Association of genetic variation in serum amyloid-A with cardiovascular disease and interactions with IL6, IL1RN, IL1beta and TNF genes in the Cardiovascular Health Study.
OBJECTIVE
Since inflammation is an important contributor to atherosclerosis, gene variants mediating inflammation are of interest. We investigated gene variants in acute phase serum amyloid-A (SAA), a sensitive indicator of inflammatory activity, and their associations with cardiovascular disease (CVD) and HDL cholesterol. Interaction of the SAA genes with genetic variants of their regulators, IL-1, IL-6 and TNF-alpha in influencing CVD was also explored.


METHODS
SNPs characterizing common variation in the SAA1 and SAA2 genes were genotyped in European-(EA) and African-American (AA) participants (n=3969 and n=719) of the Cardiovascular Health Study. Using linear and Cox proportional hazards regression, we assessed associations of SNPs with baseline carotid artery intima-media thickness (cIMT) and risk of incident myocardial infarction, ischemic stroke, total CVD events or mortality during 14 years of follow-up.


RESULTS
No associations between SAA SNPs and outcomes were observed in EA, with the exception of total CVD events; each rs4638289 minor allele was associated with an increased risk in obese individuals, HR=1.2 (95%CI: 0.981.4; p=0.086) and decreased risk among non-obese, HR=0.9 (95%CI: 0.80.99; p=0.026). In AA, we observed modest associations between SAA SNPs and cIMT, potentially modified by HDL. SAA SNPs were also associated with lower HDL in EA and AA. Suggestive gene-gene interaction findings for cIMT in AA and CVD mortality in EA were not significant in subsequent model selection tests.


CONCLUSIONS
Associations of SAA SNPs with cIMT, HDL and total CVD events were identified, unadjusted for multiple testing. These findings should be regarded as hypothesis-generating until confirmed by other studies.
Carty
Cara L
CL
Department of Epidemiology, University of Washington, WA, USA. calyca@u.washingto.edu
Heagerty
Patrick
P
Heckbert
Susan R
SR
Enquobahrie
Daniel A
DA
Jarvik
Gail P
GP
Davis
Scott
S
Tracy
Russell P
RP
Reiner
Alexander P
AP
D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D000685:Serum Amyloid A Protein / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D017539:Tunica Intima / Q000473:pathology
D008076:Cholesterol, HDL; D016207:Cytokines; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha