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Canadian Journal of Cardiology

The Genetics of Cardiovascular Disease in Canadian and International Aboriginal Populations

      Abstract

      For Aboriginal populations, as in all populations, understanding the genetic component of cardiovascular disease informs effective treatment and prevention strategies. The term, “genetics of cardiovascular disease,” broadly includes the genetics of susceptibility for atherosclerosis, cardiomyopathy, arrhythmia, and congenital heart disease, collectively a major cause of mortality and morbidity throughout the life course. Aboriginal populations are often genetically and culturally distinct, and as would be expected with distinct ethnic differences, there are also differences in rates and types of heart disease, which supports the importance of understanding possible genetic factors that might alter susceptibility. In Canada, higher rates of congenital heart malformations have been identified in some Inuit and First Nations than in the non-Aboriginal population. Moreover, at least 3 different First Nations communities in Canada have been found to have disproportionately higher rates of congenital long QT syndrome, a genetic predisposition to arrhythmia and sudden cardiac death. Although rates of ischemic heart disease historically have been lower in Aboriginal populations, more recent evidence suggests equal or higher rates than in non-Aboriginal populations. Although relatively few Aboriginal communities in Canada have participated in research to explore the genetic component of cardiovascular disease, recent progress in research standards of practice that require collaborative approaches have opened the doors for more involvement. Herein we present what has been learned to date through research and the apparent gaps in the understanding of the genetics of heart disease in Canadian, American, Circumpolar, and other international Indigenous populations.

      Résumé

      Dans les populations autochtones, comme dans l’ensemble des populations, la compréhension de la composante génétique de la maladie cardiovasculaire permet d’orienter la mise en place de stratégies de traitement et de prévention efficaces. Lorsqu’on parle de « la génétique de la maladie cardiovasculaire », il est globalement question de la prédisposition génétique à plusieurs affections, notamment l’athérosclérose, la cardiomyopathie, l’arythmie et la cardiopathie congénitale. Collectivement, ces affections sont une cause importante de mortalité et de morbidité tout au long de la vie. Les Autochtones forment souvent des peuples distincts tant culturellement que sur le plan génétique et, en général, les différences ethniques s’accompagnent aussi de différences quant à la prévalence et aux types de cardiopathies, d’où l’importance de bien comprendre les facteurs génétiques susceptibles d’influer sur les prédispositions. Au Canada, la fréquence des malformations cardiaques congénitales s’est révélée plus élevée au sein des populations inuites et de certaines Premières Nations que parmi la population non autochtone. De plus, au moins trois collectivités des Premières Nations canadiennes affichent des taux disproportionnellement élevés de syndrome du QT long congénital, une prédisposition génétique à l’arythmie et à la mort subite d’origine cardiaque. Bien que la fréquence de cardiopathie ischémique ait été dans le passé inférieure à la norme au sein des populations autochtones, de récentes données montrent qu’elle est maintenant égale ou supérieure à celle observée parmi les populations non autochtones. Relativement peu de groupes autochtones du Canada ont participé à des études visant à explorer la composante génétique de la maladie cardiovasculaire, mais des modifications récemment apportées aux normes de pratique en recherche, mettant de l’avant des approches de collaboration, ont ouvert la porte à une plus grande participation. Nous présentons ici un bilan des connaissances acquises jusqu’ici grâce à la recherche et décrivons les lacunes apparentes dans notre compréhension de la génétique de la cardiopathie propre aux peuples autochtones du Canada, de l’Amérique et de la région circumpolaire ainsi qu’aux populations indigènes d’autres pays.
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      References

        • Kathiresan S.
        • Srivastava D.
        Genetics of human cardiovascular disease.
        Cell. 2012; 148: 1242-1257
        • Hansson J.H.
        • Nelson-Williams C.
        • Suzuki H.
        • et al.
        Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome.
        Nat Genet. 1995; 11: 76-82
        • Joseph P.G.
        • Pare G.
        • Ross S.
        • Roberts R.
        • Anand S.S.
        Pharmacogenetics in cardiovascular disease: the challenge of moving from promise to realization: concepts discussed at the Canadian Network and Centre for Trials Internationally Network Conference (CANNeCTIN), June 2009.
        Clin Cardiol. 2014; 37: 48-56
        • Anand S.S.
        • Xie C.
        • Pare G.
        • et al.
        Genetic variants associated with myocardial infarction risk factors in over 8000 individuals from five ethnic groups: the INTERHEART Genetics Study.
        Circ Cardiovasc Genet. 2009; 2: 16-25
        • Lara-Pezzi E.
        • Dopazo A.
        • Manzanares M.
        Understanding cardiovascular disease: a journey through the genome (and what we found there).
        Dis Model Mech. 2012; 5: 434-443
        • Arking D.E.
        • Chugh S.S.
        • Chakravarti A.
        • Spooner P.M.
        Genomics in sudden cardiac death.
        Circ Res. 2004; 94: 712-723
        • Roberts R.
        Genomics and cardiac arrhythmias.
        J Am Coll Cardiol. 2006; 47: 9-21
        • Vincent G.M.
        • Schwartz P.J.
        • Denjoy I.
        • et al.
        High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment “failures.”.
        Circulation. 2009; 119: 215-221
        • van Langen I.M.
        • Wilde A.A.
        The outpatient clinic for cardiogenetics.
        in: Baars H.F. Doevendans P.A.F.M. van der Smagt J.J. Clinical Cardiogenetics. Springer Science & Business Media, London2011: 413-422
        • Nunn L.M.
        • Lambiase P.D.
        Genetics and cardiovascular disease–causes and prevention of unexpected sudden adult death: the role of the SADS clinic.
        Heart. 2011; 97: 1122-1127
        • Tester D.J.
        • Ackerman M.J.
        Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.
        Circulation. 2011; 123: 1021-1037
        • Blackmore H.L.
        • Ozanne S.E.
        Programming of cardiovascular disease across the life-course.
        J Mol Cell Cardiol. 2015; 83: 122-130
        • Hoffman J.I.
        • Kaplan S.
        The incidence of congenital heart disease.
        J Am Coll Cardiol. 2002; 39: 1890-1900
        • Reller M.D.
        • Strickland M.J.
        • Riehle-Colarusso T.
        • Mahle W.T.
        • Correa A.
        Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005.
        J Pediatr. 2008; 153: 807-813
        • Richards A.A.
        • Garg V.
        Genetics of congenital heart disease.
        Curr Cardiol Rev. 2010; 6: 91-97
        • Yu D.
        • Feng Y.
        • Yang L.
        • et al.
        Maternal socioeconomic status and the risk of congenital heart defects in offspring: a meta-analysis of 33 studies.
        PLoS One. 2014; 9: e111056
        • Tjepkema M.
        • Wilkins R.
        • Goedhuis N.
        • Pennock J.
        Cardiovascular disease mortality among First Nations people in Canada, 1991-2001.
        Chronic Dis Inj Can. 2012; 32: 200-207
      1. Employment and Social Development Canada. Canadians in Context - Aboriginal Population. Available at: http://www4.hrsdc.gc.ca/[email protected]?iid=36. Accessed Apil 13, 2015.

