Human Cytomegalovirus and Risk of Incident Cardiovascular Disease in UK Biobank

To The Editor—Hamilton et al’s [1] analysis of the association between cytomegalovirus (CMV) infection and incident cardiovascular disease (CVD) in 8531 UK Biobank (UKBB) participants is stronger than most observational studies of the CMV-CVD association. There was careful adjustment for age, sex, socioeconomic position, and cardiovascular risk factors. Neither inflammatory markers nor prior CVD were included as covariates, which would have been inappropriate. However, although the authors acknowledge that sections of the population are underrepresented in the UKBB, the potential impact of this on their main results is not discussed. Nonrandom sample selection can lead to spurious in-sample associations, a form of collider bias. A schematic example is presented in Figure 1A, in which individuals with high CVD risk or high CMV exposure are less likely to be sampled. This induces a negative correlation between CVD and CMV in the sample that does not hold in the broader population. To evaluate the extent to which collider bias might explain Hamilton et al’s [1] null findings, we compared CVD risk and CMV exposure in UKBB participants to that in more representative population samples. UKBB is a highly selected sample. Of 9 million 40to 69-year-olds invited to participate, only 5.5% enrolled [2]. The sample is enriched for individuals of higher socioeconomic position and white ethnicities (94.6% vs 91.3%) [2]. UKBB participants are less likely to be obese, drink less alcohol, and are less likely to smoke compared with more population representative respondents to the Health Survey for England (HSE) [2]. All-cause mortality rates among UKBB participants aged 70–74 years are 46% and 56% lower in men and women, respectively, than in the general population of England and Wales [2]. UKBB participants have lower selfreported CVD prevalence at enrollment [2], lower exposure to CVD risk factors [2, 3], and CVD mortality rates that are 2.9-fold lower than individuals of a comparable age in the HSE [3]. Previous analyses have shown that these selection effects can attenuate risk factor-CVD associations. For example, for hypertension, the hazard ratio for CVD mortality is 1.9 in UKBB and 2.6 in HSE [3]. Because CMV is more prevalent in those of lower socioeconomic position [4, 5], it is plausible that UKBB participants have lower CMV exposure than the general population. Cytomegalovirus seroprevalence appears lower in UKBB than in participants from a 2002 serosurvey using blood samples from individuals accessing National Health Service (NHS) care in England and Wales [6]. Age-specific CMV seroprevalence in the serosurvey was only presented graphically, preventing quantification of these differences. Comparing the age-specific CMV seroprevalence reported by Hamilton et al [1] with that among pregnant women in the Born in Bradford (BiB) birth cohort [7] suggests markedly lower CMV prevalence in UKBB. Cytomegalovirus seropositivity is more prevalent in older individuals, which is partly a cohort effect, with most incident infections occurring in individuals under the age of 40 years [6]. Seroprevalence in 40to C O R R E S P O N D E N C E