Project Meeting Report 61/2002

Project Meeting Report: INTERNATIONAL WORKSHOP ON CARDIOVASCULAR DISEASE AND DIABETES AMONG INDIGENOUS PEOPLES IN THE CIRCUMPOLAR NORTH August 31 – September 1, 2000 Nuuk, Greenland (Int J Circumpolar Health 2002; 61: 70-80)

Nuuk, Greenland

Medical researchers involved in autopsy and related studies among indigenous peoples of the circumpolar North met for a workshop in Nuuk, Greenland on August 31 – September 1, 2000 to repor t on current findings and discuss possible future studies. The meeting, held just prior to the NUNAMED conference, was sponsored by the Nordic Arctic Research Programme (NARP) and was organized and hosted at the Hotel Hans Egede by Drs. Peter Bjerrgaard, Gert Mulvad, and Henning Sloth Pedersen. Attending were investigators from Canada, Denmark, Faroe Islands, Greenland, Iceland, Norway, Russia, and the USA. Information on NARP is available at their website (http:// thule.oulu.fi/narp/). Peter Bjerregaard (Denmark) welcomed the participants and began the meeting with a discussion of the issues surrounding the long-held hypothesis that a low incidence of CVD existed among the Greenland Inuit, asking rhetorically, “What is the evidence?”. Citing the literature over the last 50 years, ranging from Ber telsen, the father of epidemiology in Greenland, who stated in a 1940 repor t that “Ar teriosclerosis and degeneration of the myocardium are quite common conditions among the Inuit, in particular considering the low mean age of the population”, to Dyerberg and Bang (1971) who suggested that coronary

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Donald A. Boudreau1, W. Douglas Scheer 1, Gert Mulvad2, Henning Sloth Pedersen 2, William P. Newman III 1

1

Department of Pathology, Louisiana

State University Health Sciences Center, New Orleans, Louisiana, USA, 2Center of Primar y Healthcare, Center for Arctic Environmental Medicine

Project Meeting Report 61/2002 atherosclerosis is almost unknown among the Greenland Eskimos, he noted that the “evidence” for the hypothesis seemed to be equivocal. He suggested that recent findings of no correlation between the extent of artherosclerosis in the aorta and that in the coronary arteries in Inuit was fur ther suggestive of the degree of data variance. In summary, he noted that current repor ts in the literature seem to indicate that, compared with western industrialized countries, ischemic hear t disease mor tality in Greenland tends to be low, cerebrovascular disease mor tality tends to be similar or high, and total cardiovascular mor tality tends to be high. For example, data indicate that ischemic heart disease (IHD) mortality in Greenland is less than that in Denmark, but approximately the same as in USA whites; yet, if US Whites and Blacks are combined, then together their IHD mortality figures are approximately the same as that of Denmark, and therefore greater than that of Greenland. In conclusion, he cautioned that the validity of the historical evidence may be low and that the more recent comparative conclusions may also be subject to question because of the varying methods of age-adjustment, all of which point to the need for further, more careful, study. Sven Ebbesson (USA/Alaska) presented some results of a study of the prevention of NIDDM and cardiovascular disease in Alaska Inuit. The study population was comprised of 4 Yupik villages in nor thwestern Alaska. Despite ethnic homogenity, there were genetic variations observed, e.g., differences in the apolipoprotein E4 allele distribution. It was stressed that the increasingly modern environment (available TV that detracts from outdoor activities and village stores with package foods) is leading to increased use of dietary intake with more western characteristics. It has been repor ted that the Siberian Yupik have a high prevalence of impaired glucose tolerance (IGT), and that diabetes mellitus (DM) and IGT are high risk factors for CVD in this population. The focus of his study was an aggressive educational effor t at dietary intervention, the objective of which was to improve healthy food consumption. After 4 years, he found significant decreases in blood glucose in the intervention villages, as compared to control villages. He also found significantly less IGT as well as decreased serum total cholesterol and decreased LDL (Note: approximately 10% were placed on cholesterol-

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Donald A. Boudreau, Ph.D., Professor, Department of Pathology, Section of Medical Informatics. Research interests include population studies of coronary heart disease, atherosclerosis, and Type II diabetes.