      2. Government of Canada. First Nation Profiles Interactive Map. Available at: http://fnpim-cippn.aandc-aadnc.gc.ca/index-eng.asp. Accessed April 20, 2015.

        • Wang S.
        • Lewis C.M.
        • Jakobsson M.
        • et al.
        Genetic variation and population structure in native Americans.
        PLoS Genet. 2007; 3: e185
      3. Métis National Council. Available at: http://www.metisnation.ca/. Accessed April 20, 2015.

      4. Aboriginal Affairs and Northern Development Canada. Métis. Available at: http://www.aadnc-aandc.gc.ca/eng/1100100014427/1346434788986. Accessed April 20, 2015.

        • Clemente F.J.
        • Cardona A.
        • Inchley C.E.
        • et al.
        A selective sweep on a deleterious mutation in CPT1A in Arctic populations.
        Am J Hum Genet. 2014; 95: 584-589
      5. Aboriginal Affairs and Northern Development Canada. Inuit Nunangat Map. Available at: http://www.aadnc-aandc.gc.ca/Map/irs/mp/mp-eng.asp. Accessed April 20, 2015.

      6. Aboriginal Affairs and Northern Development Canada. About British Columbia First Nations. Available at: https://www.aadnc-aandc.gc.ca/eng/1100100021009/1314809450456. Accessed April 13, 2015.

      7. A Statistical Profile on the Health of First Nations in Canada. Vital Statistics for Atlantic and Western Canada, 2001/2002. Available at : http://www.hc-sc.gc.ca/fniah-spnia/alt_formats/pdf/pubs/aborig-autoch/stats-profil-atlant/vital-statistics-eng.pdf. Accessed April 13, 2015.

        • MacMillan H.L.
        • MacMillan A.B.
        • Offord D.R.
        • Dingle J.L.
        Aboriginal health.
        CMAJ. 1996; 155: 1569-1578
        • Marmot M.G.
        • Smith G.D.
        • Stansfeld S.
        • et al.
        Health inequalities among British civil servants: the Whitehall II study.
        Lancet. 1991; 337: 1387-1393
        • Petronis A.
        Epigenetics as a unifying principle in the aetiology of complex traits and diseases.
        Nature. 2010; 465: 721-727
        • Manuck S.B.
        • Flory J.D.
        • Ferrell R.E.
        • Muldoon M.F.
        Socio-economic status covaries with central nervous system serotonergic responsivity as a function of allelic variation in the serotonin transporter gene-linked polymorphic region.
        Psychoneuroendocrinology. 2004; 29: 651-668
        • Mello M.M.
        • Wolf L.E.
        The Havasupai Indian tribe case–lessons for research involving stored biologic samples.
        N Engl J Med. 2010; 363: 204-207
        • Dalton R.
        When two tribes go to war.
        Nature. 2004; 430: 500-502
        • Tsosie R.
        Cultural challenges to biotechnology: Native American genetic resources and the concept of cultural harm.
        J Law Med Ethics. 2007; 35: 396-411
        • Foster M.W.
        • Sharp R.R.
        Genetic research and culturally specific risks: one size does not fit all.
        Trends Genet. 2000; 16: 93-95
      8. Call of the Earth Llamado de la Terra. Pacific Genes and Life Patents Book. Available at: https://calloftheearth.wordpress.com/publications/. Accessed April 13, 2015.

        • Sharp R.R.
        • Foster M.W.
        Grappling with groups: protecting collective interests in biomedical research.
        J Med Philos. 2007; 32: 321-337
      9. Canadian Institutes of Health Research. Guidelines for Health Research Involving Aboriginal People. Available at: http://www.cihr-irsc.gc.ca/e/29134.html. Accessed April 13, 2015.

      10. Minkler M. Wallerstein N. Community Based Participatory Research for Health. Jossey-Bass, San Francisco2003
        • Arbour L.
        • Cook D.
        DNA on loan: issues to consider when carrying out genetic research with aboriginal families and communities.
        Community Genet. 2006; 9: 153-160
      11. Government of Canada. Panel on Research Ethics. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Available at: http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/. Accessed April 24, 2015.

