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Technical Briefs |
1
John P. Robarts Research Institute, London, Ontario, N6A 5K8 Canada
2
Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, R3E 0W3 Canada
aaddress correspondence to this author at: Blackburn Cardiovascular Genetics Laboratory, John P. Robarts Research Institute, 406-100 Perth Dr., London, Ontario, N6A 5K8 Canada; fax 519-663-3789, e-mail robert.hegele{at}rri.on.ca
Mortality from cardiovascular disease among Inuit living in the far north of Canada is 
40% lower than in the rest of the country (1). This might be attributable to the protection resulting from environmental factors such as dietary 
-3 fatty acids in Arctic fish (1). Genetic factors may also be important. For example, the thermolabile variant of methylenetetrahydrofolate reductase is much less prevalent among Inuit than among subjects of European origin (2). However, there are also paradoxical genetic findings in these people. For example, some common genetic variants associated with a higher risk of cardiovascular disease, such as the APOE E4 and AGT T235 alleles, are more prevalent among Inuit than among subjects of European origin (3). These apparent inconsistencies may be related to the fact that there are numerous determinants of susceptibility to cardiovascular disease and that these determinants may differ among ethnic groups (4). As newer determinants of cardiovascular disease risk are identified, these can be evaluated in the Inuit.
C-Reactive protein (CRP), an acute-phase reactant originally detected through its interaction with pneumococcal C polysaccharide (5), has been proposed to be a risk factor for cardiovascular disease (6). When detected with a high-sensitivity assay (6), increased serum CRP could be related to increased vascular disease risk either directly through its association with inflammation (7) or indirectly through its association with obesity and insulin resistance (8). The serum CRP concentration in the Inuit has not been reported. Furthermore, the role of possible genetic determinants of serum CRP concentration has not been explored in depth. Our recent discovery of a silent single-nucleotide polymorphism (SNP) in the CRP gene, namely 1059G
C within exon 2 (9), and of other chromosome 1q21 SNPs near CRP (10) has allowed analysis of the association between the CRP locus and serum CRP concentration in Inuit.
The Northwest Territories are located above the 60th parallel of latitude and comprise one-third of the landmass of Canada. In 1986, the population of Northwest Territories was 52 000. Of these, 35% were Inuit (or Eskimos), 15% were Dene (or Athapaskan Indians), and 50% were predominantly migrants of European origin from other parts of Canada. The present study involved residents of eight communities from the Nunavut region, mainly from the western shore of Hudson Bay (2)(3)(11).
Randomly selected individuals (n = 516; age range, 18–80 years) participated; of these, 281 reported themselves as being Inuit, 112 reported themselves as being of mixed ethnic background, 92 reported themselves as being of European background (white), and 31 reported themselves as being of an ethnic background other than Inuit, mixed, or white. At the time of the study, these communities adhered to a traditional lifestyle, which included the consumption of Arctic fish at least three times per week. Of note was the very high prevalence of cigarette smoking (11). The white subjects were included as a contrast sample, which provided reference serum CRP concentration and SNP allele frequency from a regional control white population. The project was approved by the Institutional Review Boards of the Universities of Manitoba and Toronto.
Blood samples were obtained with informed consent. The first exclusion criterion was a self-reported ethnic background that was neither Inuit nor white. This left 373 subjects. The second exclusion criterion was an inadequate blood sample for biochemical and genetic determinations. This left 237 subjects, of whom 180 were Inuit and 57 were white. Serum CRP was measured using a high-sensitivity automated nephelometric method (Beckman Coulter) with a reported lower limit of detection of 0.05 mg/L. Genotypes were determined as described (9)(10), and SAS, Ver. 6.12, was used for all statistical comparisons.
Baseline attributes of the study subjects are shown in Table 1
. The Inuit subjects had significantly higher smoking prevalence than the white controls. Serum CRP was not significantly different, but tended to be higher in the Inuit (P = 0.10). Sources of variation of serum CRP were then evaluated. Partial regression coefficients from stepwise regression analysis in all subjects indicated that 71%, 16%, and 13% of the attributable variation in serum CRP was related to age, ethnicity, and smoking, respectively (all P <0.05). Univariate analyses performed in Inuit showed serum CRP to be significantly correlated only with age (r = 0.30; P <0.0001), the ratio of waist-to-hip circumference (r = 0.25; P <0.0001), and body mass index (r = 0.19; P <0.005).
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The CRP 1059C allele frequency was 0.122 in white controls compared with 0.0 in Inuit (P <0.0001). We also genotyped the closely linked CTSS gene using genotypes derived from the -25GA promoter SNP (10). The CTSS -25A allele frequency was 0.404 in Inuit and 0.468 in white controls (P, not significant). Frequencies did not deviate from those predicted by the Hardy-Weinberg equation in either ethnic group for both genotypes. Chromosome 1q21 haplotypes were created using the CRP and CTSS genotypes. Multivariate analysis of variance in the Inuit showed that chromosome 1q21 haplotype (P = 0.0014) and age (P = 0.0053) were each significant sources of variation of serum CRP. Pairwise analyses showed that subjects who were CTSS -25A/A homozygotes (11.0 ± 2.1 mg/L) had significantly higher serum CRP than both -25G/A heterozygotes and -25G/G homozygotes (4.1 ± 1.4 and 3.5 ± 1.5 mg/L, respectively; both pairwise P <0.005). Regression analysis in the white control sample showed that no independent variable was a source of variation of log CRP (all P >0.05).
These findings indicate that (a) serum CRP in Inuit tended to be higher than in a sample of regional white controls; (b) age, cigarette smoking, and obesity were each associated with CRP in the Inuit; and (c) chromosome 1q21 haplotype was associated with serum CRP variation. The findings suggest that protection from vascular disease in the Inuit is not associated with serum CRP. The association of serum CRP with obesity indices in the Inuit is consistent with the findings of previous studies (7). The association between serum CRP and chromosome 1q21 haplotype could have been attributable to the impact of an unexamined functional variant within or flanking the CRP gene. Alternatively, the association might have resulted from linkage dysequilibrium involving other structural differences at or near the CRP gene locus.
Although the basis for the distinctive cardiovascular risk profile of Canadian Inuit remains to be determined, these people do not have lower serum CRP compared with white subjects. There is increasing interest in inflammatory etiologies for atherosclerosis and cardiovascular end points (8). Thus, it is reasonable to consider the possibility that interindividual differences in quantitative inflammatory traits, such as serum CRP, may contribute to differences in disease expression. The results in the Inuit suggest that the low prevalence of vascular disease is unrelated to serum CRP concentration. However, the results also indicate that variation near the CRP gene locus on chromosome 1q21 is significantly associated with variation in serum CRP concentration and that this intermediate trait may be subject to genetic control.
Acknowledgments
This work was supported by grants from the Canadian Institutes for Health Research (MT13430), the Heart and Stroke Foundation of Ontario, and the Blackburn Group. Dr. Hegele is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds a Canada Research Chair in Human Genetics. Dr. Young is a Senior Scientist of the Canadian Institutes for Health Research.
References
The following articles in journals at HighWire Press have cited this article:
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  F. G. Hage and A. J. Szalai C-Reactive Protein Gene Polymorphisms, C-Reactive Protein Blood Levels, and Cardiovascular Disease Risk J. Am. Coll. Cardiol., September 18, 2007; 50(12): 1115 - 1122. [Abstract] [Full Text] [PDF]
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