A Genome-Wide Scan in Type 2 Diabetes Mellitus Provides Independent Replication of a Susceptibility Locus on 18p11 and Suggests the Existence of Novel Loci on 2q12 and 19q13

Tilburg, Jonathan H.O. van; Sandkuijl, Lodewijk A.; Strengman, Eric; Someren, H. van; Rigters-Aris, C. A. E.; Pearson, P. L.; Haeften, Timon W. van; Wijmenga, Cisca

doi:10.1210/jc.2002-021252

Cited by 55 publications

(44 citation statements)

References 35 publications

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“…9 All patients were diagnosed according to the WHO criteria (random plasma glucose level 411.1 mmol/l or a fasting plasma glucose level 47.0 mmol/l). The clinical characteristics of the patients (HbA 1c , plasma cholesterol, HDL-cholesterol and triglycerides) were available, as well as the level of obesity in each individual, as represented by the BMI (defined as weight in kg divided by height in m squared).…”

Section: Methodsmentioning

confidence: 99%

HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort

et al. 2008

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Recently, the hematopoietically expressed homeobox (HHEX) gene, encoding a transcription factor, was identified in a large genome-wide scan in French individuals as a type 2 diabetes (T2D)-susceptibility locus. We aimed to check whether this finding could be replicated in a Dutch T2D cohort. Two common variants (rs7923837 and rs1111875) located near the HHEX gene were genotyped in 501 unrelated T2D patients and in 920 healthy controls. The major alleles of both variants were overrepresented in T2D cases compared with controls (66.7 vs 64.1%, P ¼ 0.16 for rs7923837 and 64.6 vs 60.4%, P ¼ 0.027 for rs1111875). For both polymorphisms, the risk for T2D was significantly increased in carriers of the major alleles (rs7923837: odds ratio (OR): 1.57, 95% confidence interval (CI): 1.08 -2.27, P ¼ 0.017 and rs1111875: OR: 1.68, 95% CI: 1.19 -2.35, P ¼ 0.003). The haplotype analysis did not reveal a risk haplotype that provided stronger evidence for association with T2D than each variant individually. Assuming a dominant genetic model, the population-attributable risks for diabetes due to the at-risk alleles of rs7923837 and rs1111875 were estimated to be 33 and 36%, respectively. These data provide evidence that variants near the HHEX gene contribute to the risk of T2D in a Dutch population.

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Section: Methodsmentioning

confidence: 99%

HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort

et al. 2008

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“…Breda cohort DNA was available from 502 subjects with type 2 diabetes from the Breda cohort (Table 1) [4]. All patients were diagnosed according to the WHO criteria (random plasma glucose levels >11.1 mmol/l or a fasting plasma glucose level >7.0 mmol/l).…”

Section: Methodsmentioning

confidence: 99%

Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort

et al. 2006

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Aim/hypothesis A strong association between susceptibility to type 2 diabetes and common variants of transcription factor 7-like 2 (TCF7L2), encoding an enteroendocrine transcription factor involved in glucose homeostasis, has been reported in three different populations (Iceland, Denmark and USA) by Grant et al. We aimed to replicate these findings in a Dutch cohort. Methods We analysed the genotypes of two intronic single nucleotide polymorphisms (SNPs) in TCF7L2 gene in 502 unrelated type 2 diabetes patients and in a set of healthy controls (n=920). The two SNPs showed almost complete linkage disequilibrium (D′=0.91). Results We were able to replicate the previously reported association in our Breda cohort. The minor alleles of both variants were significantly over-represented in cases (odds ratio [OR] 1.29, 95% CI 1.09-1.52, p ¼ 3 Â 10 À3 for rs12255372; OR 1.41, 95% CI 1.19-1.66, p ¼ 4:4 Â 10 À5 for rs7903146). In addition, TCF7L2 haplotypes were analysed for association with the disease. The analysis of haplotypes did not reveal any strong association beyond that expected from analysing individual SNPs. The TT haplotype carrying the minor alleles was more frequent among cases (OR 1.38, p ¼ 2:7 Â 10 À3 ). Conclusions/interpretation Our data strongly confirm that variants of the TCF7L2 gene contribute to the risk of type 2 diabetes. The population-attributable risk from this factor in the Dutch type 2 diabetes population is 10%.

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“…However, we replicated a previous linkage signal for BMI on 18p11 in the subjects living in the Pacific Island of Kosrae. 47 The same locus was also reported to be linked to type 2 diabetes mellitus 48,49 and percent FM in men. 50 Kraja et al 51 conducted genome-wide linkage analysis on metabolic risk factors.…”

Section: Discussionmentioning

confidence: 87%

Genome-wide scan revealed genetic loci for energy metabolism in Hispanic children and adolescents

et al. 2008

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Objective: Genome-wide scans were conducted in search for genetic locations linked to energy expenditure and substrate oxidation in children. Design: Pedigreed data of 1030 Hispanic children and adolescents were from the Viva La Familia Study which was designed to investigate genetic and environmental risk factors for the development of obesity in Hispanic families. A respiratory calorimeter was used to measure 24-h total energy expenditure (TEE), basal metabolic rate (BMR), sleep metabolic rate (SMR), 24-h respiratory quotient (24RQ), basal metabolic respiratory quotient (BMRQ) and sleep respiratory quotient (SRQ). Protein, fat and carbohydrate oxidation (PROOX, FATOX and CHOOX, respectively) were also estimated. All participants were genotyped for 384 single tandem repeat markers spaced an average of 10 cM apart. Computer program SOLAR was used to perform the genetic linkage analyses. Results: Significant linkage for TEE was detected on chromosome 1 near marker D1S2841, with a logarithm of the odds (LOD) score of 4.0. SMR, BMRQ and PROOX were associated with loci on chromosome 18, 17 and 9, respectively, with LOD scores of 4.88, 3.17 and 4.55, respectively. A genome-wide scan of SMR per kg fat-free mass (SpFFM) peaked in the same region as SMR on chromosome 18 (LOD, 5.24). Suggestive linkage was observed for CHOOX and FATOX. Several candidate genes were found in the above chromosomal regions including leptin receptor (LEPR). Conclusion: Regions on chromosomes 1, 9, 17 and 18 harbor genes affecting variation in energy expenditure and substrate oxidation in Hispanic children and adolescents.

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A Genome-Wide Scan in Type 2 Diabetes Mellitus Provides Independent Replication of a Susceptibility Locus on 18p11 and Suggests the Existence of Novel Loci on 2q12 and 19q13

Cited by 55 publications

References 35 publications

HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort

HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort

Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort

Genome-wide scan revealed genetic loci for energy metabolism in Hispanic children and adolescents

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