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01.11.2009 | Article

Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

verfasst von: E. M. Byrne, A. F. McRae, D. L. Duffy, Z. Z. Zhao, N. G. Martin, J. B. Whitfield, P. M. Visscher, G. W. Montgomery

Erschienen in: Diabetologia | Ausgabe 11/2009

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Abstract

Aims/hypothesis

There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many case–control mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants and a number of quantitative traits related to type 2 diabetes in a large sample of >2,000 healthy Australian adolescent twins and their siblings, many of whom were measured on more than one occasion.

Methods

To the best of our knowledge, this is the first mitochondrial association study of quantitative traits undertaken using family data. The maternal inheritance pattern of mitochondria means established association methodologies are unsuitable for analysis of mitochondrial data in families. We present a methodology, implemented in the freely available program Sib-Pair for performing such an analysis.

Results

Despite our study having the power to detect variants with modest effects on these phenotypes, only one significant association was found after correction for multiple testing in any of four age groups. This was for mt14365 with triacylglycerol levels (unadjusted p = 0.0006). This association was not replicated in other age groups.

Conclusions/interpretation

We find little evidence in our sample to suggest that common European mitochondrial variants contribute to variation in quantitative phenotypes related to diabetes. Only one variant showed a significant association in our sample, and this association will need to be replicated in a larger cohort. Such replication studies or future meta-analyses may reveal more subtle effects that could not be detected here because of limitations of sample size.

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Petersen KF, Befroy D, Dufour S et al (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142CrossRefPubMed

Petersen KF, Dufour S, Befroy D, Garcia R, Schulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671CrossRefPubMed

Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1-α-responsive genes involved in oxidative phosphorylation are co-ordinately downregulated in human diabetes. Nat Genet 34:267–273CrossRefPubMed

Patti ME, Butte AJ, Crunkhorn S et al (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 100:8466–8471CrossRefPubMed

Maechler P, Carobbio S, Rubi B (2006) In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol 38:696–709CrossRefPubMed

Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE (2005) Deficiency of subsarcolemnal mitochondria in obesity and type 2 diabetes. Diabetes 54:8–14CrossRefPubMed

Alcolado JC, Laji K, Gill-Randall R (2002) Maternal transmission of diabetes. Diabet Med 19:89–98CrossRefPubMed

Barrett TG (2001) Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes. Best Pract Res Clin Endocrinol Metab 15:325–343CrossRefPubMed

van den Ouweland JM, Lemkes HH, Ruitenbeek W et al (1992) Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type 2 diabetes mellitus and deafness. Nat Genet 1:368–371CrossRefPubMed

10.

Wallace DC (2007) Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu Rev Biochem 76:781–821CrossRefPubMed

11.

Pravenec M, Hyakukoku M, Houstek J et al (2007) Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains. Genome Res 17:1319–1326CrossRefPubMed

12.

Maechler P, Wollheim CB (2001) Mitochondrial function in normal and diabetic beta-cells. Nature 414:807–812CrossRefPubMed

13.

Poulton J, Luan J, Macaulay V, Hennings S, Mitchell J, Wareham NJ (2002) Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. Hum Mol Genet 11:1581–1583CrossRefPubMed

14.

Kim JH, Park KS, Cho YM et al (2002) The prevalence of mitochondrial DNA 16189 variant in non-diabetic Korean adults and its association with higher fasting glucose and body mass index. Diabet Med 19:681–684CrossRefPubMed

15.

Weng SW, Liou CW, Lin TK et al (2005) Association of mitochondrial DNA 16189 variant with metabolic syndrome in Chinese adults. J Clin Endocrinol Metab 90:5037–5040CrossRefPubMed

16.

Chinnery PF, Elliott HR, Patel S et al (2005) Role of the mitochondrial DNA 16184–16193 poly-C tract in type 2 diabetes. Lancet 366:1650–1651CrossRefPubMed

17.

Mohlke KL, Jackson Au, Scott LJ et al (2005) Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns. Hum Genet 118:245–254CrossRefPubMed

18.

Raule N, Sevini F, Santoro A, Altilia S, Altilia A, Franceschi C (2007) Association studies on human mitochondrial DNA: methodological aspects and results in the most common age-related diseases. Mitochondrion 7:29–38CrossRefPubMed

19.

Crispim D, Canani LH, Gross JL, Tschiedel B, Souto KEP, Roisenberg I (2006) The European-specific mitochondrial cluster J/T could confer an increased risk of insulin-resistance and type 2 diabetes: an analysis of the m.4216T>C and m.4917A>G variants. Ann Hum Genet 70:488–495CrossRefPubMed

20.

