%0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2002 %T In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease. %A Jenny, Nancy S %A Tracy, Russell P %A Ogg, Malcolm S %A Luong, Le Ahn %A Kuller, Lewis H %A Arnold, Alice M %A Sharrett, A Richey %A Humphries, Steve E %K Age Factors %K Aged %K Biomarkers %K Cardiovascular Diseases %K Case-Control Studies %K Cytosine %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Genotype %K Guanine %K Health Surveys %K Humans %K Inflammation %K Interleukin-6 %K Linear Models %K Male %K Polymorphism, Genetic %K Predictive Value of Tests %K Promoter Regions, Genetic %X

OBJECTIVE: Interleukin (IL)-6-mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the -174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study.

METHODS AND RESULTS: Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The -174C allele was associated with higher C-reactive protein (11% higher, P=0.02), fibrinogen (3% higher, P=0.02), and IL-6 (5% higher; P=0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the -174C allele was associated with risk of MRI infarcts (odds ratio 1.5).

CONCLUSIONS: IL-6 levels differentiated those with subclinical CVD from those without. Although the -174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.

%B Arterioscler Thromb Vasc Biol %V 22 %P 2066-71 %8 2002 Dec 01 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/12482836?dopt=Abstract %R 10.1161/01.atv.0000040224.49362.60 %0 Journal Article %J Thromb Haemost %D 2002 %T No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study. %A Smiles, Adam M %A Jenny, Nancy S %A Tang, Zhonghua %A Arnold, Alice %A Cushman, Mary %A Tracy, Russell P %K 3' Untranslated Regions %K Aged %K Aged, 80 and over %K Alleles %K Angina Pectoris %K Blood Proteins %K Cardiovascular Diseases %K Case-Control Studies %K Comorbidity %K Diabetes Mellitus %K Female %K Genetic Predisposition to Disease %K Humans %K Hyperlipidemias %K Hypertension %K Male %K Mutation %K Myocardial Infarction %K Obesity %K Promoter Regions, Genetic %K Prothrombin %K Risk Factors %K Smoking %K Stroke %K Vermont %X

Prothrombin is a key factor in blood clotting, a process intimately involved in thrombotic disease. We assessed prothrombin levels and G20210A genotype in a case-control study within the Cardiovascular Health Study. Cases included angina, myocardial infarction, stroke, and the presence of MRI-detectable infarcts (n approximately 250 each). Population-based controls free of clinical cardiovascular disease (CVD) (n approximately 500) and a subset free of clinical and subclinical CVD (n approximately 250) were used for comparison. The 20210 A allele, frequency 2.9%, was associated with higher mean prothrombin levels: 166.3 vs. 139.5 microg/ml (P <0.001). Significant correlates of prothrombin included gender, plasma lipids, other vitamin K-dependent proteins, and inflammatory markers, but not race, smoking, hypertension, diabetes, measures of subclinical CVD, or markers of procoagulant activity. Compared to controls, neither genotype nor prothrombin level was associated with any CVD case group. We conclude that, in the elderly, neither prothrombin level nor 20210 genotype were associated with either CVD risk factors or events. This is consistent with the lack of association of prothrombin levels with measures of underlying CVD or procoagulant markers.

%B Thromb Haemost %V 87 %P 614-21 %8 2002 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12008943?dopt=Abstract %0 Journal Article %J J Thromb Haemost %D 2003 %T Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. %A Crainich, P %A Jenny, N S %A Tang, Z %A Arnold, A M %A Kuller, L H %A Manolio, T %A Sharrett, A R %A Tracy, R P %K African Continental Ancestry Group %K Aged %K Alleles %K Cardiovascular Diseases %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genotype %K Homozygote %K Humans %K Male %K Myocardial Infarction %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Genetic %K Promoter Regions, Genetic %K Risk %X

Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.

%B J Thromb Haemost %V 1 %P 1799-804 %8 2003 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/12911596?dopt=Abstract %R 10.1046/j.1538-7836.2003.00255.x %0 Journal Article %J Atherosclerosis %D 2005 %T Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. %A Reiner, Alexander P %A Diehr, Paula %A Browner, Warren S %A Humphries, Stephen E %A Jenny, Nancy S %A Cushman, Mary %A Tracy, Russell P %A Walston, Jeremy %A Lumley, Thomas %A Newman, Anne B %A Kuller, Lewis H %A Psaty, Bruce M %K Aged %K Aging %K Carboxypeptidase B2 %K Cause of Death %K Cohort Studies %K Female %K Genotype %K Health Status %K Humans %K Inflammation %K Longevity %K Male %K Middle Aged %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Genetic %K Promoter Regions, Genetic %K Prospective Studies %K Risk Factors %K Thrombosis %X

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.

