RESEARCH PAPER
RESEARCH PAPER
Epigenetics 6:10, 1257-1264; October 2011; © 2011 Landes Bioscience
Cardiovascular disease risk factors and DNA methylation at the LINE-1 repeat region in peripheral blood from Samoan islanders Haley L. Cash,1,2,* Stephen T. McGarvey,2 E. Andres Houseman,3 Carmen J. Marsit,1,3 Nicola L. Hawley,2 Geralyn M. Lambert-Messerlian,4 Satupaitea Viali,5 John Tuitele6 and Karl T. Kelsey1,3 Department of Pathology and Laboratory Medicine; Brown University; Providence, RI USA; 2International Health Institute; Public Health Program; Brown University, Providence, RI USA; 3Center for Environmental Health and Technology; Brown University; Providence, RI USA; 4Women and Infants Hospital; Alpert Medical School; Providence, RI USA; 5Ministry of Health; Government of Samoa; Apia; 6Department of Health; American Samoa Government; Pago Pago, American Samoa
1
Key words: cardiovascular disease, HDL, LDL, LINE-1, DNA methylation, Samoa
Lower levels of LINE-1 methylation in peripheral blood have been previously associated with risk of developing noncommunicable conditions, the most well-explored of these being cancer, although recent research has begun to link altered LINE-1 methylation and cardiovascular disease. We examined the relationship between LINE-1 methylation and factors associated with metabolic and cardiovascular diseases through quantitative bisulfite pyrosequencing in DNA from peripheral blood samples from participants of the Samoan Family Study of Overweight and Diabetes (2002–03). The sample included 355 adult Samoans (88 men and 267 women) from both American Samoa and Samoa. In a model including all sample participants, men had significantly higher LINE-1 methylation levels than women (p = 0.04) and lower levels of LINE-1 methylation were associated with higher levels of fasting LDL (p = 0.02) and lower levels of fasting HDL (p = 0.009). The findings from this study confirm that DNA “global” hypomethylation (as measured by methylation at LINE1 repeats) observed previously in cardiovascular disease is associated with altered levels of LDL and HDL in peripheral blood. Additionally, these findings strongly argue the need for further research, particularly including prospective studies, in order to understand the relationship between LINE-1 DNA methylation measured in blood and risk factors for cardiovascular disease.
Introduction The Samoan islands, composed of the independent nation of Samoa and the US territory of American Samoa, are geographical neighbors and are currently experiencing economic development and its associated nutritional transition at different rates, although both populations are characterized by alarmingly high prevalence of obesity.1 American Samoa has a higher prevalence of obesity compared with Samoa, with approximately 71% of women and 59% of men defined as obese (using Polynesian standards of BMI >32), relative to 53% of women and 29% of men in Samoa.1 These high prevalences of obesity has lead to rapid rises in obesity-related diseases such as cardiovascular disease (CVD) and type 2 diabetes.2 The rapid temporal rise of Samoan obesity and obesity-related diseases has been attributed to modernization and its associated nutritional transition, in which these developing nations are consuming more calorie-rich foods and expending less energy.1 Although these behavioral factors are linked to obesity and obesityrelated diseases, genetic factors have also been shown to play an important role in Samoan obesity and obesity-related risk factors.3-6
Both Samoan islands were settled by Polynesians approximately 3,000 y ago.7 Genetic evidence suggests that these island nations were originally settled by small groups of voyagers.7,8 These original settlers may have endured food shortages and cold night-time open-ocean temperatures, perhaps favoring those with the ability to store body fat and those with efficient energy metabolism, thus suggesting a role for a thrifty genotype.9 Although certain genetic loci have been associated with obesity phenotypes in Samoans,3-6 studies examining potential links of epigenetic alterations with these extreme metabolic phenotypes are currently lacking in this population. Epigenetic alterations are DNA modifications that do not involve changes to the sequence, yet alter gene expression.10 Epigenetic regulation of gene expression is based upon complex alterations in histone proteins, affecting chromatin conformation. These changes have been associated with coordinate changes in DNA methylation of cytosine bases in the context of CG dinucleotide pairs that often reside in gene promoter regions (CpG islands) or in DNA repeat regions.11 DNA methylation is heritable, in that it may be passed from mother to daughter cell and stable, due to the fact that it is not easily reversed.12 The
*Correspondence to: Haley L. Cash; Email:
[email protected] Submitted: 06/17/11; Accepted: 08/11/11 DOI: 10.4161/epi.6.10.17728 www.landesbioscience.com Epigenetics
1257
Table 1. Selected characteristics* of study sample participants American samoa (n = 198) Variable
Men
Women
(n = 57)
(n = 141)
Samoa (n = 157)
p value
Men
Women
(n = 31)
(n = 126)
A. Samoa vs. Samoa p value
Pmale
Pfemale
age (years)
36.1 (5.4)
29.7 (6.8)
