Diabetes & Metabolism Journal

Sulwon Lecture 2009

The Search for Genetic Risk Factors of Type 2 Diabetes Mellitus: Kyong Soo Park; Diabetes Metab J. 2011;35(1):12-22. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.12

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Type 2 diabetes mellitus (T2DM) is caused by complex interplay between multiple genetic and environmental factors. The three major approaches used to identify the genetic susceptibility include candidate gene approach, familial linkage analysis and genome- wide association analysis. Recent advance in genome-wide association studies have greatly improved our understanding of the pathophysiology of T2DM. As of the end of 2010, there are more than 40 confirmed T2DM-associated genetic loci. Most of the T2DM susceptibility genes were implicated in decreased β-cell function. However, these genetic variations have a modest effect and their combination only explains less than 10% of the T2DM heritability. With the advent of the next-generation sequencing technology, we will soon identify rare variants of larger effect as well as causal variants. These advances in understanding the genetics of T2DM will lead to the development of new therapeutic and preventive strategies and individualized medicine.

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Original Articles

R1467H Variants of Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) are Associated with Type 2 Diabetes Mellitus in Koreans: Qing Song Jin, So Hun Kim, Shan-Ji Piao, Hyun Ae Lim, Seung Youn Lee, Seong Bin Hong, Yong Seong Kim, Hun-Jae Lee, Moonsuk Nam; Korean Diabetes J. 2010;34(6):368-373. Published online December 31, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.6.368

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Abstract PDF PubReader

Background

The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) functions as an activator of Rho GTPases and is thought to influence insulin signaling. The R1467H variant of ARHGEF11 has been reported to be associated with susceptibility to type 2 diabetes mellitus (T2DM) in Western populations.

Methods

We investigated the effects of the R1467H variant on susceptibility to T2DM as well as related traits in a Korean population. We genotyped the R1467H (rs945508) of ARHGEF11 in 689 unrelated T2DM patients and 249 non-diabetic individuals and compared the clinical and biochemical characteristics according to different alleles.

Results

The H allele was significantly more frequent in T2DM cases than in controls (P = 0.037, 17.1% and 13.1%; respectively). H homozygocity was associated with a higher risk of T2DM compared to those with R/R or R/H genotype (odds ratio, 5.24; 95% confidence interval, 1.06 to 25.83; P = 0.042). The fasting plasma glucose, HbA1c, fasting insulin, HOMA2-IR and HOMA2-%β levels did not differ significantly between different genotypes.

Conclusion

Our study replicated associations of the ARHGEF11 polymorphism with increased risk of T2DM in a Korean population and thus supports previous data implicating a potential role of ARHGEF11 in the etiology of T2DM. Further studies revealing the underlying mechanism for this association are needed.

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Epigenetic alteration of Rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia
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Loss of Arhgef11 in the Dahl Salt-Sensitive Rat Protects Against Hypertension-Induced Renal Injury
Ashley C. Johnson, Wenjie Wu, Esinam M. Attipoe, Jennifer M. Sasser, Erin B. Taylor, Kurt C. Showmaker, Patrick B. Kyle, Merry L. Lindsey, Michael R. Garrett
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Transgenerational Obesity and Alteration of ARHGEF11 in the Rat Liver Induced by Intrauterine Hyperglycemia
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ARHGEF11 affecting the placental insulin signaling pathway in fetal macrosomia of normal glucose tolerance pregnant women
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Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis
Yutaka Mizuki, Manabu Takaki, Shinji Sakamoto, Sojiro Okamoto, Makiko Kishimoto, Yuko Okahisa, Masahiko Itoh, Norihito Yamada
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The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes
Ying-Ju Chang, Scott Pownall, Thomas E Jensen, Samar Mouaaz, Warren Foltz, Lily Zhou, Nicole Liadis, Minna Woo, Zhenyue Hao, Previn Dutt, Philip J Bilan, Amira Klip, Tak Mak, Vuk Stambolic
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Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population
Yutaka Mizuki, Manabu Takaki, Yuko Okahisa, Shinji Sakamoto, Masafumi Kodama, Hiroshi Ujike, Yosuke Uchitomi
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Genetic Association of Mitochondrial DNA Polymorphisms with Type 2 Diabetes Mellitus.: Tae Su Han, Jee Hye Choi, Jina Park, Kwang Ho Lee, Ae Ja Park; Korean Diabetes J. 2009;33(5):382-391. Published online October 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.5.382