%B Atherosclerosis %V 181 %P 175-83 %8 2005 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15939070?dopt=Abstract %R 10.1016/j.atherosclerosis.2005.01.028 %0 Journal Article %J Am J Clin Nutr %D 2007 %T Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults. %A Mukamal, Kenneth J %A Jenny, Nancy S %A Tracy, Russell P %A Siscovick, David S %K Aged %K Alcohol Drinking %K Apolipoprotein E4 %K Apolipoproteins E %K Blood Glucose %K C-Reactive Protein %K Cohort Studies %K Female %K Genotype %K Humans %K Interleukin-6 %K Male %K Promoter Regions, Genetic %K Serum Amyloid P-Component %X

BACKGROUND: Whether alcohol intake is associated with concentrations of interleukin-6 (IL-6) and serum amyloid P (SAP) is uncertain.

OBJECTIVE: We determined how alcohol intake and apolipoprotein E (apo E) and IL-6 promoter (IL-6 -174G-->C) polymorphisms interact for concentrations of IL-6 and SAP.

DESIGN: In the Cardiovascular Health Study, 2454 older adults reported their intake of beer, wine, and liquor and underwent measurements of circulating IL-6 and SAP.

RESULTS: Alcohol intake was not associated with IL-6 concentrations among apo E4-negative or IL-6C-positive participants but was positively associated among both apo E4-positive and IL-6C-negative participants (P for trend = 0.02 for both). The corresponding interactions on SAP were not significant for alcohol overall but were similar for liquor intake.

CONCLUSIONS: Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations. Genetic heterogeneity should be considered in understanding the cardiovascular effects of alcohol intake.

%B Am J Clin Nutr %V 86 %P 444-50 %8 2007 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17684217?dopt=Abstract %R 10.1093/ajcn/86.2.444 %0 Journal Article %J Hum Genet %D 2007 %T IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. %A Walston, Jeremy D %A Fallin, M Daniele %A Cushman, Mary %A Lange, Leslie %A Psaty, Bruce %A Jenny, Nancy %A Browner, Warren %A Tracy, Russell %A Durda, Peter %A Reiner, Alex %K African Americans %K Aged %K Alleles %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Interleukin-6 %K Introns %K Longitudinal Studies %K Male %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %X

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

%B Hum Genet %V 122 %P 485-94 %8 2007 Dec %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/17851695?dopt=Abstract %R 10.1007/s00439-007-0428-x %0 Journal Article %J Lancet %D 2010 %T Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. %A Sarwar, Nadeem %A Sandhu, Manjinder S %A Ricketts, Sally L %A Butterworth, Adam S %A Di Angelantonio, Emanuele %A Boekholdt, S Matthijs %A Ouwehand, Willem %A Watkins, Hugh %A Samani, Nilesh J %A Saleheen, Danish %A Lawlor, Debbie %A Reilly, Muredach P %A Hingorani, Aroon D %A Talmud, Philippa J %A Danesh, John %K Apolipoprotein A-V %K Apolipoproteins %K Apolipoproteins A %K Coronary Disease %K Gene Frequency %K Genotype %K Humans %K Lipids %K Lipoproteins, HDL %K Lipoproteins, LDL %K Lipoproteins, VLDL %K Mendelian Randomization Analysis %K Particle Size %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Risk Factors %K Triglycerides %X

BACKGROUND: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.

METHODS: We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.

FINDINGS: The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride.

INTERPRETATION: These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.

FUNDING: British Heart Foundation, UK Medical Research Council, Novartis.