International Journal of Circumpolar Health

lowering drugs during the study). The conclusion was that aggressive education effor ts for dietary intervention can be successful. Sjurdur Olsen (Faroe Islands) discussed his epidemiological studies in the Faroe Islands where little is known about the incidence or prevalence of IHD, hyper tension, or Type 2 diabetes. The study, completed in 1997, consisted of a survey of 300 subjects and 300 controls using Rose’s questionnaire and clinical exams. Data analysis has not been done; however, he presented some preliminary observations. High bir th weights and long gestational periods were found in the Faroe Islanders. There is some speculation that n-3 fatty acids from consumption of marine mammals results in an increase in prostaglandin F, thereby leading to longer gestation. He noted that if Barker’s proposal (D.J.P. Barker et al. Lancet 1:1077-1081, 1986) is correct that in utero stress may predispose (“program”) the fetus for cer tain diseases (e.g. hyper tension, CVD, DM) in adulthood, then the Faroe Islanders may be at greater risk. Bruce Holub (Canada) described his comparisons of long-chain n-3 fatty acid status in post-menopausal women in Canada (where a high prevalence of MI is observed), and in Greenland (where there is a low observed prevalence of MI). The objectives were to: (a) use dietary supplements to increase the n-3 fatty acid levels and thereby “conver t” Canadian post-menopausal women to the same levels as that of Greenland women in regard to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); and, (b) then look for differences in n-6 linoleic acid (LA) and arachidonic acid (AA). For the study, 15 Greenland (Nuuk) women and 16 Canadian (Guelph) women furnished fasting serum samples. All subjects were postmenopausal and were not taking hormone replacement therapy (It was noted that hormone replacement therapy has a significant influence on DHA status, independent of other factors, and therefore this must be considered in future studies). One-half of the 16 Canadian women received an omega-3 triglyceride concentrate (derived from fish-oil) that provided 2.4g of EPA and 1.6 g of DHA per day for 4 weeks. The fatty acid composition of serum phospholipids was determined for the 3 groups at the completion of the intervention trial. At the end of the 4 weeks of dietary supplementation, EPA and DHA in the Canadians were nearly the same as Greenlanders. While the Canadians had greatly reduced levels of AA and LA, their levels did not reach

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Project Meeting Report 61/2002 that of the Greenlanders. This may suggest that the low level of AA in Greenlanders may be due to genetic influences; however, the shor t time of the study limits the conclusions. He concluded that while short-term n-3 supplement therapy is effective in increasing the concentration of n-3 fatty acids and decreasing the concentration of n-6 fatty acids in serum phospholipids, it fails to duplicate the overall n-6/n-3 serum phospholipid fatty acid profile seen in Greenland Inuit. Andrew Koslov (Russia) described his 1990-1995 studies of the natives of Western Siberia, related his findings to that of previous earlier studies, and suggested what future trends for cardiovascular disease and diabetes may be in that area. Localities were classified as small (500), and subjects as modern workers (teachers, nurses, administrators) or traditional workers (fishing, hunting), and young (25). While BMI was found to be within desirable limits for the young subjects, it tended to increase among the older subjects, reaching the same undesirable limits as found in urban Russians. BMI increased at a faster rate (earlier) in females as compared to males after the age of 25y. Current hemoglobin levels were found to be significantly lower than in an earlier study in 1981-1985, indicating a trend of decreasing oxygen transpor t sufficiency; however, levels in older subjects (especially females) in the small settlements were still high. Iron deficiency anemia was found to be high among females. Mean blood pressure (MBP) was found to be higher among large settlement residents as compared to those in small settlements, as was the proportions of hyper tensives (27% vs. 16%). It was noted that in the 1960s and 1970s, the repor ted hyper tension rate in the populations of the rural North was no more than 7%, and in some settlements there were no cases of hyper tension repor ted at all. He also noted that there appears to be a high prevalence of gastroenterologic symptoms in the settlements and raised the issue of possible association between Helicobacter pylori infection and cardiovascular disease. Serum glucose levels were significantly higher in modern workers as compared to traditional workers. Adult hypolactasia is a characteristic trait of indigenous peoples of nor thern Eurasia. Lactase production is controlled by a gene with two alleles, designated LAC*P and LAC*R. Persistence

