Of the 180 THS twin pairs we excluded one pair because of missing MPO data, and another pair because of implausible TNF-α values. Of the remaining 178 pairs, 67 pairs were discordant for lifetime history of MDD and 111 were not. The majority of twins with MDD were in remission, with only 8 subjects meeting DMS-IV criteria for a current major depressive episode and 77% having had the last depressive episode >1 year before examination.
Both in the entire population of twins and within the MDD-discordant twin pairs, twins with MDD were less likely to be married, more likely to smoke and to have lower levels of physical activity (). They were also more likely to have PTSD, although the number of twins with PTSD was small (N=23), and to have a higher level of depressive symptoms. There were no substantial differences in other characteristics according to MDD status, including medication use except for antidepressants. There were no significant differences in study variables between monozygotic and dizygotic twins, except that dizygotic twins were slightly older. (Supplemental Table 1
Distribution of demographic, behavioral and coronary risk factors in the entire sample (n=356) and in 67 twin pairs discordant for MDD.
Most of the inflammatory biomarkers were mildly correlated with each other, both in the entire population and in the MDD-discordant co-twins: 90% of the correlation coefficients were <0.40 (Supplemental Table 2
). MPO and TNF-α were the least correlated with other markers.
In the entire sample of twins (twins analyzed as separate individuals), MPO showed a highly significant association with MDD (), with values that were 32% higher in twins with MDD than those without MDD (p<0.0001). IL-6, WBC count, fibrinogen and sTNF RII also showed significant (or borderline significant) associations, although the magnitude of the difference was smaller than for MPO. All the biomarkers considered, except TNF-α, had numerically higher values in twins with MDD. Multivariable analysis did not materially alter the association for MPO while it attenuated the association for most of the other biomarkers.
Unadjusted and adjusted differences in inflammatory biomarkers in the entire sample (n=356), considering twins as separate individuals.
and show the results of the association between MDD and inflammation from the co-twin control analysis among twin pairs discordant for MDD, stratified by zygosity. This analysis controlled by design for all factors shared by the twins. Consistent with the hypothesis of genetic confounding, larger associations between MDD and inflammatory markers were found among dizygotic twins than among monozygotic twins. Among dizygotic twins, those with MDD had significantly higher MPO, IL-6, WBC count, sTNF RII and fibrinogen levels than their brothers without MDD. Again, the difference was most marked for MPO, with 62% higher levels in MDD twins (p<0.0001). As in the analysis of the entire sample, adjustment for risk factors did not weaken the association between MPO and MDD, with 77% higher MPO levels in MDD twins in multivariable analysis. However, adjustment did attenuate the relationship of the other biomarkers, with only WBC count and (borderline) sTNF RII remaining significantly associated with MDD in multivariable analysis. In contrast, there was no evidence for an association of MDD and any of the inflammatory biomarkers in monozygotic twins. The interaction between MDD and zygosity was significant for MPO, IL-6, and sTNF RII. Although not statistically significant, the interaction p value approached significance for all the remaining biomarkers except TNF-α. These results confirm a confounding effect due to genetic factors. On the contrary, shared environment did not confound in the association between MDD and inflammation, since the paired differences in biomarker levels between dizygotic twin brothers were no less, and actually numerically larger, than in the overall analysis of twins as separate individuals.
Unadjusted and adjusted differences in inflammatory biomarkers in 67 twin pairs discordant for MDD. Matched co-twin control analysis.
Figure 1 Unadjusted and adjusted percent differences in inflammatory markers in dizygotic (upper panel) and monozygotic (lower panel) twin pairs discordant for MDD, comparing twins with MDD to their co-twins without MDD. Based on data in Table 5 (see this table (more ...)
When the analyses were repeated by including current smoking as a stand-alone variable in place of the FRS, the results were virtually identical and are not reported. In addition, we examined whether current level of depressive symptoms, measured with the BDI, would explain the relationship between MDD and inflammatory biomarkers among the dizygotic twins. The BDI score was not significantly correlated with MPO (r=0.02, p=0.69), but it was significantly associated with IL-6, CRP, WBC count and sTNF RII. However, adjustment for BDI score did not substantially affect the relationship between MDD and any of the biomarkers, suggesting that the relationship was not due to current level of depressive symptoms.