%B Lancet %V 375 %P 1634-9 %8 2010 May 08 %G eng %N 9726 %1 http://www.ncbi.nlm.nih.gov/pubmed/20452521?dopt=Abstract %R 10.1016/S0140-6736(10)60545-4 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2011 %T Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. %A Burdon, Kathryn P %A Macgregor, Stuart %A Bykhovskaya, Yelena %A Javadiyan, Sharhbanou %A Li, Xiaohui %A Laurie, Kate J %A Muszynska, Dorota %A Lindsay, Richard %A Lechner, Judith %A Haritunians, Talin %A Henders, Anjali K %A Dash, Durga %A Siscovick, David %A Anand, Seema %A Aldave, Anthony %A Coster, Douglas J %A Szczotka-Flynn, Loretta %A Mills, Richard A %A Iyengar, Sudha K %A Taylor, Kent D %A Phillips, Tony %A Montgomery, Grant W %A Rotter, Jerome I %A Hewitt, Alex W %A Sharma, Shiwani %A Rabinowitz, Yaron S %A Willoughby, Colin %A Craig, Jamie E %K Adult %K Aged %K Chromosomes, Human, Pair 7 %K Corneal Topography %K Enzyme-Linked Immunosorbent Assay %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Hepatocyte Growth Factor %K Humans %K Keratoconus %K Middle Aged %K Nucleic Acid Hybridization %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Sequence Tagged Sites %X

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

%B Invest Ophthalmol Vis Sci %V 52 %P 8514-9 %8 2011 Oct 31 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003120?dopt=Abstract %R 10.1167/iovs.11-8261 %0 Journal Article %J Brain %D 2011 %T Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. %A Schmidt, Helena %A Zeginigg, Marion %A Wiltgen, Marco %A Freudenberger, Paul %A Petrovic, Katja %A Cavalieri, Margherita %A Gider, Pierre %A Enzinger, Christian %A Fornage, Myriam %A Debette, Stephanie %A Rotter, Jerome I %A Ikram, Mohammad A %A Launer, Lenore J %A Schmidt, Reinhold %K Aged %K Aged, 80 and over %K Alleles %K Brain %K Cerebral Small Vessel Diseases %K Exons %K Female %K Follow-Up Studies %K Genetic Association Studies %K Genotype %K Humans %K Hypertension %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Phenotype %K Promoter Regions, Genetic %K Prospective Studies %K Receptor, Notch3 %K Receptors, Notch %X

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.

%B Brain %V 134 %P 3384-97 %8 2011 Nov %G eng %N Pt 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22006983?dopt=Abstract %R 10.1093/brain/awr252 %0 Journal Article %J Age (Dordr) %D 2013 %T Association of heat shock proteins with all-cause mortality. %A Broer, L %A Demerath, E W %A Garcia, M E %A Homuth, G %A Kaplan, R C %A Lunetta, K L %A Tanaka, T %A Tranah, G J %A Walter, S %A Arnold, A M %A Atzmon, G %A Harris, T B %A Hoffmann, W %A Karasik, D %A Kiel, D P %A Kocher, T %A Launer, L J %A Lohman, K K %A Rotter, J I %A Tiemeier, H %A Uitterlinden, A G %A Wallaschofski, H %A Bandinelli, S %A Dörr, M %A Ferrucci, L %A Franceschini, N %A Gudnason, V %A Hofman, A %A Liu, Y %A Murabito, J M %A Newman, A B %A Oostra, B A %A Psaty, B M %A Smith, A V %A van Duijn, C M %K Aged, 80 and over %K Aging %K Cause of Death %K Forecasting %K Genotype %K Heat-Shock Proteins %K Humans %K Longevity %K Promoter Regions, Genetic %K Retrospective Studies %K Transcription, Genetic %K United States %X

Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.

%B Age (Dordr) %V 35 %P 1367-76 %8 2013 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22555621?dopt=Abstract %R 10.1007/s11357-012-9417-7 %0 Journal Article %J Am J Clin Nutr %D 2016 %T Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Ma, Yiyi %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Manichaikul, Ani W %A Chu, Audrey Y %A Samieri, Cecilia %A Zhou, Xia %A Guan, Weihua %A Wang, Lu %A Biggs, Mary L %A Chen, Yii-der I %A Hernandez, Dena G %A Borecki, Ingrid %A Chasman, Daniel I %A Rich, Stephen S %A Ferrucci, Luigi %A Irvin, Marguerite Ryan %A Aslibekyan, Stella %A Zhi, Degui %A Tiwari, Hemant K %A Claas, Steven A %A Sha, Jin %A Kabagambe, Edmond K %A Lai, Chao-Qiang %A Parnell, Laurence D %A Lee, Yu-Chi %A Amouyel, Philippe %A Lambert, Jean-Charles %A Psaty, Bruce M %A King, Irena B %A Mozaffarian, Dariush %A McKnight, Barbara %A Bandinelli, Stefania %A Tsai, Michael Y %A Ridker, Paul M %A Ding, Jingzhong %A Mstat, Kurt Lohmant %A Liu, Yongmei %A Sotoodehnia, Nona %A Barberger-Gateau, Pascale %A Steffen, Lyn M %A Siscovick, David S %A Absher, Devin %A Arnett, Donna K %A Ordovas, Jose M %A Lemaitre, Rozenn N %K Apolipoproteins E %K ATP Binding Cassette Transporter 1 %K Cholesterol, HDL %K Cohort Studies %K Diet %K DNA Methylation %K Eicosapentaenoic Acid %K Epigenesis, Genetic %K Fatty Acids %K Gene Expression Regulation %K Humans %K Lipids %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Triglycerides %X