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Project Meeting Report 61/2002 of lactase production into adulthood results from the expression of the autosomal dominant allele LAC*P, while lactase restriction in adulthood is due to the expression of the recessive allele LAC*R. In the northern Eurasian population, there is a high proportion LAC*R alleles; however, there appears to be a change in the allele distribution in the western Siberian groups, with LAC*P replacing LAC*R. While this may seem to be favorable, it does suggest the possibility of an increased risk of elevated serum cholesterol, as lactose is a significant contributing factor. Furthermore, reports show that the Siberian Yupik are rapidly becoming more genetically mixed in current (0-25 y) age groups compared to older (50-75 y) age groups, suggesting that if there are genetically endowed metabolic adaptations in the population, these may disappear as the gene pool is changed. The conclusion was that one can expect to see an increase in CVD and diabetes in the natives of western Siberia in the future due to both genetic pool changes and changes in environment and lifestyle. Gert Mulvad (Greenland) presented a proposal for a new autopsy study. He reviewed the history of the first autopsy study in Greenland in which specimens were collected during the period 1990-1994. The objective of that study was to determine whether the prevalence and extent of atherosclerosis in Greenland was different than that in Alaska Natives and non-natives, and whether longchain n-3 fatty acid levels in adipose tissue triglyceride fatty acids (ATTFA) were related to atherosclerosis. Also included were: analyses of the ATTFA composition in the hear t, prostate, the wall of the coronary ar teries; histopathology studies of the liver and prostate; apolipoprotein E allele and angiotensin conver ting enzyme allele distributions and relation to atherosclerosis; and heavy metals and organochlorine in some of the tissues. It was in the course of this study that increasing interest developed in Greenland in regard to other health-risk issues, especially those that are environmentally related; however, the original study was not designed to address these additional factors. It was proposed that a second autopsy study be planned, open to all other circumpolar areas wishing to par ticipate, and designed to specifically address current questions of interest, including genetic studies and environmental health risk factors. He volunteered the Greenlandic group as the coordinators of the effor t, with each par ticipating group being responsible for defining, designing, and securing

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Project Meeting Report 61/2002 funding for their specific projects. Donald A. Boudreau (USA) presented an overview of preliminary results from a multi-population comparison of adipose tissue triglyceride fatty acids and atherosclerosis, using data from the autopsy studies database archived by the Department of Pathology of Louisiana State University Health Sciences Center in New Orleans, LA, USA. Data for ATTFA for seven populations from studies conducted since 1969 are available in the database: New Orleans African-Americans and New Orleans Whites (1969-1978 study, n=330); Alaska Natives and Alaska non-Natives (1989-1993, n=168 ); Greenland Natives (1990-1994, n=61); and AfricanAmericans and Whites from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study (1985-1995, n=1137). A brief review of the study methods stressed the fact that all projects were coordinated by the same core group of investigators and all analyses were standardized. Descriptive data for all groups were presented. Available data included: age, sex, smoking status (heavy smoker, light/non-smoker), hyper tension status (110mm mean BP), serum cholesterol level (total, HDL, LDL+VLDL), BMI, long-chain perirenal ATTFA mass% composition, and the type (fatty streaks, raised lesions) and extent of atherosclerotic lesions in the abdominal aor ta, thoracic aor ta, left anterior descending coronary ar tery, and the right coronary ar tery. Study limitations were discussed, including that of the differences in age range of the groups as a result of the design of the individual studies. For example, the PDAY study was limited to ages 15-34y, while the Alaska and Greenland groups spanned 10-85y. Despite this, sufficient numbers in multiple groups overlapped in all ages, including all groups from 10-34y. The Greenland group had the lowest mean total n-6 ATTFA, followed by Alaska Natives, and the reverse was true for the mean total n-3 ATTFA, with the highest amount in the Greenland group. However, there did not appear to be any strong association of atherosclerosis with ATTFA profiles. W. Douglas Scheer (USA) reviewed preliminary data from a study of Angiotensin Converting Enzyme (ACE) polymorphisms and atherosclerosis. ACE is a key component of the renin-angiotensin system and plays an important role in cardiovascular regulation. Amplifica-

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Project Meeting Report 61/2002 tion of the inser tion/deletion polymorphism in intron 16 of the ACE gene by the polymerase chain reaction yields the genotypes DD, ID, and II. An association between the ACE inser tion/deletion Alu polymorphism and increased risk for myocardial infarction has been repor ted in some studies. Other reports have indicated a lack of association between the Alu inser tion polymorphism and angiographicallyassessed coronary ar tery disease. Following the format of a previous study of apolipoprotein E in the same groups, the objectives of the ACE study are to determine the relative frequency distribution of the polymorphisms among the groups and to look for possible associations between ACE genotypes and the extent of atherosclerotic lesions of the aor ta and coronary ar teries in autopsy specimens from Greenland natives and Alaska natives and non-natives. Preliminary data show no significant difference in the genotype frequencies among the groups and no associations of the genotypes with the extent of atherosclerotic fatty streaks or raised lesions are evident in any of the arterial segments (abdominal and thoracic aor ta; right and left anterior descending coronary ar teries). These findings do not suppor t the hypothesis that a possible association between the ACE DD genotype and myocardial infarction is due to an association between the ACE Alu inser tion polymorphism and atherosclerosis. Results of a study of the traditional diet in western Greenland were presented by Tine Pars (Greenland). She first reviewed the data from a country-wide health interview survey conducted in 1993-94 that showed a large por tion (60%-70%) of the respondents were eating western or non-traditional foods rather than seal (25%) and whale (35y) were eating more of a traditional diet than younger respondents (