        • Cargo M.
        • Mercer S.L.
        The value and challenges of participatory research: strengthening its practice.
        Annu Rev Public Health. 2008; 29: 325-350
        • Macaulay A.C.
        • Commanda L.E.
        • Freeman W.L.
        • et al.
        Participatory research maximises community and lay involvement. North American Primary Care Research Group.
        BMJ. 1999; 319: 774-778
      12. Tandon SD, Phillips K, Bordeaux B, et al. A Vision for Progress in Community Health Partnerships, 2007. Available at: https://www.press.jhu.edu/journals/progress_in_community_health_partnerships/1.1tandon.pdf. Accessed April 13, 2015.

        • Potvin L.
        • Cargo M.
        • McComber A.M.
        • Delormier T.
        • Macaulay A.C.
        Implementing participatory intervention and research in communities: lessons from the Kahnawake Schools Diabetes Prevention Project in Canada.
        Soc Sci Med. 2003; 56: 1295-1305
        • Paradis G.
        • Levesque L.
        • Macaulay A.C.
        • et al.
        Impact of a diabetes prevention program on body size, physical activity, and diet among Kanien;keha:ka (Mohawk) children 6 to 11 years old: 8-year results from the Kahnawake Schools Diabetes Prevention Project.
        Pediatrics. 2005; 115: 333-339
        • Kakekagumick K.E.
        • Naqshbandi Hayward M.
        • Harris S.B.
        • et al.
        Sandy lake health and diabetes project: a community-based intervention targeting type 2 diabetes and its risk factors in a first nations community.
        Front Endocrinol (Lausanne). 2013; 4: 170
      13. Reading J. The Crisis of Chronic Disease among Aboriginal Peoples: A Challenge for Public Health, Population Health and Social Policy (2009). Available at: http://www.uvic.ca/research/centres/cahr/knowledge/publications/chronicdisease.pdf. Accessed April 24, 2015.

        • Young T.K.
        Cardiovascular health among Canada’s aboriginal populations: a review.
        Heart Lung Circ. 2012; 21: 618-622
        • Anand S.S.
        • Yusuf S.
        • Jacobs R.
        • et al.
        Risk factors, atherosclerosis, and cardiovascular disease among Aboriginal people in Canada: the Study of Health Assessment and Risk Evaluation in Aboriginal Peoples (SHARE-AP).
        Lancet. 2001; 358: 1147-1153
        • Chateau-Degat M.L.
        • Dewailly E.
        • Louchini R.
        • et al.
        Cardiovascular burden and related risk factors among Nunavik (Quebec) Inuit: insights from baseline findings in the circumpolar Inuit health in transition cohort study.
        Can J Cardiol. 2010; 26: 190-196
        • Foulds H.J.
        • Shubair M.M.
        • Warburton D.E.
        A review of the cardiometabolic risk experience among Canadian Métis populations.
        Can J Cardiol. 2013; 29: 1006-1013
      14. Aboriginal Affairs and Northern Development Canada. First Nation Profiles. Available at: http://fnp-ppn.aandc-aadnc.gc.ca/fnp/Main/index.aspx?lang=eng. Accessed April 20, 2015.

