Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients

Abstract

Background: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk.

Methods: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk.

Results: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect.

Conclusion: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.

Figure 1

Genomic localization of the investigated markers within the human mitochondrial DNA molecule. The genetic location of mtDNA markers genotyped in the present study is indicated in the inner circle. H and L stand for heavy and light strands, respectively, given the asymmetric distribution of G and C nucleotides, with H being the G-rich strand. The seven complex I subunits (ND1, 2, 3, 4L, 4, 5 and 6), one complex III subunit (Cyt b), three complex IV subunits (COI, COII, and COIII), two complex V subunits (ATPases 6 and 8), two ribosomal RNAs (12S and 16S rRNAs), 22 tRNAs and D-loop regions are shown. Gene products encoded by the L-strand are shown in the inner circle (one letter code) while the products of the H-strand are shown in the outer circle. Arrows indicate the locations of promoters P_L and P_H for the transcription and replication origin O_H. Adapted from MITOMAP [2].

Figure 2

Logistic regression odds ratios and confidence intervals (CIs) for mtDNA haplogroup association with ischemic stroke risk. Bars indicate 95% CIs and are shown as dotted lines when the upper confidence limit (CL) is over 7. The upper CL is indicated when it is over 7 and the respective lower CL is greater than 1.

Figure 3

Logistic regression odds ratios and confidence intervals (CIs) for mtDNA SNPs association with ischemic stroke risk. Bars indicate 95% CIs and are shown as dotted lines when the upper confidence limit (CL) is over 6. The upper CL is indicated when it is greater than 6.