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1.
C. Hu C. Wang R. Zhang X. Ma J. Wang J. Lu W. Qin Y. Bao K. Xiang W. Jia 《Diabetologia》2009,52(7):1322-1325
Aims/hypothesis Recent genome-wide association studies in East Asian populations reported that single nucleotide polymorphisms (SNPs) in KCNQ1 are associated with type 2 diabetes. The aim of this study was to validate this finding in a Chinese population.
Methods We genotyped four SNPs, rs2074196, rs2237892, rs2237895 and rs2237897, in a group of 3,503 Shanghai Chinese individuals, comprising
1,769 type 2 diabetic patients and 1,734 normoglycaemic controls. Both the cases and the controls were extensively phenotyped
for anthropometric and biochemical traits related to glucose metabolism. Arginine stimulation tests under fasting conditions
were performed in a subgroup of 466 cases.
Results All four of the SNPs were associated with type 2 diabetes, with rs2237892 showing strongest evidence for association (OR 1.532,
95% CI 1.381–1.698, p = 5.0 × 10−16). The SNP rs2237897 was associated with both acute insulin and C-peptide response after arginine stimulation in a subgroup
of cases (p = 0.0471 and p = 0.0156, respectively). The SNP rs2237895 was associated with both first- and second-phase insulin secretion in the controls
(p = 0.0334 and p = 0.0002, respectively).
Conclusions/interpretation In this study we found that KCNQ1 was associated with type 2 diabetes susceptibility in a Chinese population, possibly through its effect on beta cell function.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
2.
P. W. Franks O. Rolandsson S. L. Debenham K. A. Fawcett F. Payne C. Dina P. Froguel K. L. Mohlke C. Willer T. Olsson N. J. Wareham G. Hallmans I. Barroso M. S. Sandhu 《Diabetologia》2008,51(3):523-463
Aims/hypothesis Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish
case–control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from
Sweden, Finland and France, to obtain updated summary effect estimates.
Methods Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case–control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type
2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants.
Results In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR)
0.85, 95% CI 0.75–0.96, p = 0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent
replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI
0.82–0.93, p = 4.5 × 10−5). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95%
CI 0.86–0.92; p = 4.9 × 10−11).
Conclusions/interpretation In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and
the risk of type 2 diabetes.
An erratum to this article can be found at 相似文献
3.
C. S. Yajnik C. S. Janipalli S. Bhaskar S. R. Kulkarni R. M. Freathy S. Prakash K. R. Mani M. N. Weedon S. D. Kale J. Deshpande G. V. Krishnaveni S. R. Veena C. H. D. Fall M. I. McCarthy T. M. Frayling A. T. Hattersley G. R. Chandak 《Diabetologia》2009,52(2):247-252
Aims and hypothesis Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations
are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not
seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune.
Methods We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals
from Mysore, South India.
Results We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13–1.40;
p = 3 × 10−5). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01–0.10) than the
previously reported effect in Europeans (0.10 SDs; 95% CI 0.09–0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per
allele for type 2 diabetes 1.21; 95% CI 1.06–1.37; p = 4.0 × 10−3), and also for waist circumference and other anthropometric variables.
Conclusions Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely
mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body
size with type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
C. S. Janipalli, S. Bhaskar, S. R. Kulkarni and R. M. Freathy contributed equally to this study. 相似文献
4.
Bakhtadze E Cervin C Lindholm E Borg H Nilsson P Arnqvist HJ Bolinder J Eriksson JW Gudbjörnsdottir S Nyström L Agardh CD Landin-Olsson M Sundkvist G Groop LC 《Diabetologia》2008,51(12):2224-2232
Aims/hypothesis Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain
risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested
whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune
diabetes in young (15–34 years) and middle-aged (40–59 years) diabetic patients.
Methods In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in
the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5)
fasting plasma C-peptide.
