TY - JOUR T1 - Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. JF - J Clin Endocrinol Metab Y1 - 2007 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis H A1 - Strickler, Howard D A1 - Rohan, Tom E A1 - Cappola, Anne R A1 - Xue, XiaoNan A1 - Psaty, Bruce M KW - Aged KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Multivariate Analysis KW - Risk Factors KW - Stroke AB -

CONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults.

OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke.

DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study.

MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study.

RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease.

CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.

VL - 92 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17264182?dopt=Abstract ER - TY - JOUR T1 - High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly. JF - Am Heart J Y1 - 2008 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Cappola, Anne R A1 - Xue, XiaoNan A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Low levels of insulinlike growth factor 1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulinlike growth factor binding protein 1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in patients with CHF and has been associated prospectively with increased mortality among older adults and survivors of myocardial infarction. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study.

METHODS: From among 5,888 adults 65 years old and older in the Cardiovascular Health Study, we studied 566 incident CHF cases and 1,072 comparison subjects after exclusion of underweight individuals (body mass index <18.5 kg/m(2)) and insulin users. Hazard ratios (HRs) with 95% CIs for CHF were estimated after adjustment for age, race, sex, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and body mass index.

RESULTS: High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95% CI 1.07-1.39, P < .01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI 0.96-1.74, P = .09) for the second IGFBP-1 tertile and 1.47 (95% CI 1.06-2.04; P = .02) for the highest IGFBP-1 tertile (tertile cut points 19.5 and 35.8 ng/mL). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors.

CONCLUSIONS: High circulating IGFBP-1 level may be a CHF risk factor among older adults.

VL - 155 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18513511?dopt=Abstract ER - TY - JOUR T1 - Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults. JF - Growth Horm IGF Res Y1 - 2008 A1 - Rajpathak, Swapnil N A1 - McGinn, Aileen P A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Pollak, Michael A1 - Cappola, Anne R A1 - Kuller, Lewis A1 - Xue, XiaoNan A1 - Newman, Anne B A1 - Strotmeyer, Elsa S A1 - Psaty, Bruce M A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Glucose Intolerance KW - Humans KW - Inflammation KW - Insulin-Like Growth Factor Binding Proteins KW - Male KW - Signal Transduction KW - Somatomedins AB -

Increasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.

VL - 18 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17904401?dopt=Abstract ER - TY - JOUR T1 - Total insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults. JF - J Am Geriatr Soc Y1 - 2008 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Xue, XiaoNan A1 - Kritchevsky, Stephen B A1 - Newman, Anne B A1 - Psaty, Bruce M KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Enzyme-Linked Immunosorbent Assay KW - Fasting KW - Female KW - Follow-Up Studies KW - Hand Strength KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Middle Aged KW - Prognosis KW - Prospective Studies KW - Risk Factors KW - Survival Rate KW - United States KW - Walking AB -

OBJECTIVES: To assess the association between total insulinlike growth factor (IGF)-1, IGF binding protein-1 (IGFBP-1), and IGFBP-3 levels and functioning and mortality in older adults.

DESIGN: Cohort study.

SETTING/PARTICIPANTS: One thousand one hundred twenty-two individuals aged 65 and older without prior cardiovascular disease events participating in the Cardiovascular Health Study.

MEASUREMENTS: Baseline fasting plasma levels of IGF-1, IGFBP-1, and IGFBP-3 (defined as tertiles, T1-T3) were examined in relationship to handgrip strength, time to walk 15 feet, development of new difficulties with activities of daily living (ADLs), and mortality.

RESULTS: Higher IGFBP-1 predicted worse handgrip strength (P-trend(T1-T3)<.01) and slower walking speed (P-trend(T1-T3)=.03), lower IGF-1 had a borderline significant association with worse handgrip strength (P-trend(T1-T3)=.06), and better grip strength was observed in the middle IGFBP-3 tertile than in the low or high tertiles (P=.03). Adjusted for age, sex, and race, high IGFBP-1 predicted greater mortality (P-trend(T1-T3)<.001, hazard ratio (HR)(T3vsT1)=1.48, 95% confidence interval (CI)=1.15-1.90); this association was borderline significant after additional confounder adjustment (P-trend(T1-T3)=.05, HR(T3vsT1)=1.35, 95% CI=0.98-1.87). High IGFBP-1 was associated with greater risk of incident ADL difficulties after adjustment for age, sex, race, and other confounders (P-trend(T1-T3)=.04, HR(T3vsT1)=1.40, CI=1.01-1.94). Neither IGF-1 nor IGFBP-3 level predicted mortality or incident ADL difficulties.

