03161nas a2200433 4500008004100000022001400041245017600055210006900231260001300300300001100313490000700324520179400331653000902125653002802134653002102162653001402183653001102197653002902208653001102237653002702248653004602275653002202321653001802343653000902361653003602370653003202406653002802438653003202466653001802498100001902516700002202535700002302557700002702580700002002607700001702627700002202644700002502666856003602691 2009 eng d a1880-387300aAssociation of genetic variation in serum amyloid-A with cardiovascular disease and interactions with IL6, IL1RN, IL1beta and TNF genes in the Cardiovascular Health Study.0 aAssociation of genetic variation in serum amyloidA with cardiova c2009 Aug a419-300 v163 a

AIM: 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.

CONCLUSION: 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.

10aAged10aCardiovascular Diseases10aCholesterol, HDL10aCytokines10aFemale10aGene Regulatory Networks10aHumans10aInflammation Mediators10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1beta10aInterleukin-610aMale10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aSerum Amyloid A Protein10aTumor Necrosis Factor-alpha10aTunica Intima1 aCarty, Cara, L1 aHeagerty, Patrick1 aHeckbert, Susan, R1 aEnquobahrie, Daniel, A1 aJarvik, Gail, P1 aDavis, Scott1 aTracy, Russell, P1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/112601866nas a2200205 4500008004100000022001400041245016000055210006900215260000900284300001000293490000600303520117400309100002701483700002701510700002301537700002201560700002001582700002201602856003601624 2012 eng d a1948-175600aHemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study.0 aHemodynamic fluid shear stress response genes and carotid intima c2012 a174-80 v33 a

OBJECTIVE: This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway.

METHODS: Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs.

RESULTS: None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best-performing logic regression tree combined two SNPs in MAP2K5-rs745212 and rs12905175- and common cIMT; this association was not significant, corrected P-value=0.062.

CONCLUSION: There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults.

1 aSuchy-Dicey, Astrid, M1 aEnquobahrie, Daniel, A1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aMcKnight, Barbara uhttps://chs-nhlbi.org/node/139402046nas a2200229 4500008004100000022001400041245009800055210006900153260000900222300001000231490000600241520135400247100002401601700002301625700002301648700002201671700002201693700001801715700002001733700002701753856003601780 2014 eng d a1948-175600aGene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes.0 aGene expression in thiazide diuretic or statin users in relation c2014 a22-300 v53 aThiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development.1 aSuchy-Dicey, Astrid1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aMcKnight, Barbara1 aRotter, Jerome, I1 aChen, Yd, Ida1 aPsaty, Bruce, M1 aEnquobahrie, Daniel, A uhttps://chs-nhlbi.org/node/6603