Results Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p
= 9.4×10−34; 45% vs 18%, p
= 1.4 × 10−16), PTPN22 CT/TT (34% vs 26%, p
= 0.0023; 31% vs 23%, p
= 0.034), INS VNTR class I/I (69% vs 53%, p
= 1.3 × 10−8; 69% vs 51%, p
= 8.5 × 10−5) and INS VNTR class IIIA/IIIA (75% vs 63%, p
= 4.3 × 10−6; 73% vs 60%, p
= 0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type
2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p
= 0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%).
Conclusions/interpretation Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young
GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive
counterparts and share genetic features with type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
G. Sundkvist died in September 2006. 相似文献
5.
Y. M. Cho T. H. Kim S. Lim S. H. Choi H. D. Shin H. K. Lee K. S. Park H. C. Jang 《Diabetologia》2009,52(2):253-261
Aims/hypothesis New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide
association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants
and gestational diabetes mellitus (GDM).
Methods The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single
nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A−CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls.
Results Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34–1.79,
p = 4.17 × 10−9) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29–1.72, p = 1.05 × 10−7) in the CDKN2A−CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09–1.49, p = 0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01–1.38, p = 0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07–1.43, p = 0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03–2.43, p = 0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A–CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM.
Conclusions/interpretation Some of the type 2 diabetes-associated genetic variants that were discovered in the recent GWA studies are also associated
with GDM in Koreans.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
Y. M. Cho and T. H. Kim contributed equally to this study. 相似文献
6.
Q. Qi Y. Wu H. Li R. J. F. Loos F. B. Hu L. Sun L. Lu A. Pan C. Liu H. Wu L. Chen Z. Yu X. Lin 《Diabetologia》2009,52(5):834-843
Aims/hypothesis The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The
aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms
underlying these associations.
Methods The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals
(n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes.
Results The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [p
(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95%
CI 0.77–0.96, p
[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B)
and fasting triacylglycerol levels (p
[add] = 0.0169–5.3 × 10−6), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after
adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p
[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had
significantly lower HOMA-B (p
[add] = 5.8 × 10−5) in the combined analysis.
Conclusions/interpretation Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition,
we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through
obesity.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
Q. Qi and Y. Wu contributed equally to this study. 相似文献
7.
E. S. Stolerman A. K. Manning J. B. McAteer C. S. Fox J. Dupuis J. B. Meigs J. C. Florez 《Diabetologia》2009,52(4):614-620
Aims/hypothesis Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias.
We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association
of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS).
Methods We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and
rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We
used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios
and obesity measures.
Results As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 × 10−7) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92).
Conclusions/interpretation We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We
did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly
induced by the evaluation of obesity in separate groups of glycaemic cases and controls.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
8.
Holmkvist J Anthonsen S Wegner L Andersen G Jørgensen T Borch-Johnsen K Sandbaek A Lauritzen T Pedersen O Hansen T 《Diabetologia》2008,51(4):609-614
Aims/hypothesis A genome-wide association study recently identified an association between common variants, rs1535435 and rs9494266, in the
AHI1 gene and type 2 diabetes. The aim of the present study was to investigate the putative association between these polymorphisms
and type 2 diabetes or type 2 diabetes-related metabolic traits in Danish individuals.
Methods The previously associated polymorphisms were genotyped in the population-based Inter99 cohort (n = 6162), the Danish ADDITION study (n = 8428), a population-based sample of young healthy participants (n = 377) and in additional type 2 diabetes (n = 2107) and glucose-tolerant participants (n = 483) using Taqman allelic discrimination. The case–control study involved 4,104 type 2 diabetic patients and 5,050 glucose-tolerant
control participants. Type 2 diabetes-related traits were investigated in 17,521 individuals.
Results rs1535435 and rs9494266 were not associated with type 2 diabetes. Odds ratios (OR) were ORadd 1.0 (95% C.I. 0.9–1.2; p
add = 0.7) and ORadd 1.1 (0.9–1.2; p
add = 0.4), respectively, a finding supported by meta-analyses: ORadd 1.0 (0.9–1.1; p
add = 0.6) and ORadd 1.0 (0.9–1.1; p
add = 0.6), respectively. Neither rs1535435 nor rs9494266 were consistently associated with any of the tested type 2 diabetes-related
metabolic traits.