Fuku N, Park KS, Yamada Y et al (2007) Mitochondrial haplogroup N9a confers resistance against Type 2 diabetes in Asians. Am J Hum Genet 80:407–415CrossRefPubMed

21.

Saxena R, de Bakker PI, Singer K et al (2006) Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. Am J Hum Genet 79:54–61CrossRefPubMed

22.

Kannel WB (2000) The Framingham Study: its 50-year legacy and future promise. J Atheroscler Thromb 6:60–66PubMed

23.

Beekman M, Heijmans BT, Martin NG et al (2002) Heritabilities of apolipoprotein and lipid levels in three countries. Twin Res 5:87–97CrossRefPubMed

24.

Liese AD, Hense HW, Lowel H, Doring A, Tietze M, Keil U (1999) Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases. Epidemiology 10:391–397CrossRefPubMed

25.

Middelberg RPS, Medland SE, Martin NG, Whitfield JB (2007) A longitudinal genetic study of uric acid and liver enzymes in adolescent twins. Twin Res Hum Gen 10:757–764CrossRef

26.

Pompella A, Emdin M, Passino C, Paolicchi A (2004) The significance of serum gamma-glutamyltransferase in cardiovascular diseases. Clin Chem Lab Med 42:1085–1091CrossRefPubMed

27.

Nannipieri M, Gonzales C, Baldi S et al (2005) Liver enzymes, the metabolic syndrome, and incident diabetes: The Mexico City diabetes study. Diabetes Care 28:1757–1762CrossRefPubMed

28.

Lee DH, Jacob DR, Gross M et al (2003) Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem 49:1358–1366CrossRefPubMed

29.

Wright MJ, Martin NG (2004) Brisbane Adolescent Twin Study: outline of study methods and research projects. Aust J Psychol 56:65–78CrossRef

30.

Zhu G, Duffy DL, Eldridge A et al (1999) A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs. Am J Hum Genet 65:483–492CrossRefPubMed

31.

Zhu G, Montgomery GW, James MR et al (2007) A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions. Eur J Hum Genet 15:94–102CrossRefPubMed

32.

Duffy DL, Montgomery GW, Chen W et al (2007) A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Am J Hum Genet 80:241–252CrossRefPubMed

33.

McRae AF, Byrne EM, Zhao ZZ et al (2008) Power and SNP tagging in whole mitochondrial genome association studies. Genome Res 18:911–917CrossRefPubMed

34.

Byrne EM, McRae AF, Zhao ZZ et al (2008) The use of common mitochondrial variants to detect and characterise population structure in the Australian population: implications for genome-wide association studies. Eur J Hum Genet 16:1396–1403CrossRefPubMed

35.

Middelberg RPS, Martin NG, Whitfield JB (2007) A longitudinal genetic study of plasma lipids in adolescent twins. Twin Res Hum Genet 10:127–135CrossRefPubMed

36.

Nyholt DR (2004) A simple correction for multiple testing for SNPs in linkage disequilibrium with each other. Am J Hum Genet 74:765–769CrossRefPubMed

37.

Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95:221–227CrossRefPubMed

38.

Cheverud JM (2001) A simple correction for multiple comparisons in interval mapping genome scans. Heredity 87:52–58CrossRefPubMed

39.

Cornes BK, Zhu G, Martin NG (2007) Sex differences in genetic variation in weight: a longitudinal study of body mass index in adolescent twins. Behav Genet 37:648–660CrossRefPubMed

40.

Jazin EE, Cavelier L, Eriksson I, Oreland L, Gyllensten U (1996) Human brain contains high levels of heteroplasmy in the noncoding regions of mitochondrial DNA. Proc Natl Acad Sci U S A 93:12382–12387CrossRefPubMed

41.

Detjen AK, Tinschert S, Kaufmann D et al (2007) Analysis of mitochondrial DNA in discordant monozygotic twins with neurofibromatosis type 1. Twin Res Hum Genet 10:486–495CrossRefPubMed

42.

Chinnery PF, Mowbray C, Patel SK et al (2007) Mitochondrial DNA haplogroups and type 2 diabetes: a study of 897 cases and 1010 controls. J Med Genet 44:e80CrossRefPubMed

Titel: Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents
verfasst von: E. M. Byrne
A. F. McRae
D. L. Duffy
Z. Z. Zhao
N. G. Martin
J. B. Whitfield
P. M. Visscher
G. W. Montgomery
Publikationsdatum: 01.11.2009
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 11/2009
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-009-1510-9

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