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

%B Am J Clin Nutr %V 103 %P 567-78 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26791180?dopt=Abstract %R 10.3945/ajcn.115.112987 %0 Journal Article %J Nature %D 2023 %T Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. %A Weinstock, Joshua S %A Gopakumar, Jayakrishnan %A Burugula, Bala Bharathi %A Uddin, Md Mesbah %A Jahn, Nikolaus %A Belk, Julia A %A Bouzid, Hind %A Daniel, Bence %A Miao, Zhuang %A Ly, Nghi %A Mack, Taralynn M %A Luna, Sofia E %A Prothro, Katherine P %A Mitchell, Shaneice R %A Laurie, Cecelia A %A Broome, Jai G %A Taylor, Kent D %A Guo, Xiuqing %A Sinner, Moritz F %A von Falkenhausen, Aenne S %A Kääb, Stefan %A Shuldiner, Alan R %A O'Connell, Jeffrey R %A Lewis, Joshua P %A Boerwinkle, Eric %A Barnes, Kathleen C %A Chami, Nathalie %A Kenny, Eimear E %A Loos, Ruth J F %A Fornage, Myriam %A Hou, Lifang %A Lloyd-Jones, Donald M %A Redline, Susan %A Cade, Brian E %A Psaty, Bruce M %A Bis, Joshua C %A Brody, Jennifer A %A Silverman, Edwin K %A Yun, Jeong H %A Qiao, Dandi %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Cho, Michael H %A DeMeo, Dawn L %A Vasan, Ramachandran S %A Yanek, Lisa R %A Becker, Lewis C %A Kardia, Sharon L R %A Peyser, Patricia A %A He, Jiang %A Rienstra, Michiel %A van der Harst, Pim %A Kaplan, Robert %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Arnett, Donna K %A Irvin, Marguerite R %A Tiwari, Hemant %A Cutler, Michael J %A Knight, Stacey %A Muhlestein, J Brent %A Correa, Adolfo %A Raffield, Laura M %A Gao, Yan %A de Andrade, Mariza %A Rotter, Jerome I %A Rich, Stephen S %A Tracy, Russell P %A Konkle, Barbara A %A Johnsen, Jill M %A Wheeler, Marsha M %A Smith, J Gustav %A Melander, Olle %A Nilsson, Peter M %A Custer, Brian S %A Duggirala, Ravindranath %A Curran, Joanne E %A Blangero, John %A McGarvey, Stephen %A Williams, L Keoki %A Xiao, Shujie %A Yang, Mao %A Gu, C Charles %A Chen, Yii-Der Ida %A Lee, Wen-Jane %A Marcus, Gregory M %A Kane, John P %A Pullinger, Clive R %A Shoemaker, M Benjamin %A Darbar, Dawood %A Roden, Dan M %A Albert, Christine %A Kooperberg, Charles %A Zhou, Ying %A Manson, JoAnn E %A Desai, Pinkal %A Johnson, Andrew D %A Mathias, Rasika A %A Blackwell, Thomas W %A Abecasis, Goncalo R %A Smith, Albert V %A Kang, Hyun M %A Satpathy, Ansuman T %A Natarajan, Pradeep %A Kitzman, Jacob O %A Whitsel, Eric A %A Reiner, Alexander P %A Bick, Alexander G %A Jaiswal, Siddhartha %K Alleles %K Animals %K Clonal Hematopoiesis %K Genome-Wide Association Study %K Hematopoiesis %K Hematopoietic Stem Cells %K Humans %K Mice %K Mutation %K Promoter Regions, Genetic %X

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

%B Nature %V 616 %P 755-763 %8 2023 Apr %G eng %N 7958 %R 10.1038/s41586-023-05806-1