Conclusions/interpretation Data from large samples of Danish individuals do not support a role for AHI1 rs1535435 nor rs9494266 as major type 2 diabetes variants. This study highlights the importance of independent and well-powered
replication studies of the recent genome-wide association scans before a locus is robustly validated as being associated with
type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
9.
Variations in the <Emphasis Type="Italic">HHEX</Emphasis> gene are associated with increased risk of type 2 diabetes in the Japanese population 总被引:1,自引:0,他引:1
Horikoshi M Hara K Ito C Shojima N Nagai R Ueki K Froguel P Kadowaki T 《Diabetologia》2007,50(12):2461-2466
Aims/hypothesis Recently, several groups have carried out whole-genome association studies in European and European-origin populations and
found novel type 2 diabetes-susceptibility genes, fat mass and obesity associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between
single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population.
Methods Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1 ± 9.5 years
(mean±SD), BMI 24.3 ± 3.9 kg/m2) and 864 Japanese control individuals (386 men and 478 women; age 69.5 ± 6.8 years, BMI 23.8 ± 3.7 kg/m2).
Results The SNPs rs5015480 [odds ratio (OR) = 1.46 (95% CI 1.20–1.77), p = 2.0 × 10−4], rs7923837 [OR = 1.40 (95% CI 1.17–1.68), p = 2.0 × 10−4] and rs1111875 [OR = 1.30 (95% CI 1.11–1.52), p = 0.0013] in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes [OR = 1.22 (95% CI 1.03–1.46), p = 0.025]. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p = 0.023, p = 0.0083, respectively).
Conclusions/interpretation
HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
M. Horikoshi and K. Hara contributed equally to this study. 相似文献
10.
Duesing K Charpentier G Marre M Tichet J Hercberg S Froguel P Gibson F 《Diabetologia》2008,51(1):76-81
Aims/hypothesis In the present study, we sought to examine the evidence that LMNA variants are associated with type 2 diabetes and quantitative metabolic traits in French Europid individuals.
Methods We genotyped 24 single nucleotide polymorphisms (SNPs) spanning the LMNA gene in 3,093 case–control participants. The association between LMNA SNPs and quantitative metabolic traits was also examined in the 1,674 normoglycaemic adults who made up the control cohort.
Results SNP rs505058, a synonymous SNP (D446D) in exon 7, showed nominal evidence of association with type 2 diabetes [p = 0.003, odds ratio (OR) 1.30 (95% CI 1.09–1.56)] in French Europids. A meta-analysis of available rs505058 genotype data
from 7,819 participants provided support for a modest association of rs505058 with type 2 diabetes [p = 0.003, OR 1.19 (95% CI 1.06–1.35)]. We found no evidence (p = 0.91) that the tag SNP rs4641 is associated with type 2 diabetes. However, a meta-analysis of all available rs4641 genotype
data in a total of 15,591 participants produced borderline evidence of association [p = 0.054, OR 1.05 (95% CI 1.00–1.11)]. SNP rs6669212, in the 3′ untranslated region of LMNA, exhibited suggestive associations with WHR (p = 0.013), fasting serum levels of total cholesterol (p = 0.023) and triacylglycerol (p = 0.015). We emphasise that these quantitative trait associations are not corrected for multiple testing.
Conclusions/interpretation The available data do not support a major effect of common LMNA variation on type 2 diabetes susceptibility in northern Europeans.
Further large-scale studies are required to conclusively establish the extent to which LMNA variants have an impact on quantitative
metabolic traits.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
11.
12.
Hertel JK Johansson S Raeder H Midthjell K Lyssenko V Groop L Molven A Njølstad PR 《Diabetologia》2008,51(6):971-977
Aims/hypothesis Recent genome-wide association studies performed in selected patients and control participants have provided strong support
for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel
loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study).