        • Hegele R.A.
        Genetic prediction of atherosclerosis: lessons from studies in native Canadian populations.
        Clin Chim Acta. 1999; 286: 47-61
        • Hegele R.A.
        • Connelly P.W.
        • Hanley A.J.
        • et al.
        Common genomic variation in the APOC3 promoter associated with variation in plasma lipoproteins.
        Arterioscler Thromb Vasc Biol. 1997; 17: 2753-2758
        • Hegele R.A.
        • Connelly P.W.
        • Hanley A.J.
        • et al.
        Common genomic variants associated with variation in plasma lipoproteins in young aboriginal Canadians.
        Arterioscler Thromb Vasc Biol. 1997; 17: 1060-1066
        • Hegele R.A.
        • Harris S.B.
        • Brunt J.H.
        • et al.
        Absence of association between genetic variation in the LIPC gene promoter and plasma lipoproteins in three Canadian populations.
        Atherosclerosis. 1999; 146: 153-160
        • Wang J.
        • Burnett J.R.
        • Near S.
        • et al.
        Common and rare ABCA1 variants affecting plasma HDL cholesterol.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1983-1989
        • Hegele R.A.
        • Cao H.
        • Harris S.B.
        • et al.
        The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree.
        Arterioscler Thromb Vasc Biol. 2000; 20: 217-222
        • Hegele R.A.
        • Wang J.
        • Harris S.B.
        • et al.
        Variable association between genetic variation in the CYP7 gene promoter and plasma lipoproteins in three Canadian populations.
        Atherosclerosis. 2001; 154: 579-587
        • Pollex R.L.
        • Hanley A.J.
        • Zinman B.
        • Harris S.B.
        • Hegele R.A.
        Clinical and genetic associations with hypertriglyceridemic waist in a Canadian aboriginal population.
        Int J Obes (Lond). 2006; 30: 484-491
        • Al-Shali K.Z.
        • House A.A.
        • Hanley A.J.
        • et al.
        Genetic variation in PPARG encoding peroxisome proliferator-activated receptor gamma associated with carotid atherosclerosis.
        Stroke. 2004; 35: 2036-2040
        • Hegele R.A.
        • Al-Shali K.Z.
        • House A.A.
        • et al.
        Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits.
        Stroke. 2005; 36: 2566-2570
        • Pollex R.L.
        • Mamakeesick M.
        • Zinman B.
        • et al.
        Methylenetetrahydrofolate reductase polymorphism 677C>T is associated with peripheral arterial disease in type 2 diabetes.
        Cardiovasc Diabetol. 2005; 4: 17
        • Hegele R.A.
        • Harris S.B.
        • Hanley A.J.
        • et al.
        Absence of association between genetic variation of the beta 3-adrenergic receptor and metabolic phenotypes in Oji-Cree.
        Diabetes Care. 1998; 21: 851-854
        • Pollex R.L.
        • Hanley A.J.
        • Zinman B.
        • et al.
        Metabolic syndrome in aboriginal Canadians: prevalence and genetic associations.
        Atherosclerosis. 2006; 184: 121-129
        • Hegele R.A.
        • Harris S.B.
        • Hanley A.J.
        • et al.
        Angiotensinogen gene variation associated with variation in blood pressure in aboriginal Canadians.
        Hypertension. 1997; 29: 1073-1077
        • Hegele R.A.
        • Harris S.B.
        • Hanley A.J.
        • et al.
        -6A Promoter variant of angiotensinogen and blood pressure variation in Canadian Oji-Cree.
        J Hum Genet. 1998; 43: 37-41
        • Koschinsky M.L.
        • Boffa M.B.
        • Nesheim M.E.
        • et al.
        Association of a single nucleotide polymorphism in CPB2 encoding the thrombin-activable fibrinolysis inhibitor (TAF1) with blood pressure.
        Clin Genet. 2001; 60: 345-349
        • Drescher O.
        • Dewailly E.
        • Diorio C.
        • et al.
        Methylmercury exposure, PON1 gene variants and serum paraoxonase activity in Eastern James Bay Cree adults.
        J Expo Sci Environ Epidemiol. 2014; 24: 608-614
        • Lanktree M.B.
        • Johansen C.T.
        • Anand S.S.
        • et al.
        Genetic variation in hyaluronan metabolism loci is associated with plasma plasminogen activator inhibitor-1 concentration.
        Blood. 2010; 116: 2160-2163
        • Zbuk K.
        • Xie C.C.
        • Young R.
        • et al.
        BRCA2 Variants and cardiovascular disease in a multi-ethnic study.
        BMC Med Genet. 2012; 13: 56
        • Arbour L.
        • Rezazadeh S.
        • Eldstrom J.
        • et al.
        A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact.
        Genet Med. 2008; 10: 545-550
        • Jackson H.
        • Huisman L.A.
        • Sanatani S.
        • Arbour L.T.
        Long QT syndrome.
        CMAJ. 2011; 183: 1272-1275
        • Jackson H.
        • McIntosh S.
        • Whittome B.
        • et al.
        LQTS in Northern BC: homozygosity for KCNQ1 V205M presents with a more severe cardiac phenotype but with minimal impact on auditory function.
        Clin Genet. 2014; 86: 85-90
        • Gardner M.J.
        • Marcadier J.
        • Crowley A.
        • et al.
        A novel missense Scn5a gene mutation causing Lqt3 in a large First Nations family (abstract).
        Can J Cardiol. 2011; 27: S156-S157
        • Kataoka S.
        • Robbins D.C.
        • Cowan L.D.
        • et al.
        Apolipoprotein E polymorphism in American Indians and its relation to plasma lipoproteins and diabetes. The Strong Heart Study.
        Arterioscler Thromb Vasc Biol. 1996; 16: 918-925
        • North K.E.
        • Goring H.H.
        • Cole S.A.
        • et al.
        Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study.
        J Lipid Res. 2006; 47: 59-66
        • Best L.G.
        • Ferrell R.E.
        • Decroo S.
        • et al.
        Genetic and other factors determining mannose-binding lectin levels in American Indians: the Strong Heart Study.
        BMC Med Genet. 2009; 10: 5
        • Li X.
        • Monda K.L.
        • Goring H.H.
        • et al.
        Genome-wide linkage scan for plasma high density lipoprotein cholesterol, apolipoprotein A-1 and triglyceride variation among American Indian populations: the Strong Heart Family Study.
        J Med Genet. 2009; 46: 472-479
        • Devaney J.M.
        • Gordish-Dressman H.
        • Harmon B.T.
        • et al.
        AKT1 polymorphisms are associated with risk for metabolic syndrome.
        Hum Genet. 2011; 129: 129-139
        • Yang J.
        • Zhu Y.
        • Lee E.T.
        • et al.
        Joint associations of 61 genetic variants in the nicotinic acetylcholine receptor genes with subclinical atherosclerosis in American Indians: a gene-family analysis.
        Circ Cardiovasc Genet. 2013; 6: 89-96
        • Zhang L.
        • Buzkova P.
        • Wassel C.L.
        • et al.
        Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study.
        Atherosclerosis. 2013; 228: 390-399
        • Tsai C.W.
        • North K.E.
        • Tin A.
        • et al.
        Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians.
        J Clin Endocrinol Metab. 2015; 100: E345-E349
        • Zhao J.
        • Roman M.J.
        • Devereux R.B.
        • et al.
        Leukotriene haplotype x diet interaction on carotid artery hypertrophy and atherosclerosis in American Indians: the Strong Heart Family Study.
        Atherosclerosis. 2014; 233: 165-171
        • Best L.G.
        • Davidson M.
        • North K.E.
        • et al.
        Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians: the Strong Heart Study.
        Circulation. 2004; 109: 471-475
        • Franceschini N.
        • Carty C.
        • Buzkova P.
        • et al.
        Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.
        Circ Cardiovasc Genet. 2011; 4: 661-672
        • Franceschini N.
        • MacCluer J.W.
        • Goring H.H.
        • et al.
        A quantitative trait loci-specific gene-by-sex interaction on systolic blood pressure among American Indians: the Strong Heart Family Study.
        Hypertension. 2006; 48: 266-270
        • Franceschini N.
        • Tao R.
        • Liu L.
        • et al.
        Mapping of a blood pressure QTL on chromosome 17 in American Indians of the strong heart family study.
        BMC Cardiovasc Disord. 2014; 14: 158
        • Voruganti V.S.
        • Franceschini N.
        • Haack K.
        • et al.
        Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians.
        Eur J Hum Genet. 2014; 22: 938-943
        • Melton P.E.
        • Rutherford S.
        • Voruganti V.S.
        • et al.
        Bivariate genetic association of KIAA1797 with heart rate in American Indians: the Strong Heart Family Study.
        Hum Mol Genet. 2010; 19: 3662-3671
        • Seyerle A.A.
        • Young A.M.
        • Jeff J.M.
        • et al.
        Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval.
        Epidemiology. 2014; 25: 790-798
        • Breton C.V.
        • Park C.
        • Siegmund K.
        • et al.
        NOS1 methylation and carotid artery intima-media thickness in children.
        Circ Cardiovasc Genet. 2014; 7: 116-122
        • Walder K.
        • Norman R.A.
        • Hanson R.L.
        • et al.
        Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians.
        Hum Mol Genet. 1998; 7: 1431-1435
        • Jenkinson C.P.
        • Hanson R.
        • Cray K.
        • et al.
        Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians.
        Int J Obes Relat Metab Disord. 2000; 24: 1233-1238
        • Wolford J.K.
        • Colligan P.B.
        • Gruber J.D.
        • Bogardus C.
        Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians.
        Mol Genet Metab. 2003; 80: 338-343
        • Ma L.
        • Tataranni P.A.
        • Bogardus C.
        • Baier L.J.
        Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians.
        Diabetes. 2004; 53: 2696-2699
        • Ma L.
        • Tataranni P.A.
        • Hanson R.L.
        • et al.
        Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men.
        Diabetes. 2005; 54: 1598-1602
        • Franks P.W.
        • Knowler W.C.
        • Nair S.
        • et al.
        Interaction between an 11betaHSD1 gene variant and birth era modifies the risk of hypertension in Pima Indians.
        Hypertension. 2004; 44: 681-688
        • Hegele R.A.
        • Young T.K.
        • Connelly P.W.
        Are Canadian Inuit at increased genetic risk for coronary heart disease?.
        J Mol Med (Berl). 1997; 75: 364-370
        • Mandelcorn R.
        • Connelly P.W.
        • Boright A.
        • Young T.K.
        • Hegele R.A.
        F5 Q506 mutation and the low prevalence of cardiovascular disease in Canadian Inuit.
        J Investig Med. 1998; 46: 232-235
        • Hegele R.A.
        • Tully C.
        • Young T.K.
        • Connelly P.W.
        V677 mutation of methylenetetrahydrofolate reductases and cardiovascular disease in Canadian Inuit.
        Lancet. 1997; 349: 1221-1222
        • Hegele R.A.
        • Busch C.P.
        • Young T.K.
        • Connelly P.W.
        • Cao H.
        Mannose-binding lectin gene variation and cardiovascular disease in Canadian Inuit.
        Clin Chem. 1999; 45: 1283-1285
        • Hegele R.A.
        • Huff M.W.
