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Ulcerative colitis is under dual (mitochondrial and nuclear) genetic control

Publication . Rosa, Alexandra; Abrantes, Patrícia; Sousa, Inês; Francisco, Vânia; Santos, Patrícia; Francisco, David; Xavier, Joana M.; Oliveira, Sofia A.

Background: Cellular oxidative stress and genetic susceptibility have been implicated in the multifactorial etiology of ulcerative colitis (UC). The nuclear genome association with UC has been intensely investigated, but the role of the mitochondrial DNA (mtDNA) has received far less attention and may account for part of the missing heritability. This study is a comprehensive analysis of the mtDNA contribution to UC susceptibility. Methods: The association of mitochondrial single-nucleotide polymorphisms (mtSNPs) and haplogroups with UC was tested in 488 cases and 833 controls of European ancestry from the NIDDK IBD Genetics Consortium Ulcerative Colitis Genome-Wide Association Study available through dbGaP and from the Illumina Genotype Control Database (studies 64 and 65). Results: No evidence of population stratification could be detected using 218 ancestry informative markers for European Americans. Seven of the 58 tested mtSNPs were nominally associated with UC, and A10550G in MT-ND4L withstands the Bonferroni correction (P ¼ 1.29E-06, odds ratio [ORG] [95% confidence interval (CI)] ¼ 4.80 [2.54–9.05], 10550G allele: 8.1% of patients and 1.9% of controls). A10550G remains equally associated after conditional analyses on the 11 UC genome-wide association studies (GWAS) top SNPs (6.35E-07 , Pcond , 4.58E-06), which suggests that it constitutes an independent risk factor from nuclear-encoded susceptibility loci. We detected additive (but not multiplicative) epistatic interactions between A10550G and all 11 top GWAS hits. Subhaplogroup K1 (P ¼ 0.021, OR [95% CI] ¼ 1.71 [1.08–2.69]) increased the risk for UC, whereas the U5b lineage conferred protection (P ¼ 0.016, OR [95% CI] ¼ 0.34 [0.14–0.82]). Conclusions: These results suggest that UC has a dual mitochondrial and nuclear genetic control that warrants further replication in independent data sets and reinforces its etiopathogenic complexity.

2016Journal article

Open access

Mitochondrial genome association study with peripheral arterial disease and venous thromboembolism

Publication . Abrantes, Patrícia; Rosa, Alexandra; Francisco, Vânia; Sousa, Inês; Xavier, Joana M.; Oliveira, Sofia A.

Background and aims: Peripheral arterial disease (PAD) and venous thromboembolism (VTE) are vascular traits sharing common modifiable and non-modifiable risk factors. These vascular pathologies have known nuclear-encoded genetic risk factors and the mitochondrial DNA may account for part of the missing heritability. To determine if PAD and VTE have a dual genetic control (mitochondrial and nu clear), we hereby investigated the association of mitochondrial DNA polymorphisms and haplogroups with these vascular traits. Methods: The association of mitochondrial single nucleotide polymorphisms (mtSNPs) and haplogroups was tested in 1652 PAD cases and 1629 controls from the eMERGE PAD genome-wide association study (GWAS), and 1241 VTE cases and 1278 controls from the GENEVA GWAS of venous thrombosis (dbGaP accession numbers phs000203.v1.p1 and phs000289.v2.p1, respectively). Results: 66 and 72 mtSNPs passed quality control filters and were tested for association with PAD and VTE, respectively. Significant evidence of population stratification could not be detected in both datasets. Three mtSNPs (m.477T > C, m.9667A > G, and m.10915T > C) were nominally associated (3.01 10 3 pa 3.96 10 2 ) with PAD in the logistic regression adjusted for confounding factors, and m.11914G > A was nominally associated (pa ¼ 4.14 10 2 ) with VTE. None of the nine major mito chondrial haplogroups were associated with either PAD or VTE. Conclusion: Unlike other vascular diseases such as stroke and diabetes, these results suggest that com mon mitochondrial variants individually or in combination do not play a major role in PAD and VTE susceptibility.

2016Journal article

Open access