Systemic Inflammation is Associated with Cardiometabolic Risk Factors and Clinical Outcomes

Figures & data

Table 1 Baseline Characteristics of the Study Sample

Characteristic	Off Spring Exam 7, 1998–2001	Third Generation Exam 1, 2002–2005	TotalN = 7287^a
	N = 3254^a	N = 4033^a
Age, years	61 (9)	40 (9)	49 (14)
Women	1739 (53%)	2145 (53%)	3884 (53%)
Body Mass Index, kg/m^2	28.2 (5.3)	26.9 (5.5)	27.4 (5.5)
Weight, lbs	175 (39)	173 (41)	174 (40)
Current Smokers	430 (13%)	704 (17%)	1134 (16%)
Hypertensive	1994 (61%)	1532 (38%)	3526 (49%)
Hypertension treatment	1108 (34%)	349 (8.7%)	1457 (20%)
Triglycerides, mg/dL	144 (97)	118 (95)	129 (97)
Total Cholesterol, mg/dL	212 (41)	193 (40)	202 (41)
Diabetic	365 (11%)	119 (3.0%)	484 (6.6%)
Diabetes treatment	218 (6.7%)	73 (1.8%)	291 (4.0%)
Glucose, mg/dL	106 (31)	96 (20)	100 (26)

Notes: ^aMean (SD); n (%).

Table 2 Aggregate Inflammatory Score: Cross-Sectional Associations with Cardiometabolic Risk Factors

A
	Model 1^a			Model 2^b
Risk Factor	Beta (95% CI)	Standard Error	P value	Beta (95% CI)	Standard Error	P value
Age (years)	0.26 (0.24–0.28)	0.01	8.60E-107	0.22 (0.20–0.24)	0.01	8.40E-99
Sex (Male)	2.26 (1.85–2.67)	0.21	9.90E-27	1.10 (0.73–1.47)	0.19	7.89E-09
Never vs Current Smokers	3.27 (2.66–3.88)	0.31	2.61E-26	3.35 (2.82–3.88)	0.27	6.98E-34
Never vs Former Smokers	0.24 (−0.23–0.71)	0.24	3.32E-01	−0.02 (−0.45–0.41)	0.22	9.24E-01
Former vs Current Smokers	3.22 (2.57–3.87)	0.33	2.70E-22	3.68 (3.09–4.27)	0.30	1.98E-34
B
	Model 1^a			Model 2^b
Risk Factor	Beta (95% CI)	Standard Error	P value	Beta (95% CI)	Standard Error	P value
Triglycerides (mg/dL)	0.009 (0.009–0.009)	> 0.000	1.69E-191	0.007 (0.007–0.007)	> 0.000	1.90E-87
Total Cholesterol (mg/dL)	0.454 (0.352–0.556)	0.052	3.59E-18	0.26 (0.146–0.374)	0.058	7.14E-06
HDL-Cholesterol (mg/dL)	−0.539 (−0.576–−0.502)	0.019	1.30E-171	−0.389 (−0.430 - −0.348)	0.021	1.73E-77
Glucose (mg/dL)	0.608 (0.547–0.669)	0.031	1.49E-83	0.368 (0.301–0.435)	0.034	5.32E-27
SBP (mmHg)	0.426 (0.383–0.469)	0.022	3.66E-82	0.225 (0.178–0.272)	0.024	6.65E-21
DBP (mmHg)	0.211 (0.186–0.236)	0.013	2.40E-55	0.067 (0.040–0.094)	0.014	3.68E-06
BMI (kg/m^2)	0.266 (0.254–0.278)	0.006	< 1.00E-200	*	*	*
C
	Model 1^a			Model 1 + Risk Factor Adjustments^c
Outcome	OR	95% CI	P value	OR	95% CI	P value
Hypertension	1.67	(1.57–1.76)	9.18E-67	1.30	(1.16–1.46)	1.23E-05
Diabetes	2.38	(2.13–2.66)	1.90E-53	1.11	**	1.00E+00
Obesity	2.70	(2.52–2.90)	1.71E-175	2.70	**	9.96E-01