CONCLUSION: In adults aged 65 and older, high IGFBP-1 levels were associated with greater risk of mortality and poorer functional ability, whereas IGF-1 and IGFBP-3 had little association with these outcomes.

VL - 56 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18312313?dopt=Abstract ER - TY - JOUR T1 - Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2009 A1 - Kaplan, Robert C A1 - Fitzpatrick, Annette L A1 - Pollak, Michael N A1 - Gardner, Jeffrey P A1 - Jenny, Nancy S A1 - McGinn, Aileen P A1 - Kuller, Lewis H A1 - Strickler, Howard D A1 - Kimura, Masayuki A1 - Psaty, Bruce M A1 - Aviv, Abraham KW - Aged KW - Aging KW - Cross-Sectional Studies KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor Binding Proteins KW - Insulin-Like Growth Factor I KW - Leukocytes KW - Linear Models KW - Male KW - Sex Characteristics KW - Telomere AB -

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.

VL - 64 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19349587?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. JF - Hum Mol Genet Y1 - 2011 A1 - Kaplan, Robert C A1 - Petersen, Ann-Kristin A1 - Chen, Ming-Huei A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Döring, Angela A1 - Lam, Carolyn S P A1 - Friedrich, Nele A1 - Newman, Anne A1 - Müller, Martina A1 - Yang, Qiong A1 - Homuth, Georg A1 - Cappola, Anne A1 - Klopp, Norman A1 - Smith, Holly A1 - Ernst, Florian A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Sawyer, Douglas B A1 - Biffar, Reiner A1 - Rotter, Jerome I A1 - Gieger, Christian A1 - Sullivan, Lisa S A1 - Völzke, Henry A1 - Rice, Kenneth A1 - Spyroglou, Ariadni A1 - Kroemer, Heyo K A1 - Ida Chen, Y-D A1 - Manolopoulou, Jenny A1 - Nauck, Matthias A1 - Strickler, Howard D A1 - Goodarzi, Mark O A1 - Reincke, Martin A1 - Pollak, Michael N A1 - Bidlingmaier, Martin A1 - Vasan, Ramachandran S A1 - Wallaschofski, Henri KW - Aged KW - Chromosomes, Human, Pair 7 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Polymorphism, Single Nucleotide AB -

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

VL - 20 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract ER - TY - JOUR T1 - Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study. JF - J Clin Endocrinol Metab Y1 - 2012 A1 - Kaplan, Robert C A1 - Bůzková, Petra A1 - Cappola, Anne R A1 - Strickler, Howard D A1 - McGinn, Aileen P A1 - Mercer, Laina D A1 - Arnold, Alice M A1 - Pollak, Michael N A1 - Newman, Anne B KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Longitudinal Studies KW - Male KW - Mortality KW - Predictive Value of Tests KW - Risk Factors AB -

BACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.

STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.

RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10% decreases over time in IGF-I levels (CM = 29.6%), individuals who had at least 10% increases over time in IGF-I levels (CM = 24.7%), and individuals who had IGF-I levels remaining within ±10% over time (CM = 23.5%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.

CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22442270?dopt=Abstract ER - TY - JOUR T1 - Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults. JF - J Am Geriatr Soc Y1 - 2015 A1 - Aneke-Nash, Chino S A1 - Parrinello, Christina M A1 - Rajpathak, Swapnil N A1 - Rohan, Thomas E A1 - Strotmeyer, Elsa S A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Bůzková, Petra A1 - Kizer, Jorge R A1 - Newman, Anne B A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Retrospective Studies AB -

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.

DESIGN: Retrospective analysis of a cohort study.

SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).

MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).