        • Young T.K.
        Common genomic variation in LMNA modulates indexes of obesity in Inuit.
        J Clin Endocrinol Metab. 2001; 86: 2747-2751
        • Hegele R.A.
        • Ban M.R.
        • Young T.K.
        Serum C-reactive protein in Canadian Inuit and its association with genetic variation on chromosome 1q21.
        Clin Chem. 2001; 47: 1707-1709
        • Rudkowska I.
        • Dewailly E.
        • Hegele R.A.
        • et al.
        Gene-diet interactions on plasma lipid levels in the Inuit population.
        Br J Nutr. 2013; 109: 953-961
        • Rudkowska I.
        • Ouellette C.
        • Dewailly E.
        • et al.
        Omega-3 fatty acids, polymorphisms and lipid related cardiovascular disease risk factors in the Inuit population.
        Nutr Metab (Lond). 2013; 10: 26
        • de Knijff P.
        • Johansen L.G.
        • Rosseneu M.
        • et al.
        Lipoprotein profile of a Greenland Inuit population. Influence of anthropometric variables, Apo E and A4 polymorphism, and lifestyle.
        Arterioscler Thromb. 1992; 12: 1371-1379
        • de Maat M.P.
        • Green F.
        • deKnijff P.
        • Jespersen J.
        • Kluft C.
        Factor VII polymorphisms in populations with different risks of cardiovascular disease.
        Arterioscler Thromb Vasc Biol. 1997; 17: 1918-1923
        • Lahiry P.
        • Ban M.R.
        • Pollex R.L.
        • et al.
        Common variants APOC3, APOA5, APOE and PON1 are associated with variation in plasma lipoprotein traits in Greenlanders.
        Int J Circumpolar Health. 2007; 66: 390-400
        • Rajakumar C.
        • Ban M.R.
        • Cao H.
        • et al.
        Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I.
        J Lipid Res. 2009; 50: 1223-1228
        • Johansen C.T.
        • Gallinger Z.R.
        • Wang J.
        • et al.
        Rare ATGL haplotypes are associated with increased plasma triglyceride concentrations in the Greenland Inuit.
        Int J Circumpolar Health. 2010; 69: 3-12
        • Voruganti V.S.
        • Cole S.A.
        • Ebbesson S.O.
        • et al.
        Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos.
        Am J Clin Nutr. 2010; 91: 1574-1583
        • Lemas D.J.
        • Wiener H.W.
        • O'Brien D.M.
        • et al.
        Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos.
        J Lipid Res. 2012; 53: 175-184
        • Aslibekyan S.
        • Wiener H.W.
        • Havel P.J.
        • et al.
        DNA methylation patterns are associated with n-3 fatty acid intake in Yup'ik people.
        J Nutr. 2014; 144: 425-430
        • Vaughan L.K.
        • Wiener H.W.
        • Aslibekyan S.
        • et al.
        Linkage and association analysis of obesity traits reveals novel loci and interactions with dietary n-3 fatty acids in an Alaska Native (Yup'ik) population.
        Metabolism. 2015; 64: 689-697
        • Lehtinen S.
        • Luoma P.
        • Nayha S.
        • et al.
        Apolipoprotein A-IV polymorphism in Saami and Finns: frequency and effect on serum lipid levels.
        Ann Med. 1998; 30: 218-223
        • Dubé J.B.
        • Wang J.
        • Cao H.
        • et al.
        Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar Inuit populations.
        Circ Cardiovasc Genet. 2015; 8: 100-105
        • Pollex R.L.
        • Ban M.R.
        • Young T.K.
        • et al.
        Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample.
        BMC Med Genet. 2007; 8: 80
        • Aguilar C.A.
        • Talavera G.
        • Ordovas J.M.
        • et al.
        The apolipoprotein E4 allele is not associated with an abnormal lipid profile in a Native American population following its traditional lifestyle.
        Atherosclerosis. 1999; 142: 409-414
        • Norma P.H.
        • Carlos M.P.
        • Isabel H.O.
        • et al.
        PON1Q192R polymorphism is associated with lipid profile in Mexican men with Mayan ascendancy.
        Exp Mol Pathol. 2008; 85: 129-134
        • Bailon-Soto C.E.
        • Galaviz-Hernandez C.
        • Lazalde-Ramos B.P.
        • et al.
        Influence of CYP1A1*2C on high triglyceride levels in female Mexican indigenous Tarahumaras.
        Arch Med Res. 2014; 45: 409-416
        • Ko A.
        • Cantor R.M.
        • Weissglas-Volkov D.
        • et al.
        Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.
        Nat Commun. 2014; 5: 3983
        • Valdez-Velazquez L.L.
        • Mendoza-Carrera F.
        • Perez-Parra S.A.
        • et al.
        Renin gene haplotype diversity and linkage disequilibrium in two Mexican and one German population samples.
        J Renin Angiotensin Aldosterone Syst. 2011; 12: 231-237
        • Juarez-Velazquez R.
        • Canto P.
        • Canto-Cetina T.
        • et al.
        Analysis of polymorphisms in genes (AGT, MTHFR, GPIIIa, and GSTP1) associated with hypertension, thrombophilia and oxidative stress in Mestizo and Amerindian populations of Mexico.
        Dis Markers. 2010; 28: 323-331
        • Rupert J.L.
        • Kidd K.K.
        • Norman L.E.
        • et al.
        Genetic polymorphisms in the renin-angiotensin system in high-altitude and low-altitude Native American populations.
        Ann Hum Genet. 2003; 67: 17-25
        • Santos J.L.
        • Perez-Bravo F.
        • Martinez J.A.
        • et al.
        No evidence for an association between genetic polymorphisms of beta(2)- and beta(3)-adrenergic receptor genes with body mass index in Aymara natives from Chile.
        Nutrition. 2002; 18: 255-258
        • Perez-Bravo F.
        • Fuentes M.
        • Angel B.
        • et al.
        Lack of association between the fatty acid binding protein 2 (FABP2) polymorphism with obesity and insulin resistance in two aboriginal populations from Chile.
        Acta Diabetol. 2006; 43: 93-98
        • Acuna-Alonzo V.
        • Flores-Dorantes T.
        • Kruit J.K.
        • et al.
        A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.
        Hum Mol Genet. 2010; 19: 2877-2885
        • Huang M.C.
        • Wang T.N.
        • Liu Y.L.
        • et al.
        Effect of SstI polymorphism of the apolipoprotein CIII gene and environmental factors on risks of hypertriglyceridemia in Taiwan aborigines.
        Circ J. 2006; 70: 1030-1036
        • Wang T.N.
        • Huang M.C.
        • Chang W.T.
        • et al.
        G-2548A polymorphism of the leptin gene is correlated with extreme obesity in Taiwanese aborigines.
        Obesity (Silver Spring). 2006; 14: 183-187
        • Wang T.N.
        • Huang M.C.
        • Lin H.L.
        • et al.
        UCP2 A55V variant is associated with obesity and related phenotypes in an aboriginal community in Taiwan.
        Int J Obes (Lond). 2007; 31: 1746-1752
        • Shaw J.T.
        • Tate J.
        • Kesting J.B.
        • et al.
        Apolipoprotein E polymorphism in indigenous Australians: allelic frequencies and relationship with dyslipidaemia.
        Med J Aust. 1999; 170: 161-164
        • McDonald S.P.
        • Hoy W.E.
        • Maguire G.P.
        • et al.
        The p53Pro72Arg polymorphism is associated with albuminuria among aboriginal Australians.
        J Am Soc Nephrol. 2002; 13: 677-683
        • McDonald S.
        • Maguire G.
        • Duarte N.
        • Wang X.L.
        • Hoy W.
        Homocysteine, renal disease and cardiovascular disease in a remote Australian Aboriginal community.
        Intern Med J. 2005; 35: 289-294
        • Earle N.
        • Yeo Han D.
        • Pilbrow A.
        • et al.
        Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome.
        Heart Rhythm. 2014; 11: 76-82
        • Han Z.
        • Heath S.C.
        • Shmulewitz D.
        • et al.
        Candidate genes involved in cardiovascular risk factors by a family-based association study on the island of Kosrae, Federated States of Micronesia.
        Am J Med Genet. 2002; 110: 234-242
        • Burkhardt R.
        • Kenny E.E.
        • Lowe J.K.
        • et al.
        Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.
        Arterioscler Thromb Vasc Biol. 2008; 28: 2078-2084
        • Smith J.G.
        • Lowe J.K.
        • Kovvali S.
        • et al.
        Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae.
        Heart Rhythm. 2009; 6: 634-641
        • Shmulewitz D.
        • Heath S.C.
        • Blundell M.L.
        • et al.
        Linkage analysis of quantitative traits for obesity, diabetes, hypertension, and dyslipidemia on the island of Kosrae, Federated States of Micronesia.
        Proc Natl Acad Sci U S A. 2006; 103: 3502-3509
        • Triggs-Raine B.L.
        • Kirkpatrick R.D.
        • Kelly S.L.
        • et al.
        HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community.
        Proc Natl Acad Sci U S A. 2002; 99: 4614-4619
        • Harries L.W.
        • Sloman M.J.
        • Sellers E.A.
        • Hattersley A.T.
        • Ellard S.
        Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts.
        Diabetes. 2008; 57: 1978-1982
        • Kuhnlein H.V.
        • Chan H.M.
        Environment and contaminants in traditional food systems of northern indigenous peoples.
        Annu Rev Nutr. 2000; 20: 595-626
        • Chan H.M.
        • Egeland G.M.
        Fish consumption, mercury exposure, and heart diseases.
        Nutr Rev. 2004; 62: 68-72
        • Roman H.A.
        • Walsh T.L.
        • Coull B.A.
        • et al.
        Evaluation of the cardiovascular effects of methylmercury exposures: current evidence supports development of a dose-response function for regulatory benefits analysis.
        Environ Health Perspect. 2011; 119: 607-614
        • Ayotte P.
        • Carrier A.
        • Ouellet N.
        • et al.
        Relation between methylmercury exposure and plasma paraoxonase activity in inuit adults from Nunavik.
        Environ Health Perspect. 2011; 119: 1077-1083
        • Moffatt M.E.
        • Young T.K.
        • O'Neil J.D.
        • et al.
        The Keewatin Health Assessment Study, NWT, Canada.
        Arctic Med Res. 1993; 52: 18-21
        • Saudny H.
        • Leggee D.
        • Egeland G.
        Design and methods of the Adult Inuit Health Survey 2007-2008.
        Int J Circumpolar Health. 2012; 71
        • Bjerregaard P.
        • Curtis T.
        • Borch-Johnsen K.
        • et al.
        Inuit health in Greenland: a population survey of life style and disease in Greenland and among Inuit living in Denmark.
        Int J Circumpolar Health. 2003; 62: 3-79
        • Mohatt G.V.
        • Plaetke R.
        • Klejka J.
        • et al.
        The Center for Alaska Native Health Research Study: a community-based participatory research study of obesity and chronic disease-related protective and risk factors.
        Int J Circumpolar Health. 2007; 66: 8-18
        • Collins S.A.
        • Sinclair G.
        • McIntosh S.
        • et al.
        Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut.
        Mol Genet Metab. 2010; 101: 200-204
      15. Zhou S, Xiong L, Ambalavanan L, et al. Exome sequencing revealing unique genetic profile of Quebec Nunavik Inuit population, 2013. Available at: http://www.ashg.org/2013meeting/abstracts/fulltext/f130122275.htm. Accessed April 22, 2015.

