According to the sample size estimation formula of linear correlation analysis (see Formula 1), and the correlation coefficient r = 0.351 between serum TC and age in FH patients obtained in this study, substituted into the formula, the theoretical sample size n = 81, our actual sample size n = 103. It can be seen that the sample size of this study has exceeded the minimum required sample size, indicating that this study can guarantee the reliability of the conclusion.
In fact, after analyzing the correlation between age and the serum TC level in the FH group, we also analyzed the correlation between age and the serum LDL-C level through Spearman correlation analysis, partial correlation analysis, and multiple regression analysis following the same path and obtained the same results. In other words, age was found to be an independent factor that influenced serum TC and LDL-C levels in the FH group. It is known that age is an independent risk factor for many diseases, including hypertension and a variety of tumor diseases, and with increasing age the incidence of various diseases gradually increases. By analyzing the relationship between serum TC level and age in FH families, the results of this study also showed a positive correlation that was consistent with our previous conjecture. Therefore, it is reasonable to believe that the serum cholesterol level, which has been proposed by previous studies to be an independent risk factor for the occurrence of CVD in patients with FH , would increase the exposure time (also age), accelerating the increases in CVD risk in patients with FH. Michael J Domanski et al. evaluated the relationship between the areas under the LDL-C and age curves and the risk of developing CVD in these patients using data from the Coronary Artery Risk Development Study in Young Adults. It was found that both the areas under the LDL-C and age curves and the time course of area accumulation were significantly correlated with the risk of a CVD event . It can be seen that the risk of a CVD event depends on the time course of area accumulation. Therefore, this study has important implications for the control of TC and LDL-C in early life and the prevention of CVD in patients with FH. This was in line with the results of this study, which showed that the FH group had a higher family history of CHD than the control group.
Genotypes and phenotypes are the main causes of ASCVD in FH patients , and several vast cohort studies have confirmed that age is an independent risk factor for CVD in FH patients [10-13], while the results of this study indicate that age is an independent influencing factor for serum TC and LDL-C elevation in FH patients. The clinical significance of this study lies in the following points: On the one hand, the time accumulation effect of serum cholesterol reveals that age is an independent risk factor for ASCVD in FH patients; on the other hand, it is consistent with the spatial–temporal expression theory of genes for inherited diseases [19, 20]. That is, with an increase in age, the risk of disease gradually increases. In conclusion, early identification and the early application of cholesterol-regulating therapy should be encouraged to reduce the risk of temporal cumulative effects of serum cholesterol in patients with FH. At the same time, we should encourage the screening of blood lipid levels in those with abnormal blood lipids and pay more attention to the early identification of FH. In support of this, Lidewij et al. highlighted a shift in thinking from adult screening to childhood screening . In view of the rapid development of genetic and molecular diagnostic technologies in recent years, the detection rate of FH in patients with dyslipidemia in China has also been increasing [5, 10]. Therefore, we call for early screening and early intervention for FH patients. Providing statins and other lipid-regulating drugs to FH patients in their early life will be of great significance for effectively preventing early CVD events.
Although gender differences may also lead to different lipid levels in FH patients [22, 23], the current study showed show that serum TC value still presents an obvious positive correlation with age after adjusting for gender, and age accumulation will be the increase in blood lipid TC, whether the patients is male or female. Therefore, gender differences will not lead to an increase in lipid levels in FH patients or age-related changes. Additionally, smoking is considered to be a risk factor for cardiovascular diseases, and it is also believed to cause an increase in serum lipids such as TC, LDL-C and TG [24-26]. However, in our study, compared with the male non-smoking group, the serum TC concentration in the male smoking group decreased with age. Although this trend was not statistically significant (possibly limited by sample size), it still suggested that we cannot ignore the possibility of reduced TC values due to smoking, since smoking has been reported to be associated with lower cholesterol, which reduce the risk of death from CVD . In addition to smoking, some factors that affect the progression of atherosclerosis, such as alcohol consumption, Lp(a), glucose metabolism, blood pressure, and the use of lipid-regulating drugs, also affect lipid metabolism and lead to changes in the TC level. Nevertheless, after adjusting for these influencing factors in this study, the results also showed an independent association between age and cholesterol level in the FH group. They also suggested that age was an independent risk factor for serum cholesterol level change in the FH group. Moreover, this was not seen in the control group. The results of this study showed that serum TC in the FH group was also significantly positively correlated with SBP, but not in the control group. This suggested a mutual interaction between cholesterol and arterial blood pressure in the FH group that was independent of the normal population. In support of this, it was found that elevated serum cholesterol levels led to decreased arterial wall compliance, resulting in increased cardiac after-load and increased SBP due to the accelerated return of systolic arterial waves from the periphery, which further led to left ventricular over-pressure [28, 29]. Additionally, the positive correlation between age and SBP under the action of this mechanism further expands the age exposure effect of cholesterol-induced atherosclerosis, which could explain, to some extent, why FH patients have a risk of CVD events that is tens of times higher than that of the general population . It is worth mentioning in this study that population characteristics showed that FH men accounted for only 39%, which does not match the current situation: that the proportion of men in the Chinese population is much higher than that of women. Indeed, as an autosomal genetic disease, FH has a 50/50 ratio of men to women in the population. Thus, we have to consider the possibility of early death in men with FH [31, 32], which further underlines the need for the cascade screening of family members with known indicator cases.
With the progression of urbanization, family members are often distributed in different places with different environments and have differences in their way of life and diet, which may mask some clinical characteristics of FH. For example, xanthoma and lipid profile changes are not obvious [5, 33], which increases the difficulty of collecting detailed information regarding FH. The collaboration of clinical, public health, and advocacy groups should therefore be encouraged to promote genetic screening for FH . Our current research, through the strict screening of raw data, was based on a relatively small number of samples. Therefore, further large cohort studies are necessary to clarify the correlation between age and serum TC among subgroups of patients with FH. In addition, because FH has no independent code in the World Health Organization's international classification of diseases, it is difficult to estimate the number of people diagnosed with this disease or the proportion of people with FH in the general population. In the current situation, where there still exists a deficiency in the diagnosis and treatment of FH, there is an urgent need to implement screening and early treatment for this extremely high-risk disease .
Our study has some limitations. First, genetic diagnosis was not performed in FH patients who were diagnosed according to the DLCN criteria. Second, although our actual sample size exceeds the theoretical sample size obtained according to the calculation formula, it is still necessary to further verify the investigation with a larger sample size. Third, we excluded participants younger than 18 years old, which might lead to selection bias and limit the extrapolation of our results.