Methods We genotyped single nucleotide polymorphisms (SNPs) in PKN2, IGFBP2, FLJ39370 (also known as C4ORF32), CDKAL1, SLC30A8, CDKN2B, HHEX and FTO using a Norwegian population-based sample of 1,638 patients with type 2 diabetes and 1,858 non-diabetic control participants
(the HUNT Study), for all of whom data on BMI, WHR, cholesterol and triacylglycerol levels were available. We used diabetes,
measures of obesity and lipid values as phenotypes in case-control and quantitative association study designs.
Results We replicated the association with type 2 diabetes for rs10811661 in the vicinity of CDKN2B (OR 1.20, 95% CI: 1.06–1.37, p = 0.004), rs9939609 in FTO (OR 1.14, 95% CI: 1.04–1.25, p = 0.006) and rs13266634 in SLC30A8 (OR 1.20, 95% CI: 1.09–1.33, p = 3.9 × 10−4). We found borderline significant association for the IGFBP2 SNP rs4402960 (OR 1.10, 95% CI: 0.99–1.22). Results for the HHEX SNP (rs1111875) and the CDKAL1 SNP (rs7756992) were non-significant, but the magnitude of effect was similar to previous estimates. We found no support
for an association with the less consistently replicated FLJ39370 or PKN2 SNPs. In agreement with previous studies, FTO was most strongly associated with BMI (p = 8.4 × 10−4).
Conclusions/interpretation Our data show that SNPs near IGFBP2, CDKAL1, SLC30A8, CDKN2B, HHEX and FTO are also associated with diabetes in non-selected patients with type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
13.
E. Reiling E. van ’t Riet M. J. Groenewoud L. M. C. Welschen E. C. van Hove G. Nijpels J. A. Maassen J. M. Dekker L. M. ’t Hart 《Diabetologia》2009,52(9):1866-1870
Aims/hypothesis Variation in fasting plasma glucose (FPG) within the normal range is a known risk factor for the development of type 2 diabetes.
Several reports have shown that genetic variation in the genes for glucokinase (GCK), glucokinase regulatory protein (GCKR), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2) and melatonin receptor type 1B (MTNR1B) is associated with FPG. In this study we examined whether these loci also contribute to type 2 diabetes susceptibility.
Methods A random selection from the Dutch New Hoorn Study was used for replication of the association with FGP (2,361 non-diabetic
participants). For the genetic association study we extended the study sample with 2,628 participants with type 2 diabetes.
Risk allele counting was used to calculate a four-gene risk allele score for each individual.
Results Variants of the GCK, G6PC2 and MTNR1B genes but not GCKR were associated with FPG (all, p ≤ 0.001; GCKR, p = 0.23). Combining these four genes in a risk allele score resulted in an increase of 0.05 mmol/l (0.04–0.07) per additional
risk allele (p = 2 × 10−13). Furthermore, participants with less than three or more than five risk alleles showed significantly different type 2 diabetes
susceptibility compared with the most common group with four risk alleles (OR 0.77 [0.65–0.93], p = 0.005 and OR 2.05 [1.50–2.80], p = 4 × 10−6 respectively). The age at diagnosis was also significantly associated with the number of risk alleles (p = 0.009).
Conclusions A combined risk allele score for single-nucleotide polymorphisms in four known FPG loci is significantly associated with FPG
and HbA1c in a Dutch population-based sample of non-diabetic participants. Carriers of low or high numbers of risk alleles show significantly
different risks for type 2 diabetes compared with the reference group.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
14.
Sparsø T Andersen G Albrechtsen A Jørgensen T Borch-Johnsen K Sandbaek A Lauritzen T Wasson J Permutt MA Glaser B Madsbad S Pedersen O Hansen T 《Diabetologia》2008,51(9):1646-1652
Aim/hypothesis Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucose-tolerant people and in individuals with abnormal glucose regulation.
Methods The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals
and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes
patients.
