Nasal carriage of S. aureus
, the major risk factor for invasive S. aureus
serious infections with high mortality [3
], is a complex condition determined by both bacterial and host genetics as well as environmental factors. We have collected the largest reported cohort of twin nasal samples and investigated the heredity of S. aureus
nasal carriage in a sample size >6 times the size of all previous twin studies performed [5
]. We furthermore performed a long-term follow-up on concordant twin pairs to evaluate the role of host genetics for long-term carriers, which has not been performed in earlier studies. The size of the study and the use of robust twin statistical methods make the results and conclusions of this study very strong.
Our study clearly demonstrates that the host genetic contribution to nasal colonization with S. aureus
is, at most, very limited. This conclusion is consistent with other recent studies among Amish families [15
] and among a large Dutch genome-wide association study on Dutch nasal carriers (A. van Belkum, personal communication). Early cross-sectional concordance studies of S. aureus
nasal carriage were either too small to clearly determine heritability [5
] or contained cohabitating individuals [16
] that might have increased carriage prevalence. The large number of both MZ and DZ twins in this study allowed for a more thorough estimation of heritability for S. aureus
colonization and carriage.
A number of studies estimate the prevalence of S. aureus
colonization in the general population to be approximately 20%–32% [2
]. In the present study, we found a prevalence of 325 carriers in 1234 individuals, corresponding to 26.3%, which shows good accordance with these general findings as well as with the average prevalence estimate of 27% [18
]. Moreover, it is estimated that approximately 20% of the general population are persistent carriers [4
]. Therefore, in a cross-sectional sample such as ours, approximately 20% of the 27% should also be carriers at a second culture, corresponding to a recurrence percentage of about 20 of 27 (74.1%), which is very similar to the 60 of 74 (81.1%) we found in our sample of first-time carrier-concordant twins. Because this sample does not differ with respect to recurrence when compared with the general population, it is not likely that it should differ from the recurrence in the sample of first-time carrier-discordant twins either.
Our study confirms the gender bias of nasal carriage, with men more prevalent carriers than women [19
]. Only 1 twin pair of 617 twin pairs carried S. aureu
s isolates of the same clonal lineage, indicating that twins are not generally colonized with the same isolate and that the nasal S. aureus
is not transferred from one twin to the other. Thus, our study clearly shows that despite common environment and, particularly for the MZ twins, closer relationships than most siblings, the childhood environment does not determine the long-term S. aureus
carried in the nose. In early childhood, there is a high prevalence of S. aureus
], which decreases to adult levels in the teens [4
]. To our knowledge, no study has addressed the long-term carriage from childhood into adulthood.
Our results from 2 samplings are also in agreement with previous findings for which different approaches were followed to determine persistent carriage [9
] because we found 21% persistent carriers overall. Persistent carriage of S. aureus
as determined from 2 nasal swabs is also not a strongly heritable trait; we could not find an overrepresentation of concordant persistent S. aureus
carriers among the MZ twins. Assuming that 81% of the first carriers among the first carrier discordant twins are S. aureus
persistent carriers, we find a heritability estimate of 20.5%, (assuming an ADE model, which is the best fitting nonparsimonious model for these predicted tables). This heritability estimate is not significantly statistically different from 0 and is quite similar to the heritability estimate for S. aureus
colonization of 12%.
Individuals carry the same strain over time in more than half of cases, as we observed among the first-time concordant twins with a long-term carriage of the same clonal lineage in approximately 55% of the individuals. Other studies have implicated that only carriers of the same clone should be considered truly persistent carrier [24
] because change of nasal isolate could also implicate intermittent carriage; we therefore also investigated whether persistence of the same clonal isolate over time was influenced by genetic factors. However, assuming a 55% chance of same clonal lineage among first carrier twins of discordant pairs yielded results similar to those seen for first-time carriers and persistent carriers, with no statistically significant genetic component, and only a modest heritability estimate of 29.6% (95% CI, 0%–62.8%), although there was a trend with higher heritability estimates in the analyses of S. aureus
persistent and lineage carriers.
Previous studies have suggested that host genetics are important determinants of S. aureus
nasal carriage. Different results have been obtained from candidate gene case–control studies with both genetic association to glucocorticoid receptor gene [27
] and genes encoding interleukin 4, complement factor H, C-reactive protein [28
], and HLA [29
] and no genetic association to the Vitamin D receptor [30
] or beta-defensins [31
]. Neither of the former studies has so far been confirmed in other populations. Our present study does not preclude such findings, and there certainly may be genetic factors weakly associated with carriage.
The present study, although the largest so far, is still limited in power to identify modest heritability. The number of samplings required to identify persistent carriers and noncarriers has been debated over time, and the more samplings that are performed, the more accurate the classification [22
]. However, due to limited access to test persons, this study relied on only 2 samplings, similar to Olsen et al [9
], which has been shown to have a sensitivity of 95.5% and specificity of 88.8% in the detection of persistent carriers [22
]. Another limitation of the study may be the age groups investigated because genetic association may be age dependent as carriage in general is. Carriage among elderly people appears to differ from that among younger people [23
What may determine S. aureus
carriage if the strains themselves alone cannot determine carriage [19
] and there is little heritability? Gene–environment interactions appear to be the most likely determinants, as has recently been shown in a large Norwegian study in which smoking and vitamin D levels were shown to be associated with S. aureus
nasal carriage [9
]. The microbial community may be another important factor. A recent study implicated that nasal carriage of specific strains of Staphylococcus epidermidis
appeared to exclude carriage of S. aureus
], and another study concluded that nasal microbiomes may be grouped into 12 supergroups, with S. aureus
present in 2 but absent in others [35
]. Thus, limited direct host heritability together with these intriguing recent findings suggests a very complex background for S. aureus
nasal carriage, and further studies in the area of micro- and macro-environment are clearly warranted.