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Abstract PDF: BACKGROUND
Although many single nucleotide polymorphisms (SNPs) of mtDNA have been found to be associated with type 2 diabetes mellitus, the results of studies using different population samples and different methods are mixed. Therefore, we conducted a genetic association study of mtDNA SNPs and type 2 diabetes mellitus in a Korean sample and compared our results with those of studies conducted in other human populations. METHODS: A total of 298 blood samples from 147 type 2 diabetic patients and 151 normal controls were surveyed for SNPs via PCR directed sequencing. Sequencing analyses were performed using the SeqMan module of the DNASTAR program. The identified SNPs were compared to previously reported SNP lists on NCBI and V-mitoSNP. RESULTS: A total of 24 SNPs were identified in the MT-RNR2, MR-TL1 and MT-ND1 mtDNA genes in Korean type 2 diabetes mellitus patients and normal controls. The SNPs identified in the Korean sample were not closely associated with the type 2 diabetes mellitus phenotype, a significantly different result from those previously observed in European, Chinese and Japanese samples. Additionally, a haplotype and prevalence analysis could not detect any differences between the type 2 diabetes mellitus patients and normal controls. CONCLUSION: The 24 mtDNA SNPs were not associated with type 2 diabetes mellitus risk in our Korean sample. The results of the present study support the possibility that mtDNA SNPs have a differential effect on the risk of type 2 diabetes mellitus according to geographical origin.

An Association between 609 C --> T Polymorphism in NAD(P)H: Quinone Oxidoreductase 1 (NQO1) Gene and Blood Glucose Levels in Korean Population.: Dohee Kim; Korean Diabetes J. 2009;33(1):24-30. Published online February 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.1.24

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Abstract PDF

BACKGROUND
NAD(P)H: quinone oxidoreductase 1 (NQO1), which is an obligate two-electron reductase that utilizes NAD(P)H as an electron donor and is involved in the protection against oxidative stress, is likely involved in beta-cell destruction. We evaluated the frequency of the NQO1 polymorphism and its association with blood glucose levels. METHODS: Genotypes were determined using a polymerase chain reaction restriction fragment length polymorphism-based assay in 56 patients and 48 healthy subjects. Fasting blood glucose, insulin, and lipid profiles were measured and homeostasis model assessment (HOMA)-insulin resistance (IR) was calculated from fasting glucose and insulin levels in the healthy subjects. RESULTS: The genotype frequencies of NQO1 polymorphism were C/C (56.7%), C/T (42.3%), and T/T (1.0%). There were no associations between the NQO1 polymorphism and body mass index, blood pressure, lipid profile, HbA1c, postprandial glucose, and HOMA-IR. However, NQO1 mutants (C/T and T/T) showed weak but significantly higher fasting blood glucose levels compared with wild type (C/C). CONCLUSION: Our data suggest that NQO1 609 C --> T polymorphism may be associated with glucose metabolism.

Citations

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Association of Nuclear Factor-Erythroid 2-Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase-1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients
Angélica Saraí Jiménez-Osorio, Susana González-Reyes, Wylly Ramsés García-Niño, Hortensia Moreno-Macías, Martha Eunice Rodríguez-Arellano, Gilberto Vargas-Alarcón, Joaquín Zúñiga, Rodrigo Barquera, José Pedraza-Chaverri
Oxidative Medicine and Cellular Longevity.2016; 2016: 1. CrossRef

Genetic Polymorphism of Glucagon-Like Peptide 1 Receptor in Korean Type 2 Diabetes Mellitus.: Kyung Wook Lee, Meihua Jiang, Shanji Piao, Eun A Kim, Seong Bin Hong, Moon Suk Nam, Yong Seong Kim, Kyong Soo Park, Hyun Chul Lee; Korean Diabetes J. 2005;29(1):30-38. Published online January 1, 2005

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Abstract PDF: BACKGROUND
Glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal L-cells, which stimulates insulin secretion from cells. The biological action of GLP-1 is mediated by the glucagon-like peptide-1 receptor (GLP-1R), which is 463 amino acids in size, with 7 transmembrane domains. Because GLP-1 plays an important modulatory role in regulating glucose-stimulated insulin, the GLP-1R could be a candidate gene contributing to impaired -cell function and the development of this genetically heterogeneous disorder. Recently, four GLP-1R SNPs were identified in Caucasian diabetic individuals, and for the SNP at the Leu- 260Phe (A/C) position, statistically significant differences were detected in the distribution of genotypes between type 2 diabetic and nondiabetic subjects. We replicated the genetic association between the SNP at the leu260Phe (A/C) position in the GLP-1R gene and Korean type 2 diabetes mellitus. METHODS: The Leu260Phe polymorphism in the GLP-1R gene was determined using a PCR- RFLP method (the genotypes were determined according to the results of polymerase chain reaction products after digestion and the digestive enzyme was BbsI) in 419 Korean type 2 diabetic patients and 345 nondiabetic subjects. RESULTS: In contrast to the Caucasian report, there was no significant difference in the frequencies of alleles, and genotypes between Korean type 2 diabetic and nondiabetic subjects. When analyzed according to gender, BMI and age of onset, the genotype distribution of type 2 diabetic subjects was not significantly different from nondiabetic subjects. CONCLUSION: The Leu260Phe polymorphism in the GLP-1R gene was not associated with type 2 diabetes mellitus, and we were unable to replicate the genetic association between this polymorphism and Korean type 2 diabetes mellitus

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