Genetic association analysis of 13 nuclear-encoded mitochondrial candidate genes with type II diabetes mellitus: the DAMAGE study.

Department of Molecular Cell Biology, Leiden University Medical Center, The Netherlands.
European journal of human genetics: EJHG (Impact Factor: 4.23). 03/2009; 17(8):1056-62. DOI: 10.1038/ejhg.2009.4
Source: PubMed

ABSTRACT Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes mellitus (T2DM) using a two-stage design. In the first stage, we analyzed 62 tagging single nucleotide polymorphisms (SNPs) in the Hoorn study (n=999 participants) covering all common variation in 13 biological candidate genes. These 13 candidate genes were selected from four clusters regarded essential for correct mitochondrial protein synthesis and biogenesis: aminoacyl tRNA synthetases, translation initiation factors, tRNA modifying enzymes and mitochondrial DNA transcription and replication. SNPs showing evidence for association with T2DM were measured in second stage genotyping (n=10164 participants). After a meta-analysis, only one SNP in SIRT4 (rs2522138) remained significant (P=0.01). Extending the second stage with samples from the Danish Steno Study (n=1220 participants) resulted in a common odds ratio (OR) of 0.92 (0.85-1.00), P=0.06. Moreover, in a large meta-analysis of three genome-wide association studies, this SNP was also not associated with T2DM (P=0.72). In conclusion, we did not find evidence for association of common variants in 13 nuclear-encoded mitochondrial proteins with T2DM.

Download full-text


Available from: Leen M 't Hart, Aug 10, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims/hypothesis LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. MethodsWe combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. ResultsNo association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95–1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90–1.08], p = 0.78, n = 35,715 respectively). Conclusions/interpretationIn this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility. KeywordsGenetics- LARS2 -Mitochondria-SNP-Type 2 diabetes
    Diabetologia 01/2010; 53(1):103-110. DOI:10.1007/s00125-009-1557-7 · 6.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that obesity is the most important trigger of metabolic impairment, the MetS definition in this thesis was chosen to include the obesity measure waist circumference as an essential component. In the study described in chapter 2, the heritability of the metabolic syndrome was addressed and compared to the heritability of its individual components. Since the individual components of MetS were shown to be more heritable than MetS itself, the studies described in chapter 3 and 4 focused on the genetics of the individual MetS component plasma TG. For this purpose, a candidate gene approach was employed using HTG patients and healthy controls. The involvement of a series of candidate genes was confirmed. The study described in chapter 5 followed a similar approach to that used in the studies described in chapter 3 and 4. Several candidate genes were studied in patients suffering from hyperlipoproteinemia (HLP) type III, which is characterized by elevated levels of total plasma cholesterol and plasma TG. HLP type III is characterized by APOE2 homozygosity. Contributing genetic factors in the (metabolically stressed) APOE2/2 environment were confirmed. Plasma adiponectin, an adipose tissue secreted hormone (adipokine), has been suggested to be a biomarker for MetS. In chapter 6 we describe a study which particularly aimed to determine the effect of menopause on the discriminating accuracy of adiponectin to predict MetS. Especially low levels of plasma adiponectin in postmenopausal women were found to be a risk for MetS. However, the discriminating accuracy of adiponectin for the presence of MetS was exceeded by BMI in men and pre –and post menopausal women. Since plasma adiponectin levels are very well correlated with MetS components or related traits, the study described in chapter 7 addressed the question whether these correlations are caused by a genetic overlap (genetic correlation). The genetic correlation was mono-laterally validated with regard to the adiponectin gene (ADIPOQ). Chapter 8 describes a study towards finding novel loci associated with adiponectin or loci that are possibly involved in the genetic overlap between adiponectin and MetS components or related traits. This study followed a genome-wide association (GWA) approach. The results of this GWA were used in a joined analysis with two other cohorts in a meta-analysis. In addition, a selected proportion of SNPs was submitted for replication in several cohorts. Chapter 9 provides a general discussion by reviewing all previous chapters in the thesis. Furthermore, chapter 9 includes suggestions and proposals for future analyses towards unraveling genetic and environmental factors involved in the expression and manifestation of metabolic risk factors.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 Diabetes (T2D) is a chronic disease, characterized by hyperglycaemia, caused by decreased insulin secretion by beta-cells and insulin resistance of target tissues of insulin. Several risk factors are known, like decreased exercise, ageing and western diet. Also genetic variance can alter susceptibility to develop T2D. Until recently only four T2D susceptibility genes were identified (PPARG, KCNJ11, CAPN10 and TCF7L2). However, recent Genome Wide Association Studies (GWAS) have increased this number to at least 20. My thesis describes the search for additional T2D susceptibility genes. For this we used a classical candidate gene approach and we case/control studies from the Netherlands, Scandinavia and the UK. We selected 14 nuclear encoded candidate genes, all regarded essential for mitochondrial protein synthesis and biogenesis. Since mitochondrial function was shown to be associated with T2D, we hypothesized that genes in these pathways are good candidates. Tagging SNPs were selected, which should cover all known common variation (minor allele frequency (MAF) > 0.05) in the candidate genes. These tagging SNPs were measured in our first stage, comprising of the Dutch Hoorn study and significant associations were than taking forward for replication in our replication cohorts in the second stage of this study. However, after second stage genotyping non of the signals remained significant, indicating that the selected candidate genes do not play a major role in T2D susceptibility. Furthermore, nuclear encoded mitochondrial genes were not among the top hits of GWAS, which were made available online after completion of our study. Therefore, we conclude that nuclear encoded mitochondrial genes do not have a major contribution to the development of T2D. Next, we analyzed the association of mitochondrial DNA (mtDNA) content with T2D. First we estimated the heritability in Dutch twins and found a heritability of 35% (19%-48%). Next we analyzed the association with prevalent and incident T2D in a Dutch case control study and two prospective studies from the Netherlands and Finland. However, no associations were observed. Therefore, we conclude that mtDNA content does not play a major role in the development of T2D. Finally, we analyzed four known fasting plasma glucose (FPG) influencing genes (GCK, GCKR, G6PC2 and MTNR1B). In a Dutch population based sample we could replicate the association of these genes with FPG levels (except for GCKR). Furthermore, the combined risk alleles (ranging from 0 to 8 risk alleles) were strongly associated with FPG and HbA1C levels. This risk allele score was also associated with T2D susceptibility and age of diagnosis at T2D. We therefore conclude that the FPG influencing genes have a combined effect on FPG and are associated with T2D susceptibility and age at diagnosis of T2D. In conclusion, we could not find evidence that nuclear encoded mitochondrial proteins and mtDNA content are associated with T2D susceptibility. The four known FPG genes do not only influence FPG levels, but also have a combined effect on T2D susceptibility and age at diagnosis of T2D.
Show more