title: Synergistic and Non-synergistic Associations for Cigarette Smoking and Non-tobacco Risk Factors for Cardiovascular Disease Incidence in the Atherosclerosis Risk In Communities (ARIC) Study.
abstract: BACKGROUND
  Cigarette smoking, various metabolic and lipid-related factors and hypertension are well-recognized cardiovascular disease (CVD) risk factors. Since smoking affects many of these factors, use of a single imprecise smoking metric, for example, ever or never smoked, may allow residual confounding and explain inconsistencies in current assessments of interactions.
  
  
  METHODS
  Using a comprehensive model in pack-years and cigarettes/day for the complex smoking-related relative risk (RR) of CVD to reduce residual confounding, we evaluated interactions with non-tobacco risk factors, including additive (non-synergistic) and multiplicative (synergistic) forms. Data were from the prospective Atherosclerosis Risk in Communities (ARIC) Study from four areas of the United States recruited in 1987-1989 with follow-up through 2008. Analyses included 14 127 participants, 207 693 person-years and 2857 CVD events.
  
  
  RESULTS
  Analyses revealed distinct interactions with smoking: including statistical consistency with additive (body mass index [BMI], waist to hip ratio [WHR], diabetes mellitus [DM], glucose, insulin, high density lipoproteins [HDL] and HDL(2)); and multiplicative (hypertension, total cholesterol [TC], low density lipoproteins [LDLs], apolipoprotein B [apoB], TC to HDL ratio and HDL(3)) associations, as well as indeterminate (apolipoprotein A-I [apoA-I] and triglycerides) associations.
  
  
  CONCLUSIONS
  The forms of the interactions were revealing but require confirmation. Improved understanding of joint associations may help clarify the public health burden of smoking for CVD, links between etiologic factors and biological mechanisms, and the consequences of joint exposures, whereby synergistic associations highlight joint effects and non-synergistic associations suggest distinct contributions.
  
  
  CONCLUSIONS
  Joint associations for cigarette smoking and non-tobacco risk factors were distinct, revealing synergistic/multiplicative (hypertension, TC, LDL, apoB, TC/HDL, HDL(3)), non-synergistic/additive (BMI, WHR, DM, glucose, insulin, HDL, HDL(2)) and indeterminate (apoA-I and TRIG) associations. If confirmed, these results may help better define the public health burden of smoking on CVD risk and identify links between etiologic factors and biologic mechanisms, where synergistic associations highlight joint impacts and non-synergistic associations suggest distinct contributions from each factor.
authors.affiliation: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lubin
authors.affiliation: Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.
authors.forename: David
authors.initials: D
authors.lastname: Couper
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Lutsey
authors.affiliation: Department of Public Health, Fujita Health University School of Medicine, Kutsukake-cho, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yatsuya
mesh_terms: D016632:Apolipoprotein A-I / Q000097:blood; D015992:Body Mass Index; D003324:Coronary Artery Disease / Q000097:blood / Q000453:epidemiology* / Q000209:etiology / Q000401:mortality; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology*; D062789:Tobacco Products / Q000706:statistics & numerical data*; D014481:United States / Q000453:epidemiology
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I