Differences in MtDNA Haplogroup Distribution Among 3 Jewish Populations Alter Susceptibility to T2DM Complications

Overview

Journal BMC Genomics

Publisher Biomed Central

Specialty Genetics

Date 2008 May 1

PMID 18445251

Citations 20

Authors

Jeanette Feder

Ilana Blech

Ofer Ovadia

Shirly Amar

Julio Wainstein

Itamar Raz

Sarah Dadon

Dan E Arking

Benjamin Glaser

Dan Mishmar

Affiliations

Soon will be listed here.

Abstract

Background: Recent genome-wide association studies searching for candidate susceptibility loci for common complex diseases such as type 2 diabetes mellitus (T2DM) and its common complications have uncovered novel disease-associated genes. Nevertheless these large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders.

Results: We have analyzed the mitochondrial DNA (mtDNA) genetic variability in Ashkenazi (Ash), Sephardic (Seph) and North African (NAF) Jewish populations (total n = 1179). Our analysis showed significant differences (p < 0.001) in the distribution of mtDNA genetic backgrounds (haplogroups) among the studied populations. To test whether these differences alter the pattern of disease susceptibility, we have screened our three Jewish populations for an association of mtDNA genetic haplogroups with T2DM complications. Our results identified population-specific susceptibility factors of which the best example is the Ashkenazi Jewish specific haplogroup N1b1, having an apparent protective effect against T2DM complications in Ash (p = 0.006), being absent in the NAF population and under-represented in the Seph population. We have generated and analyzed whole mtDNA sequences from the disease associated haplogroups revealing mutations in highly conserved positions that are good candidates to explain the phenotypic effect of these genetic backgrounds.

Conclusion: Our findings support the possibility that recent bottleneck events leading to over-representation of minor mtDNA alleles in specific genetic isolates, could result in population-specific susceptibility loci to complex disorders.

Citing Articles

Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to 'Mismatched' Mitochondrial DNA.

Januszewski A, Blake R, Zhang M, Ma B, Anand S, Pinkert C Antioxidants (Basel). 2024; 13(2).

PMID: 38397785 PMC: 10886269. DOI: 10.3390/antiox13020187.

Mitochondrial DNA in Human Diversity and Health: From the Golden Age to the Omics Era.

Hernandez C Genes (Basel). 2023; 14(8).

PMID: 37628587 PMC: 10453943. DOI: 10.3390/genes14081534.

Disease-causing mutations in subunits of OXPHOS complex I affect certain physical interactions.

Barshad G, Zlotnikov-Poznianski N, Gal L, Schuldiner M, Mishmar D Sci Rep. 2019; 9(1):9987.

PMID: 31292494 PMC: 6620328. DOI: 10.1038/s41598-019-46446-8.

Mitochondrial DNA Haplogroup JT is Related to Impaired Glycaemic Control and Renal Function in Type 2 Diabetic Patients.

Diaz-Morales N, Lopez-Domenech S, Iannantuoni F, Lopez-Gallardo E, Sola E, Morillas C J Clin Med. 2018; 7(8).

PMID: 30115863 PMC: 6111716. DOI: 10.3390/jcm7080220.

MtDNA meta-analysis reveals both phenotype specificity and allele heterogeneity: a model for differential association.

Marom S, Friger M, Mishmar D Sci Rep. 2017; 7:43449.

PMID: 28230165 PMC: 5322532. DOI: 10.1038/srep43449.

References

van den Ouweland J, Bruining G, Lindhout D, Wit J, Veldhuyzen B, Maassen J . Mutations in mitochondrial tRNA genes: non-linkage with syndromes of Wolfram and chronic progressive external ophthalmoplegia. Nucleic Acids Res. 1992; 20(4):679-82. PMC: 312004. DOI: 10.1093/nar/20.4.679. View

Wang D, Taniyama M, Suzuki Y, Katagiri T, Ban Y . Association of the mitochondrial DNA 5178A/C polymorphism with maternal inheritance and onset of type 2 diabetes in Japanese patients. Exp Clin Endocrinol Diabetes. 2001; 109(7):361-4. DOI: 10.1055/s-2001-17407. View