Notes: ^a Model 1: AIS = Age + Sex + Cohort; Risk Factor = AIS + Age + Sex + Cohort. ^bModel 2: AIS = Age + Sex + Cohort + BMI; Risk Factor = AIS + Age + Sex + Cohort + BMI. ^cModel: Outcome = AIS + Age + Sex + Cohort + Relevant Risk Factor (SBP and DBP for hypertension, glucose for diabetes, and BMI for obesity). *Model 2 includes an adjustment for BMI. **Upper and lower confidence limits approach infinity and negative infinity. (A) Two logistic regression models were used utilizing the AIS as the independent variable and the dichotomous risk factors as the dependent variable: Model 1 (age, sex, and cohort adjusted) and Model 2 (age, sex, cohort, and BMI adjusted). In both models, the appropriate covariate (age or sex) was removed as a covariate when that variable is investigated as the outcome. (B) Two linear regression models were used utilizing the risk factors as independent variables and the AIS as the dependent variable using the same list of covariates. Only participants with fasting measurements were included in triglycerides, total cholesterol, HDL, and glucose analyses. Triglyceride levels were log transformed (log₁₀) in order to obtain normality. For age and sex analyses, the relevant model excluding the adjustment for that respective risk factor was utilized. Bonferroni corrected p value = 3.33E-03 (0.05/15). (C) For the disease outcomes, logistic regression was used, in accordance with Models 1 and 2. There were 3526 cases of hypertension at baseline of the 7270 participants at risk, 484 cases of diabetes at baseline out of the 7284 participants at risk, and 1881 cases of obesity at baseline of the 7287 participants at risk. Odds ratios (OR) are presented per 1-SD increase in the respective inflammatory score.

Abbreviations: SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure.

Table 3 Principal Component Analysis Score: Cross-Sectional Associations with Cardiometabolic Risk Factors

A
	Model 1^a			Model 2^b
Risk Factor	Beta	Standard Error	P value	Beta	Standard Error	P value
Age (years)	9.21 (8.60–9.82)	0.31	8.52E-189	8.69 (8.10–9.28)	0.30	1.43E-178
Sex (Male)	−1.31 (−12.25–9.63)	5.58	8.15E-01	−18.51 (−29.21 - −7.81)	5.46	7.07E-04
Never vs Current Smokers	41.93 (26.80–57.06)	7.72	5.81E-08	43.01 (28.31–57.71)	7.50	1.03E-08
Never vs Former Smokers	0.24 (−12.50–12.98)	6.50	9.71E-01	−3.64 (−15.95–8.67)	6.28	5.62E-01
Former vs Current Smokers	49.94 (31.67–68.21)	9.32	8.90E-08	57.4 (39.68–75.12)	9.04	2.38E-10
B
	Model 1^a			Model 2^b
Risk Factor	Beta	Standard Error	P value	Beta	Standard Error	P value
Triglycerides (mg/dL)	> 0.000 (>0.000 - >0.000)	> 0.000	3.96E-49	> 0.000 (>0.000 - >0.000)	> 0.000	8.60E-18
Total Cholesterol (mg/dL)	−0.003 (−0.007–0.001)	0.002	1.25E-01	−0.009 (−0.013 - −0.005)	0.002	1.47E-05
HDL-Cholesterol (mg/dL)	−0.009 (−0.011 - −0.007)	0.001	6.43E-32	−0.004 (−0.006 - −0.002)	0.001	1.11E-08
Glucose (mg/dL)	0.015 (0.013–0.017)	0.001	1.64E-33	0.008 (0.006–0.010)	0.001	3.89E-12
SBP (mmHg)	0.012 (0.010–0.014)	0.001	2.62E-47	0.007 (0.005–0.009)	0.001	6.00E-19
DBP (mmHg)	0.003 (0.001–0.005)	0.001	2.42E-07	−0.001 (−0.003–0.001)	0.001	1.50E-01
BMI (kg/m^2)	0.006 (0.006–0.006)	> 0.000	1.15E-102	*	*	*
C
	Model 1^a			Model 1 + Risk Factor Adjustments^c
Outcome	OR	95% CI	P value	OR	95% CI	P value
Hypertension	1.41	(1.32–1.50)	1.85E-25	1.35	(1.18–1.54)	7.07E-06
Diabetes	1.62	(1.48–1.78)	4.30E-24	1.07	**	1.00E+00
Obesity	1.70	(1.59–1.81)	5.59E-58	1661.74	**	9.94E-01

Notes: Two logistic regression models were used utilizing the PCA score as the independent variable and the dichotomous risk factors as the dependent variable: Model 1 (age, sex, and cohort adjusted) and Model 2 (age, sex, cohort, and BMI adjusted). In both models, the appropriate covariate (age or sex) was removed as a covariate when that variable is investigated as the outcome. Two linear regression models were used utilizing the risk factors as independent variables and the PCA score as the dependent variable using the same list of covariates. Only participants with fasting measurements were included in triglycerides, total cholesterol, HDL, and glucose analyses. Triglyceride levels were log transformed (log₁₀) in order to obtain normality. For age and sex analyses, the relevant model excluding the adjustment for that respective risk factor was utilized. Bonferroni corrected p value = 3.33E-03 (0.05/15). For the disease outcomes, logistic regression was used, in accordance with Models 1 and 2. There were 3526 cases of hypertension at baseline of the 7270 participants at risk, 484 cases of diabetes at baseline out of the 7284 participants at risk, and 1881 cases of obesity at baseline of the 7287 participants at risk. Odds ratios (OR) are presented per 1-SD increase in the respective inflammatory score. ^aModel 1: PCA Score = Age + Sex + Cohort; Risk Factor = PCA Score + Age + Sex + Cohort. ^bModel 2: PCA Score = Age + Sex + Cohort + BMI; Risk Factor = PCA Score + Age + Sex + Cohort + BMI. ^cModel: Outcome = PCA Score + Age + Sex + Cohort + Relevant Risk Factor (SBP and DBP for hypertension, glucose for diabetes, and BMI for obesity). * Model 2 includes an adjustment for BMI. ** Upper and lower confidence limits approach infinity and negative infinity.