        • Gessner B.D.
        • Gillingham M.B.
        • Birch S.
        • Wood T.
        • Koeller D.M.
        Evidence for an association between infant mortality and a carnitine palmitoyltransferase 1A genetic variant.
        Pediatrics. 2010; 126: 945-951
        • Collins S.A.
        • Surmala P.
        • Osborne G.
        • et al.
        Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011.
        BMC Pediatr. 2012; 12: 190
        • Brown N.F.
        • Mullur R.S.
        • Subramanian I.
        • et al.
        Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme.
        J Lipid Res. 2001; 42: 1134-1142
        • Lee E.T.
        • Welty T.K.
        • Fabsitz R.
        • et al.
        The Strong Heart Study. A study of cardiovascular disease in American Indians: design and methods.
        Am J Epidemiol. 1990; 132: 1141-1155
        • North K.E.
        • Howard B.V.
        • Welty T.K.
        • et al.
        Genetic and environmental contributions to cardiovascular disease risk in American Indians: the strong heart family study.
        Am J Epidemiol. 2003; 157: 303-314
        • Kizer J.R.
        • Krauser D.G.
        • Rodeheffer R.J.
        • et al.
        Prognostic value of multiple biomarkers in American Indians free of clinically overt cardiovascular disease (from the Strong Heart Study).
        Am J Cardiol. 2009; 104: 247-253
        • Jordan J.E.
        • Montalto M.C.
        • Stahl G.L.
        Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury.
        Circulation. 2001; 104: 1413-1418
        • Madsen H.O.
        • Garred P.
        • Thiel S.
        • et al.
        Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein.
        J Immunol. 1995; 155: 3013-3020
        • Roden D.M.
        Keep the QT interval: it is a reliable predictor of ventricular arrhythmias.
        Heart Rhythm. 2008; 5: 1213-1215
        • Okin P.M.
        • Devereux R.B.
        • Howard B.V.
        • et al.
        Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: The Strong Heart Study.
        Circulation. 2000; 101: 61-66
        • Algra A.
        • Tijssen J.G.
        • Roelandt J.R.
        • Pool J.
        • Lubsen J.
        QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest.
        Circulation. 1991; 83: 1888-1894
        • Bokil N.J.
        • Baisden J.M.
        • Radford D.J.
        • Summers K.M.
        Molecular genetics of long QT syndrome.
        Mol Genet Metab. 2010; 101: 1-8
        • Goldenberg I.
        • Zareba W.
        • Moss A.J.
        Long QT syndrome.
        Curr Probl Cardiol. 2008; 33: 629-694
        • Ackerman M.J.
        Cardiac channelopathies: it’s in the genes.
        Nat Med. 2004; 10: 463-464
        • Noseworthy P.A.
        • Newton-Cheh C.
        Genetic determinants of sudden cardiac death.
        Circulation. 2008; 118: 1854-1863
        • Schwartz P.J.
        • Stramba-Badiale M.
        • Crotti L.
        • et al.
        Prevalence of the congenital long-QT syndrome.
        Circulation. 2009; 120: 1761-1767
        • Eldstrom J.
        • Wang Z.
        • Werry D.
        • Wong N.
        • Fedida D.
        Microscopic mechanisms for long QT syndrome type 1 revealed by single-channel analysis of I(Ks) with S3 domain mutations in KCNQ1.
        Heart Rhythm. 2015; 12: 386-394
        • Vincent G.M.
        • Timothy K.W.
        • Leppert M.
        • Keating M.
        The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome.
        N Engl J Med. 1992; 327: 846-852
        • Hofman N.
        • Wilde A.A.
        • Kaab S.
        • et al.
        Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?.
        Eur Heart J. 2007; 28: 575-580
        • Priori S.G.
        • Napolitano C.
        • Schwartz P.J.
        Low penetrance in the long-QT syndrome: clinical impact.
        Circulation. 1999; 99: 529-533
        • Aasebo W.
        • Erikssen J.
        • Jonsbu J.
        • Stavem K.
        ECG changes in patients with acute ethanol intoxication.
        Scand Cardiovasc J. 2007; 41: 79-84
        • Munday F.
        Systemic lupus erythematosus patients in the Gitxsan First Nations community of northern British Columbia have an elevated QTc when compared to individuals negative for the KCNQ1 V205M missense mutation [thesis]. Victoria, BC: University of Victoria.
        2011
        • Priori S.G.
        • Schwartz P.J.
        • Napolitano C.
        • et al.
        Risk stratification in the long-QT syndrome.
        N Engl J Med. 2003; 348: 1866-1874
        • Grunnet M.
        • Behr E.R.
        • Calloe K.
        • et al.
        Functional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome.
        Heart Rhythm. 2005; 2: 1238-1249
        • Goldenberg I.
        • Horr S.
        • Moss A.J.
        • et al.
        Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals.
        J Am Coll Cardiol. 2011; 57: 51-59
        • Goldenberg I.
        • Moss A.J.
        • Bradley J.
        • et al.
        Long-QT syndrome after age 40.
        Circulation. 2008; 117: 2192-2201
      16. BC Inherited Arrhythmia Program. Available at: http://www.sscbc.ca/sites/default/files/BCIAP_Poster.pdf. Accessed April 20, 2015.