Bhat A, Koul A, Sharma S, Rai E, Bukhari S, Dhar M . The possible role of 10398A and 16189C mtDNA variants in providing susceptibility to T2DM in two North Indian populations: a replicative study. Hum Genet. 2006; 120(6):821-6. DOI: 10.1007/s00439-006-0272-4. View

Maechler P, Wollheim C . Mitochondrial function in normal and diabetic beta-cells. Nature. 2001; 414(6865):807-12. DOI: 10.1038/414807a. View

Ross O, McCormack R, Curran M, Duguid R, Barnett Y, Rea I . Mitochondrial DNA polymorphism: its role in longevity of the Irish population. Exp Gerontol. 2001; 36(7):1161-78. DOI: 10.1016/s0531-5565(01)00094-8. View

Ballinger S, Shoffner J, Hedaya E, Trounce I, Polak M, Koontz D . Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet. 1992; 1(1):11-5. DOI: 10.1038/ng0492-11. View

Ingman M, Kaessmann H, Paabo S, Gyllensten U . Mitochondrial genome variation and the origin of modern humans. Nature. 2000; 408(6813):708-13. DOI: 10.1038/35047064. View

Rothman K . No adjustments are needed for multiple comparisons. Epidemiology. 1990; 1(1):43-6. View

Soejima A, Inoue K, Takai D, Kaneko M, Ishihara H, Oka Y . Mitochondrial DNA is required for regulation of glucose-stimulated insulin secretion in a mouse pancreatic beta cell line, MIN6. J Biol Chem. 1996; 271(42):26194-9. DOI: 10.1074/jbc.271.42.26194. View

10.

Thomas M, Weale M, Jones A, Richards M, Smith A, Redhead N . Founding mothers of Jewish communities: geographically separated Jewish groups were independently founded by very few female ancestors. Am J Hum Genet. 2002; 70(6):1411-20. PMC: 379128. DOI: 10.1086/340609. View

11.

Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace D . Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004; 303(5655):223-6. DOI: 10.1126/science.1088434. View

12.

Dato S, Passarino G, Rose G, Altomare K, Bellizzi D, Mari V . Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet. 2004; 12(12):1080-2. DOI: 10.1038/sj.ejhg.5201278. View

13.

Maitra A, Cohen Y, Gillespie S, Mambo E, Fukushima N, Hoque M . The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res. 2004; 14(5):812-9. PMC: 479107. DOI: 10.1101/gr.2228504. View

14.

Hudson G, Keers S, Yu-Wai-Man P, Griffiths P, Huoponen K, Savontaus M . Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet. 2005; 77(6):1086-91. PMC: 1285165. DOI: 10.1086/498176. View

15.

Sreekumar R, Halvatsiotis P, Schimke J, Nair K . Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes. 2002; 51(6):1913-20. DOI: 10.2337/diabetes.51.6.1913. View

16.

Feder J, Ovadia O, Glaser B, Mishmar D . Ashkenazi Jewish mtDNA haplogroup distribution varies among distinct subpopulations: lessons of population substructure in a closed group. Eur J Hum Genet. 2007; 15(4):498-500. DOI: 10.1038/sj.ejhg.5201764. View

17.

Stern E, Blau J, Rusecki Y, Rafaelovsky M, Cohen M . Prevalence of diabetes in Israel. Epidemiologic survey. Diabetes. 1988; 37(3):297-302. DOI: 10.2337/diab.37.3.297. View

18.

Behar D, Hammer M, Garrigan D, Villems R, Bonne-Tamir B, Richards M . MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population. Eur J Hum Genet. 2004; 12(5):355-64. DOI: 10.1038/sj.ejhg.5201156. View

19.

Wallace D . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39:359-407. PMC: 2821041. DOI: 10.1146/annurev.genet.39.110304.095751. View

20.

Kumar S, Tamura K, Nei M . MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform. 2004; 5(2):150-63. DOI: 10.1093/bib/5.2.150. View