Abbreviations: SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure.

Table 4 Logistic Regression: Prospective Associations of PCA and AIS Scores with New-Onset Hypertension, Diabetes, and Obesity

A
	Model 1^a			Model 2^b
Outcome	OR	95% CI	P value	OR	95% CI	P value
New Onset Hypertension	1.45	(1.32–1.60)	4.46E-15	1.33	(1.21–1.47)	1.14E-08
New Onset Diabetes	1.78	(1.57–2.03)	2.53E-18	1.32	(1.14–1.52)	1.88E-04
New Onset Obesity	1.60	(1.43–1.79)	1.31E-16	1.02	(0.88–1.17)	8.29E-01
B
	Model 1^a			Model 2^b
Outcome	OR	95% CI	P value	OR	95% CI	P value
New Onset Hypertension	1.31	(1.17–1.46)	2.45E-06	1.26	(1.12–1.42)	1.30E-04
New Onset Diabetes	1.29	(1.12–1.47)	2.58E-04	1.07	(0.92–1.24)	3.65E-01
New Onset Obesity	1.27	(1.12–1.43)	1.40E-04	1.06	(0.91–1.23)	4.51E-01

Notes: Logistic regression models were used to explore the prospective associations of the AIS (A) and PCA score (B) with new-onset hypertension, diabetes, and obesity. There were 948 new-onset cases of hypertension of the 3220 participants at risk with follow-up events data, 306 new-onset cases of diabetes of the 5709 participants at risk with follow-up events data, and 496 new-onset cases of obesity of the 4524 participants at risk with follow-up data. Odds ratios (OR) are presented per 1-SD increase in the respective inflammatory score. ^aModel 1: Outcome = Inflammatory Score + Baseline Age + Sex + Cohort + Years to Follow-up Exam. ^bModel 2: Outcome = Inflammatory Score + Baseline Age + Sex + Cohort + Years to Follow-up Exam + Relevant Risk Factor (baseline SBP and DBP for hypertension, baseline glucose for diabetes, and baseline BMI for obesity).

Table 5 Proportional Hazards Regression: Associations of AIS and PCA Scores with New-Onset All-Cause Mortality and Cardiovascular Disease

Primary Outcomes^a	AIS			PCA Score
	HR^c	95% CI	P value	HR^c	95% CI	P value
New-onset CVD	1.25	1.14–1.37	1.21E-06	1.22	1.13–1.33	8.81E-07
All-cause Mortality	1.32	1.23–1.42	1.20E-14	1.40	1.31–1.49	< 1.00E-20
Secondary Outcomes^b
Coronary Heart Disease	1.09	0.95–1.25	2.20E-01	< 1.00	0.87–1.14	9.67E-01
Heart Failure	1.54	1.36–1.74	1.83E-11	1.52	1.37–1.69	2.30E-15
Atherothrombotic Stroke	1.22	0.98–1.52	7.74E-02	1.26	1.04–1.52	1.81E-02
Revascularization Procedure	1.23	1.09–1.40	1.11E-03	1.14	1.02–1.28	2.60E-02
CVD Death	1.42	1.22–1.64	3.43E-06	1.61	1.42–1.81	8.48E-15

Notes: A separate proportional hazards regression model was used to explore the associations of each inflammatory score with either all-cause mortality or a composite of CVD events (coronary heart disease, heart failure, atherothrombotic stroke, revascularization procedures, or CVD death) during patient follow-up. The associations of the inflammatory scores with the individual endpoints of the CVD composite were investigated in secondary analyses. ^aAll-cause Mortality: 1070 events / 3488 at risk; New-onset CVD: 627 events / 3101 at risk. ^bCoronary Heart Disease: 288 events / 3188 at risk; Heart Failure: 319 events / 3465 at risk; Atherothrombotic Stroke: 109 events / 3453 at risk; Revascularization Procedure: 332 events / 3494 at risk; CVD Death: 249 events / 3453 at risk. ^cHazard ratios are presented per 1-SD increase in the respective inflammatory score.