        • Wilde A.A.
        Is there a role for implantable cardioverter defibrillators in long QT syndrome?.
        J Cardiovasc Electr. 2002; 13: S110-S113
        • Arbour L.
        • Gilpin C.
        • Millor-Roy V.
        • et al.
        Heart defects and other malformations in the Inuit in Canada: a baseline study.
        Int J Circumpolar Health. 2004; 63: 251-266
        • Lowry R.B.
        • Thunem N.Y.
        • Silver M.
        Congenital anomalies in American Indians of British Columbia.
        Genet Epidemiol. 1986; 3: 455-467
        • McCrindle B.W.
        • Wood M.M.
        • Collins G.F.
        • Wheatley B.
        • Rowe R.D.
        An increased incidence of total anomalous pulmonary venous drainage among aboriginal Canadians.
        Can J Cardiol. 1996; 12: 81-85
        • Elliott A.M.
        • Simard L.R.
        • Coghlan G.
        • et al.
        A novel mutation in KIAA0196: identification of a gene involved in Ritscher-Schinzel/3C syndrome in a First Nations cohort.
        J Med Genet. 2013; 50: 819-822
        • Aggarwal D.
        • Warmerdam B.
        • Wyatt K.
        • Ahmad S.
        • Shaw G.M.
        Prevalence of birth defects among American-Indian births in California, 1983-2010.
        Birth Defects Res A Clin Mol Teratol. 2015; 103: 105-110
      17. Defining “Indigenous Peoples” - the United Nations. Available at: http://www.un.org/esa/socdev/unpfii/documents/workshop_data_background.doc. Accessed April 26, 2015

