The distribution of P/LP variants and the carrier and prevalence rates of each type of porphyria vary by ethnicity due to genetic heterogeneity, making it complex to assess. Data on the genetics of porphyria currently come mainly from individual countries in Europe and the Japanese population in Asia. Studies on autosomal dominant porphyria have produced various findings. Grandchamp B's review on AIP5 suggests that asymptomatic heterozygotes for the AIP gene variants may be around 1/2000, while Hugo Lenglet6 states that the lowest estimate of the prevalence of AIP in the general population is 1/1299. The prevalence of AIP is extremely low, with a general population prevalence of approximately 0.5%-1%.6The prevalence of AIP in Europe is 5.9/10000007, while in Japan it is 1.5/100000.8 Our team's previous findings also predicted that the prevalence of the pathogenic HMBS variant in the Chinese population would be 1/1765.9 PCT is the most prevalent type of porphyria in Europe, with a prevalence of 1/10,000.10 Meanwhile, the estimated prevalence of HCP in Europe is 0.2/10000000.7 HCP is more prevalent in the South African population, with a prevalence of about 1/100000,11 while VP is rarer in Europe, with a prevalence of 3.2/1000000.7 The prevalence of VP in Finland is 2.4/1000000.7 When it comes to autosomal recessive porphyria, the overall prevalence of ADP, CEP, and HEP is 0.13/10000000, with CEP accounting for more than half.7 The prevalence of EPP varies significantly among different populations, largely due to the influence of the low expression allele IVS−48-C-T. EPP is found worldwide at a prevalence ranging from 1/75,000 to 1/200,000,12 with a prevalence of 9.2/1,000,000 in Europe.7 There is a lack of data from large-scale population-based genetic studies in these regions, with reports limited to case reports, small group studies, and family studies. The limited diagnosis, treatment, and genetic research on porphyria within the Chinese medical system result in a high rate of clinical misdiagnosis and pose challenges in treatment, sometimes even endangering the patient's life.
In this study, we utilized the ChinaMAP genetic database, a reliable and scientific database suitable for the Chinese population. This marks the first extensive genetic study of porphyria in the Chinese population, offering dependable genetic reference data for genetic screening, preventive interventions, early diagnosis, and the management of patients with latent porphyria in China. Simultaneously, an analysis of genetic data on porphyria in the Chinese population was conducted and compared with that of other ethnic groups to gain a better understanding of its distinct characteristics. This serves as a valuable reference for porphyria-related research in the Chinese population.
In ChinaMAP, a total of 23 P/LP porphyria-associated genetic variants were identified in seven genes. The predicted carrier and prevalence rates for each porphyria type in the Chinese population were then calculated based on H-W equilibrium. The predicted prevalence of EPP in the Chinese population was the highest among the 10 ethnic groups, whereas the predicted carrier and prevalence rates of the other porphyria were moderate or low. We have found 12 P/LP variants in the porphyria-associated gene that are specific to the Chinese population, in comparison to gnomAD Genome V3.0. In our previous study, we classified the HMBS c.1064G > A (p.Arg355Gln) locus as VUS-P. However, in our current study, after reviewing recent literature, we found that Hugo Lenglet confirmed the presence of this locus resulted in almost zero activity of HMBS. As a result, we added PS3 evidence for this locus according to the ACMG guidelines and upgraded it to LP in this study. Figure 5 illustrates the distribution of P/LP variant sites of porphyria-related genes in ChinaMAP across the 10 populations studied. From the above, it can be seen that the variant profiles of porphyria-associated genes differ between the Chinese population and other ethnic groups.
