dc.contributor.author |
Gosling, Anna L |
en |
dc.contributor.author |
Boocock, James |
en |
dc.contributor.author |
Dalbeth, Nicola |
en |
dc.contributor.author |
Harré Hindmarsh, Jennie |
en |
dc.contributor.author |
Stamp, Lisa K |
en |
dc.contributor.author |
Stahl, Eli A |
en |
dc.contributor.author |
Choi, Hyon K |
en |
dc.contributor.author |
Matisoo-Smith, Elizabeth A |
en |
dc.contributor.author |
Merriman, Tony R |
en |
dc.date.accessioned |
2018-10-22T19:56:02Z |
en |
dc.date.issued |
2018-04 |
en |
dc.identifier.issn |
0003-4967 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/43039 |
en |
dc.description.abstract |
OBJECTIVE:Mitochondria have an important role in the induction of the NLRP3 inflammasome response central in gout. The objective was to test whether mitochondrial genetic variation and copy number in New Zealand Māori and Pacific (Polynesian) people in Aotearoa New Zealand associate with susceptibility to gout. METHODS:437 whole mitochondrial genomes from Māori and Pacific people (predominantly men) from Aotearoa New Zealand (327 people with gout, 110 without gout) were sequenced. Mitochondrial DNA copy number variation was determined by assessing relative read depth using data produced from whole genome sequencing (32 cases, 43 controls) and targeted resequencing of urate loci (151 cases, 222 controls). Quantitative PCR was undertaken for replication of copy number findings in an extended sample set of 1159 Māori and Pacific men and women (612 cases, 547 controls). RESULTS:There was relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sublineages. A B haplogroup heteroplasmy in hypervariable region I was found to associate with a higher risk of gout among the mitochondrial sequenced sample set (position 16181: OR=1.57, P=0.001). Increased copies of mitochondrial DNA were found to protect against gout risk with the effect being consistent when using hyperuricaemic controls across each of the three independent sample sets (OR=0.89, P=0.007; OR=0.90, P=0.002; OR=0.76, P=0.03). Paradoxically, an increase of mitochondrial DNA also associated with an increase in gout flare frequency in people with gout in the two larger sample sets used for the copy number analysis (β=0.003, P=7.1×10-7; β=0.08, P=1.2×10-4). CONCLUSION:Association of reduced copy number with gout in hyperuricaemia was replicated over three Polynesian sample sets. Our data are consistent with emerging research showing that mitochondria are important for the colocalisation of the NLRP3 and ASC inflammasome subunits, a process essential for the generation of interleukin-1β in gout. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Annals of the rheumatic diseases |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Mitochondria |
en |
dc.subject |
Humans |
en |
dc.subject |
Gout |
en |
dc.subject |
Case-Control Studies |
en |
dc.subject |
Adult |
en |
dc.subject |
Middle Aged |
en |
dc.subject |
Oceanic Ancestry Group |
en |
dc.subject |
Ethnic Groups |
en |
dc.subject |
New Zealand |
en |
dc.subject |
Polynesia |
en |
dc.subject |
Female |
en |
dc.subject |
Male |
en |
dc.subject |
CARD Signaling Adaptor Proteins |
en |
dc.subject |
DNA Copy Number Variations |
en |
dc.subject |
Inflammasomes |
en |
dc.subject |
NLR Family, Pyrin Domain-Containing 3 Protein |
en |
dc.subject |
Whole Genome Sequencing |
en |
dc.title |
Mitochondrial genetic variation and gout in Māori and Pacific people living in Aotearoa New Zealand. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1136/annrheumdis-2017-212416 |
en |
pubs.issue |
4 |
en |
pubs.begin-page |
571 |
en |
pubs.volume |
77 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
29247128 |
en |
pubs.end-page |
578 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
719688 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
School of Medicine |
en |
pubs.org-id |
Medicine Department |
en |
dc.identifier.eissn |
1468-2060 |
en |
pubs.record-created-at-source-date |
2017-12-17 |
en |
pubs.dimensions-id |
29247128 |
en |