        • Choudhary D.
        • Jansson I.
        • Stoilov I.
        • Sarfarazi M.
        • Schenkman J.B.
        Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1.
        Drug Metab Dispos. 2004; 32: 840-847
        • Bustamante C.D.
        • Burchard E.G.
        • De la Vega F.M.
        Genomics for the world.
        Nature. 2011; 475: 163-165
        • McPherson R.
        From genome-wide association studies to functional genomics: new insights into cardiovascular disease.
        Can J Cardiol. 2013; 29: 23-29
        • Genne-Bacon E.A.
        Thinking evolutionarily about obesity.
        Yale J Biol Med. 2014; 87: 99-112
        • Speakman J.R.
        Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints.
        Annu Rev Nutr. 2013; 33: 289-317
      18. Canadian Alliance for Healthy Hearts and Minds. Available at: http://cahhm.mcmaster.ca/?page_id=7. Accessed April 26, 2015.

      19. Canada Health Act. Justice Laws Website. Available at: http://laws-lois.justice.gc.ca/eng/acts/c-6/. Accessed April 26, 2015.

        • Hawkins A.K.
        • Hayden M.R.
        A grand challenge: providing benefits of clinical genetics to those in need.
        Genet Med. 2011; 13: 197-200
        • McInnes R.R.
        2010 Presidential Address. Culture: the silent language geneticists must learn–genetic research with indigenous populations.
        Am J Hum Genet. 2011; 88: 254-261