HLA-DRB1 haplotypes predict cardiovascular mortality in inflammatory polyarthritis independent of CRP and anti-CCP status

Sharma, Seema; Plant, Darren; Bowes, John; Macgregor, Alex; Verstappen, Suzanne; Barton, Anne; Viatte, Sebastien

doi:10.1186/s13075-022-02775-0

Table 3 Mediation analysis

From: HLA-DRB1 haplotypes predict cardiovascular mortality in inflammatory polyarthritis independent of CRP and anti-CCP status

*Step 1: Association of serine at position 11 and mediators*
Model	Variable	B coefficient	p value	Interpretation
Linear regression: serine 11, CRP	CRP	−2.49 (−4.13, −0.85)	0.003	Suggests serine 11 is associated with CRP
Logistic regression: serine 11, anti-CCP	Anti-CCP	−0.85 (−1.00, −0.70)	0.000	Suggests serine 11 is associated with anti-CCP status
Multivariate regression: serine 11, anti-CCP and CRP	CRP	0.00 (0.00, 0.00)	0.614	Suggests association between serine 11 and CRP fully mediated by ACPA status.
Multivariate regression: serine 11, anti-CCP and CRP	Anti-CCP	−0.37 (−0.43, −0.30)	0.000
*Step 2: Association of serine at position 11 and cardiovascular mortality*
Model	Variable	Hazard ratio	p value	Interpretation
Model predicting CV mortality (controlled for cv risk factors) with serine 11	Serine 11	0.82 (0.70, 0.96)	0.016	Suggests association between serine 11 and CV mortality
*Step 3: Association of Serine at position 11 and cardiovascular mortality*
Model	Variable	Hazard ratio	p value	Interpretation
Model predicting CV mortality (controlled for cv risk factors) with serine 11, CRP	CRP	1.01 (1.00, 1.01)	0.001	Suggests association of CRP and CV mortality
	Serine 11	0.83 (0.70, 0.99)	0.034	Suggests association of serine 11 and CV mortality, independent of CRP
Model predicting CV mortality (controlled for cv risk factors) with serine 11, ACPA	Anti-CCP	1.50 (1.18, 1.92)	0.001	Suggests association of anti-CCP and CV mortality
	Serine 11	0.81 (0.68, 0.98)	0.027	Suggests association of serine 11 and CV mortality, independent of anti-CCP
Model predicting CV mortality (controlled for cv risk factors) with serine 11, ACPA, CRP	CRP	1.00 (1.00, 1.01)	0.005	Suggests association of CRP and CV mortality, independent of anti-CCP
	Anti-CCP	1.40 (1.08, 1.81)	0.011	Suggests association of anti-CCP and CV mortality
	Serine 11	0.83 (0.69, 1.00)	0.048	Suggests association of serine 11 and CV mortality, independent of anti-CCP and CRP
*Other relevant models*
Model	Variable	B coefficient	p value
Regression CRP, anti-CCP	Anti-CCP	12.71 (10.55, 14.87)	0.000
Association of serine at position 11 and rheumatoid factor was also tested which showed a significant association. However, when adjusted for anti-CCP, this association no longer stood. For this reason, the rheumatoid factor was not included in further mediation analysis. See below:
Model	Variable	B coefficient	p value
Regression model serine 11, rheumatoid factor and anti-CCP	Anti-CCP	− 0.35 (− 0.42, − 0.28)	0.000
Regression model serine 11, rheumatoid factor and anti-CCP	Rheumatoid factor	− 0.01 (− 0.09, 0.06)	0.691

The results of mediation analysis which was performed as per principles according to Baron and Kennedy. This was performed in steps as shown in order to determine whether the association of the above genetic factors with CV mortality was likely to be through intermediate parameters of inflammation. Proposed pathways are summarised in Fig. 2

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ISSN: 1478-6362

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