doi:10.1186/1471-2350-11-140
PMCID: PMC2958899  PMID: 20929593
21.  Association Analysis of Variation in/Near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B With Type 2 Diabetes and Related Quantitative Traits in Pima Indians 
Diabetes  2009;58(2):478-488.
OBJECTIVE—In recent genome-wide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians.
RESEARCH DESIGN AND METHODS—Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits.
RESULTS—FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI (P = 0.002). None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects (P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion.
CONCLUSIONS—Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic “genetic risk profile” identified in Caucasians is associated with diminished early insulin secretion in Pima Indians.
doi:10.2337/db08-0877
PMCID: PMC2628623  PMID: 19008344
22.  Cross-Sectional and Longitudinal Replication Analyses of Genome-Wide Association Loci of Type 2 Diabetes in Han Chinese 
PLoS ONE  2014;9(3):e91790.
This study aimed to examine genomic loci of type 2 diabetes (T2D) initially identified by genome-wide association studies in populations of European ancestry for their associations with T2D and quantitative glycemic traits, as well as their effects on longitudinal change in fasting plasma glucose (FPG) and T2D development, in the Chinese population. Single nucleotide polymorphisms (SNP) from 25 loci were genotyped in a large case-control sample of 10,001 subjects (5,338 T2D cases and 4,663 controls) and a prospective cohort of 1,881 Chinese. In the case-control sample, 8 SNPs in or near WFS1, CDKAL1, CDKN2A/2B, CDC123, HHEX, TCF7L2, KCNQ1, and MTNR1B were significantly associated with T2D (P<0.05). Thirteen SNPs were associated with quantitative glycemic traits. For example, the most significant SNP, rs10811661 near CDKN2A/2B (P = 1.11×10−8 for T2D), was also associated with 2-h glucose level of an oral glucose tolerance test (P = 9.11×10−3) and insulinogenic index (P = 2.71×10−2). In the cohort study, individuals carrying more risk alleles of the replicated SNPs had greater FPG increase and T2D incidence in a 7.5-year follow-up period, with each quartile increase in the number of risk alleles being associated with a 0.06 mmol/l greater increase in FPG (P = 0.03) and 19% higher odds of developing T2D (P = 0.058). Our study identified the associations of several established T2D-loci in Europeans with T2D and quantitative glycemic traits in the Chinese population. The prospective data also suggest their potential role in the risk prediction of T2D in the Chinese population.
doi:10.1371/journal.pone.0091790
PMCID: PMC3956742  PMID: 24637646
23.  Diabetes genes and prostate cancer in the Atherosclerosis Risk in Communities study 
There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms (SNPs) from genome-wide association (GWA) studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D SNPs from pre-GWA studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987–2000, there were 397 incident PrCa cases among 6,642 men aged 45–64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele (hazard ratio [HR]=1.20; 95% confidence interval [CI]=1.00, 1.44) and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR=0.85; 95% CI=0.72, 1.00), the UCP2 rs660339 Val55 allele (HR=0.84; 95% CI=0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR=0.79; 95% CI=0.61, 1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR=0.79; 95% CI=0.65, 0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology.
doi:10.1158/1055-9965.EPI-09-0902
PMCID: PMC2820124  PMID: 20142250
Diabetes Mellitus; Type 2; Genetics; Risk; Polymorphism; Single Nucleotide; Prostatic Neoplasms
24.  Use of Net Reclassification Improvement (NRI) Method Confirms The Utility of Combined Genetic Risk Score to Predict Type 2 Diabetes 
PLoS ONE  2013;8(12):e83093.
Background
Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we investigated their individual and combined effects on T2D in a Chinese population.
Methodology
We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI).
Results
We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10−18
Conclusion
In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).
doi:10.1371/journal.pone.0083093
PMCID: PMC3869744  PMID: 24376643
PLoS Genetics  2011;7(4):e1001363.
Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.
Author Summary
Type 2 diabetes mellitus (T2D) is a chronic disease which can lead to complications such as heart disease, stroke, hypertension, blindness due to diabetic retinopathy, amputations from peripheral vascular diseases, and kidney disease from diabetic nephropathy. The increasing prevalence and complications of T2D are likely to increase the health and economic burden of individuals, families, health systems, and countries. Our study carried out in three major Asian ethnic groups (Chinese, Malays, and Indians) in Singapore suggests that the findings of studies carried out in populations of European ancestry (which represents most studies to date) may be relevant to populations in Asia. However, our study also raises the possibility that different genes, and within the genes different variants, may confer susceptibility to T2D in these populations. These findings are particularly relevant in Asia, where the greatest growth of T2D is expected in the coming years, and emphasize the importance of studying diverse populations when trying to localize the regions of the genome associated with T2D. In addition, we may need to consider novel methods for combining data across populations.
doi:10.1371/journal.pgen.1001363
PMCID: PMC3072366  PMID: 21490949

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