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Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole.

Achilli A, Olivieri A, Pala M, Hooshiar Kashani B, Carossa V, Perego UA, Gandini F, Santoro A, Battaglia V, Grugni V, Lancioni H, Sirolla C, Bonfigli AR, Cormio A, Boemi M, Testa I, Semino O, Ceriello A, Spazzafumo L, Gadaleta MN, Marra M, Testa R, Franceschi C, Torroni A - PLoS ONE (2011)

Bottom Line: We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables.MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene.In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia, Italy.

ABSTRACT
Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.

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MtDNA tree encompassing the roots of haplogroups associated with T2DM and/or its complications.The distinguishing mutational motifs for the haplogroups shown in the tree are reported on the branches and they are transitions unless a base is explicitly indicated. The position of the rCRS [43] is indicated for reading off sequence motifs. Suffixes indicate transversions (to A), insertions (+), synonymous or non-synonymous changes (s or ns), gene locus (for tRNA, rRNA and non-synonymous mutations – following the nomenclature proposed by MITOMAP). A role for haplogroups R0a/R0a2, H, H1, H3/H3 h, V, and U3/U3a has been proposed in this study. The protective or pejorative haplogroup effect is indicated by down or up arrows. Continuous arrow lines mean highly significant values. Previous analyses found associations (gray arrows) with J1 [13], JT and T [14], and N9a [11], [12].
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pone-0021029-g002: MtDNA tree encompassing the roots of haplogroups associated with T2DM and/or its complications.The distinguishing mutational motifs for the haplogroups shown in the tree are reported on the branches and they are transitions unless a base is explicitly indicated. The position of the rCRS [43] is indicated for reading off sequence motifs. Suffixes indicate transversions (to A), insertions (+), synonymous or non-synonymous changes (s or ns), gene locus (for tRNA, rRNA and non-synonymous mutations – following the nomenclature proposed by MITOMAP). A role for haplogroups R0a/R0a2, H, H1, H3/H3 h, V, and U3/U3a has been proposed in this study. The protective or pejorative haplogroup effect is indicated by down or up arrows. Continuous arrow lines mean highly significant values. Previous analyses found associations (gray arrows) with J1 [13], JT and T [14], and N9a [11], [12].

Mentions: As a first step in this study, we examined the relationships between T2DM and a wide range of mtDNA haplogroups and sub-haplogroups in a large-scale association study carried out on an Italian regional population. A reduced susceptibility to diabetes was possibly detected only for the H1 mtDNA background (9.4% and 15.8% in patients and controls, respectively). This H sub-branch is common in Western Europe (∼22% in the Iberian Peninsula, ∼13.7% in France and ∼15.3% in Scandinavia) and North Africa (average frequency of ∼16%) [28], and probably marks the expansions from the Franco-Cantabrian refuge zone when climatic conditions improved after the Last Glacial Maximum [29]. As shown in the schematic tree of figure 2, which illustrates the basal mutational motifs of all haplogroups associated with T2DM and/or its complications until now, H1 differs from the root of H only for the G3010A transition in the MTRNR2 gene. It is important to note that the same nucleotide change, due to an independent mutational event, characterizes also haplogroup J1 (Figure 2), whose protective role in diabetes has been previously postulated [13]. It is also worth mentioning that polymorphic variations in the mtDNA rRNA genes have been proposed as modulators affecting the penetrance of some specific pathogenic mutations causing non-syndromic deafness and LHON [30], [31]. Taking into account that the entire haplogroup H is characterized by another base substitution in MTRNR2 (G2706A), it is conceivable that such a combination of polymorphisms in the same gene might modulate susceptibility to diabetes.


Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole.

Achilli A, Olivieri A, Pala M, Hooshiar Kashani B, Carossa V, Perego UA, Gandini F, Santoro A, Battaglia V, Grugni V, Lancioni H, Sirolla C, Bonfigli AR, Cormio A, Boemi M, Testa I, Semino O, Ceriello A, Spazzafumo L, Gadaleta MN, Marra M, Testa R, Franceschi C, Torroni A - PLoS ONE (2011)

MtDNA tree encompassing the roots of haplogroups associated with T2DM and/or its complications.The distinguishing mutational motifs for the haplogroups shown in the tree are reported on the branches and they are transitions unless a base is explicitly indicated. The position of the rCRS [43] is indicated for reading off sequence motifs. Suffixes indicate transversions (to A), insertions (+), synonymous or non-synonymous changes (s or ns), gene locus (for tRNA, rRNA and non-synonymous mutations – following the nomenclature proposed by MITOMAP). A role for haplogroups R0a/R0a2, H, H1, H3/H3 h, V, and U3/U3a has been proposed in this study. The protective or pejorative haplogroup effect is indicated by down or up arrows. Continuous arrow lines mean highly significant values. Previous analyses found associations (gray arrows) with J1 [13], JT and T [14], and N9a [11], [12].
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111471&req=5

pone-0021029-g002: MtDNA tree encompassing the roots of haplogroups associated with T2DM and/or its complications.The distinguishing mutational motifs for the haplogroups shown in the tree are reported on the branches and they are transitions unless a base is explicitly indicated. The position of the rCRS [43] is indicated for reading off sequence motifs. Suffixes indicate transversions (to A), insertions (+), synonymous or non-synonymous changes (s or ns), gene locus (for tRNA, rRNA and non-synonymous mutations – following the nomenclature proposed by MITOMAP). A role for haplogroups R0a/R0a2, H, H1, H3/H3 h, V, and U3/U3a has been proposed in this study. The protective or pejorative haplogroup effect is indicated by down or up arrows. Continuous arrow lines mean highly significant values. Previous analyses found associations (gray arrows) with J1 [13], JT and T [14], and N9a [11], [12].
Mentions: As a first step in this study, we examined the relationships between T2DM and a wide range of mtDNA haplogroups and sub-haplogroups in a large-scale association study carried out on an Italian regional population. A reduced susceptibility to diabetes was possibly detected only for the H1 mtDNA background (9.4% and 15.8% in patients and controls, respectively). This H sub-branch is common in Western Europe (∼22% in the Iberian Peninsula, ∼13.7% in France and ∼15.3% in Scandinavia) and North Africa (average frequency of ∼16%) [28], and probably marks the expansions from the Franco-Cantabrian refuge zone when climatic conditions improved after the Last Glacial Maximum [29]. As shown in the schematic tree of figure 2, which illustrates the basal mutational motifs of all haplogroups associated with T2DM and/or its complications until now, H1 differs from the root of H only for the G3010A transition in the MTRNR2 gene. It is important to note that the same nucleotide change, due to an independent mutational event, characterizes also haplogroup J1 (Figure 2), whose protective role in diabetes has been previously postulated [13]. It is also worth mentioning that polymorphic variations in the mtDNA rRNA genes have been proposed as modulators affecting the penetrance of some specific pathogenic mutations causing non-syndromic deafness and LHON [30], [31]. Taking into account that the entire haplogroup H is characterized by another base substitution in MTRNR2 (G2706A), it is conceivable that such a combination of polymorphisms in the same gene might modulate susceptibility to diabetes.

Bottom Line: We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables.MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene.In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia, Italy.

ABSTRACT
Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.

Show MeSH
Related in: MedlinePlus