Explaining the variability in cardiovascular risk factors among First Nations communities in Canada: a population-based study.

BACKGROUND: Historical, colonial, and racist policies continue to influence the health of Indigenous people, and they continue to have higher rates of chronic diseases and reduced life expectancy compared with non-Indigenous people. We determined factors accounting for variations in cardiovascular risk factors among First Nations communities in Canada. METHODS: Men and women (n=1302) aged 18 years or older from eight First Nations communities participated in a population-based study. Questionnaires, physical measures, blood samples, MRI of preclinical vascular disease, and community audits were collected. In this cross-sectional analysis, the main outcome was the INTERHEART risk score, a measure of cardiovascular risk factor burden. A multivariable model was developed to explain the variations in INTERHEART risk score among communities. The secondary outcome was MRI-detected carotid wall volume, a measure of subclinical atherosclerosis. FINDINGS: The mean INTERHEART risk score of all communities was 17·2 (SE 0·2), and more than 85% of individuals had a risk score in the moderate to high risk range. Subclinical atherosclerosis increased significantly across risk score categories (p<0·0001). Socioeconomic advantage (-1·4 score, 95% CI -2·5 to -0·3; p=0·01), trust between neighbours (-0·7, -1·2 to -0·3; p=0·003), higher education level (-1·9, -2·9 to -0·8, p<0·001), and higher social support (-1·1, -2·0 to -0·2; p=0·02) were independently associated with a lower INTERHEART risk score; difficulty accessing routine health care (2·2, 0·3 to 4·1, p=0·02), taking prescription medication (3·5, 2·8 to 4·3; p<0·001), and inability to afford prescription medications (1·5, 0·5 to 2·6; p=0·003) were associated with a higher INTERHEART risk score. Collectively, these factors explained 28% variation in the cardiac risk score among communities. Communities with higher socioeconomic advantage and greater trust, and individuals with higher education and social support, had a lower INTERHEART risk score. Communities with difficulty accessing health care, and individuals taking or unable to afford prescription medications, had a higher INTERHEART risk score. INTERPRETATION: Cardiac risk factors are lower in communities with high socioeconomic advantage, greater trust, social support and educational opportunities, and higher where it is difficult to access health care or afford prescription medications. Strategies to optimise the protective factors and reduce barriers to health care in First Nations communities might contribute to improved health and wellbeing. FUNDING: Heart and Stroke Foundation of Canada, Canadian Partnership Against Cancer, Canadian Institutes for Health Research.

Canadian Alliance for Healthy Hearts and Minds: First Nations Cohort Study Rationale and Design.

BACKGROUND: This is the first national indigenous cohort study in which a common, in-depth protocol with a common set of objectives has been adopted by several indigenous communities across Canada. OBJECTIVES: The overarching objective of the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort is to investigate how the community-level environment is associated with individual health behaviors and the presence and progression of chronic disease risk factors and chronic diseases such as cardiovascular disease (CVD) and cancer. METHODS: CAHHM aims to recruit approximately 2,000 First Nations indigenous individuals from up to nine communities across Canada and have participants complete questionnaires, blood collection, physical measurements, cognitive assessments, and magnetic resonance imaging (MRI). RESULTS: Through individual- and community-level data collection, we will develop an understanding of the specific role of the socioenvironmental, biological, and contextual factors have on the development of chronic disease risk factors and chronic diseases. CONCLUSIONS: Information collected in the indigenous cohort will be used to assist communities to develop local management strategies for chronic disease, and can be used collectively to understand the contextual, environmental, socioeconomic, and biological determinants of differences in health status in harmony with First Nations beliefs and reality.

Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci.

BACKGROUND & AIMS: Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations. METHODS: In all, 44 individuals with Primary Biliary Cholangitis and 61 unaffected relatives from 32 First Nations families participated. Family history and co-morbidities were documented. Medical records were reviewed and available biopsies were re-reviewed by our team pathologist. Genotyping was performed on DNA from 36 affected persons and 27 unaffected relatives using the Affymetrix Human Mapping 500K Array Set. MERLIN software was used to carry out multipoint parametric and nonparametric linkage analysis. Candidate genes were identified and entered into InnateDB and KEGG software to identify potential pathways affecting pathogenesis. RESULTS: In all, 34% of families were multiplex. Fifty per cent of cases and 33% of unaffected relatives reported other autoimmune disease. Three genomic regions (9q21, 17p13 and 19p13) produced LOD scores of 2.3 or greater suggestive of linkage, but no single linkage peak reached statistical significance. Candidate genes identified in the three regions suggested involvement of IL17, NFκB, IL6, JAK-STAT, IFNγ and TGFß immune signalling pathways. Specifically, four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in these pathways that may influence Primary Biliary Cholangitis pathogenesis. CONCLUSIONS: Our whole genome linkage study results reflect the multifactorial nature of Primary Biliary Cholangitis, support previous studies suggesting signalling pathway involvement and identify new candidate genes for consideration.

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1.

BACKGROUND: Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. METHODS: 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. RESULTS: For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. CONCLUSIONS: Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.

Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.

BACKGROUND: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. METHODS AND RESULTS: Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant. CONCLUSIONS: We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.

The development of a comprehensive maternal-child health information system for Nunavut-Nutaqqavut (Our Children).