Results The WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with
previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated
in an allele-dependent manner with a decrease in insulinogenic index (p = 0.025) and decreased 30-min serum insulin levels (p = 0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting
serum insulin concentration (p = 0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.026). To study the complex interaction of WFS1 rs734312 on insulin release and insulin resistance we introduced Hotelling’s T
2 test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR
when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation
on the insulinogenic index and HOMA-IR was significantly associated with the traits (p = 0.0017).
Conclusions/interpretation Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose
regulation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
15.
Teran-Garcia M Rankinen T Rice T Leon AS Rao DC Skinner JS Bouchard C 《Diabetologia》2007,50(9):1858-1866
Aims/hypothesis The expression of the four and a half LIM domains 1 gene (FHL1) is increased in the muscle of individuals who show an improvement in insulin sensitivity index (S
I) after 20 weeks of exercise training. The aim of the present study was to investigate associations between three FHL1 single nucleotide polymorphisms (SNPs) and variables derived from an IVGTT, both in the sedentary state and in response to
exercise training, in participants in the HERITAGE Family Study.
Materials and methods SNPs were typed using fluorescence polarisation methodology. Analyses were performed separately by sex and in black and white
individuals.
Results In black participants, no associations were found with any of the SNPs. In white women (n = 207), SNP rs9018 was associated with the disposition index (D
I), which is calculated as S
I generated from the MINMOD program (×10−4 min−1[μU/ml]−1) multiplied by acute insulin response to glucose (AIRg; pmol/l × 10 min), and the glucose disappearance index (K
g) training responses (p = 0.016 and p = 0.008, respectively). In white men (n = 222), all SNPs were associated with fasting glucose levels (p ≤ 0.05) and SNP rs2180062 with the insulin sensitivity index (S
I) (p = 0.04) in the sedentary state. Two SNPs were associated with fasting insulin training response. Fasting insulin decreased
to a greater extent in carriers of the rs2180062 C allele (p = 0.01) and rs9018 T allele (p = 0.04). With exercise training, S
I (×10−4 min−1[μU/ml]−1: 0.68 ± 0.20 vs −0.77 ± 0.44, p = 0.046), D
I (319 ± 123 vs –528 ± 260, p = 0.006) and K
g (per 100 min: 0.09 ± 0.04 vs −0.14 ± 0.8, p = 0.03) improved more in the C allele carriers at rs2180062 than in the T allele carriers.
Conclusions/interpretation Fasting insulin and S
I responses to exercise training were associated with DNA sequence variation in FHL1 in white men. Whether these associations exist only in white men remains to be investigated.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
16.
Holmkvist J Tojjar D Almgren P Lyssenko V Lindgren CM Isomaa B Tuomi T Berglund G Renström E Groop L 《Diabetologia》2007,50(12):2467-2475
Aims/hypothesis Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell
ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca2+ channel CaV2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase
insulin secretion.
Methods Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case–control
sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups
(1) a new case–control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort;
and (3) 935 individuals with insulin secretion data from an IVGTT.
Results The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case–control sample [odds
ratio (OR) 1.4, 95% CI 1.0–2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0–1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1–1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D
I) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D
I over time in the Botnia prospective cohort (p = 0.05).
Conclusions/interpretation We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
17.
18.
Florez JC Sjögren M Agapakis CM Burtt NP Almgren P Lindblad U Berglund G Tuomi T Gaudet D Daly MJ Ardlie KG Hirschhorn JN Altshuler D Groop L 《Diabetologia》2007,50(6):1209-1217
Aims/hypothesis Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several
reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants
might account for the putative association signal.
Subjects and methods We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers
in several family-based and case-control samples of European descent totalling 12,129 subjects.
Results In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism
showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03–1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96–1.39,
p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits.
Conclusions/interpretation Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
D. Altshuler and L. Groop jointly supervised this project. 相似文献
19.
González-Sánchez JL Martínez-Larrad MT Zabena C Pérez-Barba M Serrano-Ríos M 《Diabetologia》2008,51(11):1993-1997