Appendix A

Increased levels of plasma fibrinogen predict total mortality in CHS [35] as well as other cohort studies of older adults [36]. Nonetheless, we and others did not observe an association with longevity for the fibrinogen promoter polymorphism. The negative findings may reflect the relatively small portion of the overall variance in fibrinogen level explained by the 455 G/A polymorphism [37].

Steering committee chairman: Curt D. Furberg, MD PhD, Wake Forest University School of Medicine. NHLBI project office: Jean Olson, MD MPH. L. Burke, MD. Wake Forest University ECG Reading Center: Ronald Prineas, MD PhD. University of California, Davis: John Robbins, MD MHS. The Johns Hopkins University: Linda P. Fried, MD MPH. The Johns Hopkins University MRI Reading Center: David Yousem, MD MBA. University of Pittsburgh: Lewis H. Kuller, MD DrPH. University of California, Irvine Echocardiography Reading Center (baseline): Julius M. Gardin, MD. Georgetown Medical Center Echocardiography Reading Center (follow-up): John S. Gottdiener, MD. New England Medical Center, Boston Ultrasound Reading Center: Daniel H. OLeary, MD. University of Vermont Central Blood Analysis Laboratory: Russell P. Tracy, PhD. University of Arizona, Tucson Pulmonary Reading Center: Paul Enright, MD. Retinal Reading Center University of Wisconsin: Ronald Klein, MD. University of Washington Coordinating Center: Richard A. Kronmal, PhD.

Increased plasma IL-6 levels have been associated with age-related morbidity and all-cause mortality in older adults. In older men, the IL-6 promoter 174 G/G genotype was associated with increased IL-6 levels and decreased longevity [4,38]. Other case-control studies of long-lived individuals reported conflicting results [39,40]. Overall, we observed a non-significant trend toward increased longevity associated with the IL-6 174 C allele. The possible interaction of anti-inflammatory drugs and interleukin-6 174 C/C genotype on mortality and years of healthy life should be interpreted cautiously. These data wereElderly Japanese-American men. Arterioscler Thromb Vasc Biol; 20: [1] de Maat MP, Bladbjerg EM, Hjelmborg JB, et al. Genetic influence on inflammation variables in the elderly. Arterioscler Thromb Vasc Biol; 20: [2] Giacconi R, Cipriano C, Albanese F, et al. The G/C polymorphism of IL-6 is useful to screen old subjects at risk for atherosclerosis or to reach successful aging. Exp Gerontol; 39: [3] Capurso C, Solfrizzi V, D'Introno A, et al. Interleukin-6 G/C promoter gene polymorphism in centenarians: no evidence of association with human longevity or interaction with apolipoprotein E from coronary heart disease: a 10-year follow-up of Swedish twins. J Intern Med; 252: [4] Wienke A, Holm NV, Christensen K, et al. The heritability of cause-specific mortality: a correlated gamma-frailty model applied to mortality due to respiratory diseases in Danish twins born 1870-1930. Stat Med; 22: [5] Mannucci PM, Mari D, Merati G, et al. Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins. A study in centenarians. Arterioscler Thromb Vasc Biol; 19: [6] Bonafe M, Olivieri F, Cavallone L, et al. A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol; 30: [7] Lio D, Scola L, Crivello A, et al. Allele frequencies of +874TA single nucleotide polymorphism at the first intron of interferon-gamma gene in a group of Italian centenarians. Exp Gerontol; 38: [8] Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol; 1: [9] Diehr P, Patrick DL, Bild DE, Burke GL, Williamson JD. Predicting future years of healthy life for older adults. J Clin Epidemiol; 51: [10] Diehr P, Newman AB, Jackson SA, Kuller L, Powe N. Weight modification trials in older adults: what should the outcome measure be? Curr Control Trials Cardiovasc Med; 1: [11] Jenny NS, Tracy RP, Ogg MS, et al. In the elderly, interleukin-6 plasma levels and the G>C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol; 22: [12] Crainich P, Jenny NS, Tang Z, et al. Lack of association of the plasminogen activator inhibitor-1 G/PAI-1 4G promoter polymorphism with cardiovascular disease in the elderly. J Thromb Haemost; 1: [13] Thomas A, Lamlum H, Humphries S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeII), C/T-854 (HinII/Alu), T/G+1689 (AviI), and Bcl (beta-fibrinogen) and TaqI (alpha-fibrinogen), and their detection by PCR. Hum Mutat; 11: [14] Crainich P, Tang Z, Macy EM, et al. A polymorphism at position -844 in the promoter region of thrombin-activatable fibrinolysis inhibitor (TAFI) is strongly associated with plasma antigen levels in healthy older men and women. Circulation; 106:II-501 [15] Suissa S, Edwardes MD, Boivin JF. External comparisons from nested case-control designs. Epidemiology; 12: [16] Lin DY, Wei LJ. The robust inference of the Cox proportional hazards model. J Am Stat Assoc; 84: [17] Lamarca R, Alonso J, Gomez G, Munoz A. Left-truncated data with age as time scale: an alternative for survival analysis in the elderly population. J Gerontol A Biol Sci Med Sci; 56:B [January]. [18] Jackson AU, Galecki AT, Burke DT, Miller RA. Mouse loci associated with life span exhibit sex-specific and epistatic effects. J Gerontol A Biol Sci Med Sci; 54:B(5):B218-22 [19] Juhan