OBJECTIVES: Nunavut is the most northerly jurisdiction in Canada of which 85% of inhabitants are Inuit. Although most infants are born healthy, Nunavut leads the country for adverse early child health outcomes such as infant mortality, rates of birth defects, prematurity and low birth weight. Public health and community efforts are needed to understand and improve outcomes. METHODS: To inform these issues, a combined University of British Columbia/Nunavut Public Health Strategy effort has initiated a comprehensive maternal-child health surveillance system (from 16 weeks gestation to age 5). A diverse group of professional and lay stakeholders were brought together initially to determine local interest. Following this, a series of small working groups were held to decide on potential prenatal, perinatal and early child health variables, to be documented. RESULTS: Over 100 Nunavut participants have now had some role in the development of the system which has been initiated. Pre-existing standard prenatal forms and well-child assessment forms have been modified to include "Nunavut specific" variables of nutrition, food and domestic security, exposures in pregnancy, birth defects, development, chronic diseases of childhood and paternal information. CONCLUSION: This comprehensive maternal-child health information system has been developed with the extensive input of health care providers and stakeholders, utilizing community and public health systems already in place. Careful assessment of local needs has contributed to database development, privacy protection, potential data utilization for health promotion and plans for dissemination of findings. It is hoped that this will be a user-friendly surveillance system, adaptable to other community and public health systems that will improve the understanding of Aboriginal maternal-child health determinants.

Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut.

Carnitine palmitoyltransferase 1A (CPT1A), encoded by the gene CPT1A, is the hepatic isoform of CPT1 and is a major regulatory point in long-chain fatty acid oxidation. CPT1A deficiency confers risk for hypoketotic hypoglycaemia, hepatic encephalopathy, seizures, and sudden unexpected death in infancy (SUDI). It remains controversial whether the CPT1A gene variant, c.1436C>T (p.P479L), identified in Inuit, First Nations, and Alaska Native infants, causes susceptibility to decompensation, in particular during times of fever and intercurrent illness. Although newborn screening for the P479L variant occurs in some jurisdictions, background knowledge about the presence of the variant in Canadian Aboriginal populations is lacking. In an effort to understand the population implications of the variant in northern Canada, overall frequencies of the variant were assessed. Further studies are underway to determine associated risk. Ethics approval was obtained from university REBs, local research institutes, and with consultation with territorial Aboriginal groups. Newborn screening blood spots from all infants born in 2006 in the three territories were genotyped for the p.P479L variant. p.P479L (c.1436C>T) allele frequencies in the three territories were 0.02, 0.08, and 0.77 in Yukon (n=325), Northwest Territories (n=564), and Nunavut (n=695), respectively. Homozygosity rates were 0%, 3%, and 64%. Aboriginal status was available only in NWT, with allele frequencies of 0.04, 0.44, 0.00, and 0.01 for First Nations, Inuvialuit/Inuit, Métis, and non-Aboriginal populations. Although individual blood spots were not identified for Aboriginal ethnicity in Nunavut infants, ~90% of infants in Nunavut are born to Inuit women. The allele frequency and rate of homozygosity for the CPT1A P479L variant were high in Inuit and Inuvialuit who reside in northern coastal regions. The variant is present at a low frequency in First Nations populations, who reside in areas less coastal than the Inuit or Inuvialuit in the two western territories. The significance of the population and geographic distribution remains unclear, but the high population frequencies of the variant suggest a historically low penetrance for adverse outcomes. Further evidence is needed to determine if there is an increased risk for infant mortality and morbidity and whether newborn screening will be indicated on a population basis.

The current state of birth outcome and birth defect surveillance in northern regions of the world.

OBJECTIVES: Little is known about the rates of congenital anomalies in the northernmost regions of the world. As in other parts of the world, it is crucial to assess the relative rates and trends of adverse birth outcomes and birth defects, as indicators of population health and to develop public health strategies for prevention. The aim of this review is to catalogue existing and developing birth outcome and birth defect surveillance within and around the geographic jurisdiction of the International Union of Circumpolar Health (IUCH). STUDY DESIGN: Descriptive study. METHODS: The representatives of the IUCH Birth Defects Working Group catalogued existing and developing birth and birth defect surveillance systems and the extent of information they contain to determine inter-regional comparability. RESULTS: Systematic population-based registration of birth outcomes including birth defects occurs to some degree in all circumpolar countries, but the quality of collection and the coverage in northernmost regions vary. There are limited circumpolar jurisdictions with surveillance systems collecting birth defect information beyond the perinatal period. Efforts are underway in Canada and Russia to improve the quality and comprehensiveness of the information collected in the northern regions. CONCLUSIONS: Although there is variability in the comprehensiveness of information collected in northern jurisdictions limiting sophisticated comparative analyses between regions, there is untapped potential for baseline analyses of specific risks and outcomes that could provide insight into geographic differences and gaps in surveillance that could be improved.

Second-trimester maternal serum screening for Down syndrome in in vitro fertilization pregnancies.

OBJECTIVES: To examine whether second-trimester maternal serum triple marker screening results differ between in vitro fertilization (IVF) pregnancies and naturally conceived pregnancies. METHODS: Second-trimester maternal serum triple marker screening results from 88 IVF pregnancies were compared with 596 naturally conceived pregnancies (controls). Controls were matched to each IVF pregnancy by maternal age, gestational age and date of blood collection. All pregnancies in the study were known to have normal outcome. Multiple of the median (MoM) levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and alpha-fetoprotein (AFP), and the false-positive rate for Down syndrome were compared between the two groups. RESULTS: No statistically significant differences in analyte levels or in Down syndrome false-positive rate were observed between the IVF and naturally conceived pregnancies. CONCLUSION: IVF patients can be counselled about maternal serum triple marker screening in the same manner as patients with naturally conceived pregnancies. There is no evidence to support the general use of analyte correction factors in the interpretation of second-trimester maternal serum screen results in IVF pregnancies.