RESULTS: At baseline, mean age was 76.3±3.6, and 18.5% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3% for IGF-I, 59.7% for IGFBP-1, -13.4% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7% for IGF-I, 25.6% for IGFBP-1, -6.4% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.

CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.

VL - 63 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25989565?dopt=Abstract ER - TY - JOUR T1 - Agreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies. JF - Growth Horm IGF Res Y1 - 2016 A1 - Aneke-Nash, Chino S A1 - Dominguez-Islas, Clara A1 - Bůzková, Petra A1 - Qi, Qibin A1 - Xue, XiaoNan A1 - Pollak, Michael A1 - Strickler, Howard D A1 - Kaplan, Robert C AB -

OBJECTIVE: Levels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available.

DESIGN: In a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS).

RESULTS: Results were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X-1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated.

CONCLUSIONS: Care is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.

VL - 26 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26774400?dopt=Abstract ER - TY - JOUR T1 - Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. JF - Aging Cell Y1 - 2016 A1 - Teumer, Alexander A1 - Qi, Qibin A1 - Nethander, Maria A1 - Aschard, Hugues A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Berndt, Sonja I A1 - Bidlingmaier, Martin A1 - Broer, Linda A1 - Cappola, Anne A1 - Ceda, Gian Paolo A1 - Chanock, Stephen A1 - Chen, Ming-Huei A1 - Chen, Tai C A1 - Chen, Yii-Der Ida A1 - Chung, Jonathan A1 - Del Greco Miglianico, Fabiola A1 - Eriksson, Joel A1 - Ferrucci, Luigi A1 - Friedrich, Nele A1 - Gnewuch, Carsten A1 - Goodarzi, Mark O A1 - Grarup, Niels A1 - Guo, Tingwei A1 - Hammer, Elke A1 - Hayes, Richard B A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Houwing-Duistermaat, Jeanine J A1 - Hu, Frank A1 - Hunter, David J A1 - Husemoen, Lise L A1 - Isaacs, Aaron A1 - Jacobs, Kevin B A1 - Janssen, Joop A M J L A1 - Jansson, John-Olov A1 - Jehmlich, Nico A1 - Johnson, Simon A1 - Juul, Anders A1 - Karlsson, Magnus A1 - Kilpeläinen, Tuomas O A1 - Kovacs, Peter A1 - Kraft, Peter A1 - Li, Chao A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Lu, Yingchang A1 - Maggio, Marcello A1 - Mägi, Reedik A1 - Meigs, James A1 - Mellström, Dan A1 - Nauck, Matthias A1 - Newman, Anne B A1 - Pollak, Michael N A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Psaty, Bruce M A1 - Reincke, Martin A1 - Rimm, Eric B A1 - Rotter, Jerome I A1 - Saint Pierre, Aude A1 - Schurmann, Claudia A1 - Seshadri, Sudha A1 - Sjögren, Klara A1 - Slagboom, P Eline A1 - Strickler, Howard D A1 - Stumvoll, Michael A1 - Suh, Yousin A1 - Sun, Qi A1 - Zhang, Cuilin A1 - Svensson, Johan A1 - Tanaka, Toshiko A1 - Tare, Archana A1 - Tönjes, Anke A1 - Uh, Hae-Won A1 - van Duijn, Cornelia M A1 - van Heemst, Diana A1 - Vandenput, Liesbeth A1 - Vasan, Ramachandran S A1 - Völker, Uwe A1 - Willems, Sara M A1 - Ohlsson, Claes A1 - Wallaschofski, Henri A1 - Kaplan, Robert C AB -

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27329260?dopt=Abstract ER - TY - JOUR T1 - The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study. JF - J Clin Endocrinol Metab Y1 - 2017 A1 - Aneke-Nash, Chino S A1 - Xue, XiaoNan A1 - Qi, Qibin A1 - Biggs, Mary L A1 - Cappola, Anne A1 - Kuller, Lewis A1 - Pollak, Michael A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Mukamal, Kenneth A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Longitudinal Studies KW - Male KW - New England KW - Prospective Studies KW - Risk AB -

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

VL - 102 IS - 12 ER -