When comparing the allele frequency of the FECH low-expression SNP locus c.315-48T > C in different ethnic populations, the Chinese population comes in second place. Figure 6 displays the distribution of this locus among the various ethnic groups. We conducted calculations to determine the expected prevalence of compound heterozygotes for the FECH P/LP variant in different ethnic groups. Additionally, we calculated the prevalence of compound heterozygotes for the low-expression SNP locus c.315-48T > C and the P/LP variant in various ethnic groups. We then combined the two sets of data to estimate the total prevalence of EPP in different ethnic groups, as shown in Table 3. Our findings suggest that the distribution of the FECH low-expression SNP locus c.315-48T > C in the population significantly influences the population prevalence of EPP. This underscores the importance of considering the impact of this SNP locus in genetic studies of porphyria. The Chinese population has the second highest gene frequency of this locus among the 10 ethnic groups, and this directly contributes to the highest predicted overall prevalence of EPP among the 10 ethnic groups. Xiao-Fei Kong and colleagues genotyped 52 voluntary Han Chinese individuals without porphyria and found that the allele frequency of the FECH low-expression SNP locus c.315-48T > C is 41.35% among normal Han Chinese individuals.13 According to the reference ChinaMAP database, this locus has a gene frequency of 31.79% in the general Chinese population. In comparison, ChinaMAP is a biobank that focuses on Chinese populations and was formed by conducting whole genome sequencing on 10,588 healthy Chinese individuals. Nevertheless, the current literature on EPP in the Chinese population is limited to case reports, family lineage studies, and reports of novel loci. There is a lack of large-scale epidemiological investigations of EPP in the Chinese population.
The ChinaMAP database provided a significant number of Chinese population-specific variants, highlighting the genetic traits of porphyria within the Chinese population in comparison to the gnomAD database. Although GnomAD did not include porphyria-associated P/LP variants in Chinese populations and East Asian populations, reports of such variants have been retrieved in East Asian populations such as China, Japan, and Thailand. Additionally, the ChinaMAP database included 23 porphyria-associated P/LP variants. The predicted prevalence of AIP in the Chinese population was significantly different from that in the Japanese population, and the allele frequency of the FECH low-expression SNP locus IVS-48-C-T in the Chinese population also differed significantly from that in the Japanese population. This suggests that using data from the Japanese population as a proxy for data from the East Asian populations in some genetics studies lacks rigor and can sometimes lead to errors in the results. The prevalence and distribution of porphyria-associated variants differ significantly across ethnic groups. Certain mutation sites are found in multiple ethnic populations, while others are unique to specific groups. Some ethnicities have a wide range of mutation sites, while others have very few or none at all. These differences reflect the significant genetic diversity in porphyria and are associated with higher rates of specific types of the condition in certain regions and ethnic groups, particularly those affected by founder effects. As a result, these groups have higher carrier and prevalence rates of certain forms of porphyria compared to other populations.
Understanding the genetic characteristics of each type of porphyria in various racial populations is crucial for effectively managing patients of different races. The majority of porphyria genetics studies are retrospective and based on small patient samples, with few large-sample prospective studies using population-based genetic databases. The ChinaMAP database, cited in this research, is a cohort study that encompasses various regions and ethnicities in China. It provides a vast resource for genetic studies in Chinese, even in East Asian populations, ensuring the precision and dependability of the experiments. The ChinaMAP database serves as an exclusive resource and guide for detecting and confirming P/LP variants in genes related to porphyria.
For this research, we opted for a reliable genetic database that applies to the Chinese population. This database helps to fill in some of the gaps in the study of porphyria genetics in Chinese populations and underscores their unique genetic features. It also assists in exploring the population-specificity of porphyria.14 In a certain sense, the ChinaMAP database complements the gnomAD database.
In this study, we estimated the expected carrier rate of the pathogenic AIP variant in the Chinese population to be 1/1059, aligning with the results of Grandchamp B and Hugo Lenglet. The anticipated prevalence of AIP in the Chinese population ranges from 1/211800 to 1/105900, with a penetrance of 0.5–1%. Nevertheless, the penetrance of all porphyrias in the Chinese population has not been retrieved for reference, highlighting the significance of ongoing follow-up and management of porphyria patients.
Our study still has some limitations. Firstly, the variants in this study were rated according to the ACMG guidelines. As the guidelines are updated and diagnostic and treatment standards improve, as well as experimental techniques develop, many of the VUS-P variants identified in this study may be confirmed as P/LP variants in the future. Secondly, the data in ChinaMAP were sourced from natural populations with good metabolism-related traits across China,1 and gnomAD also excluded individuals known to have severe pediatric diseases and their first- and second-degree relatives. Furthermore, we conducted our research under the assumption that ethnic groups adhere to Hardy-Weinberg equilibrium. However, it is important to note that certain groups, such as consanguineous family lines, may not conform to this assumption. As a result, the actual prevalence of porphyria in these specific groups may be greater than what is predicted based on Hardy-Weinberg equilibrium. To sum up, our current estimates for the carrier rate and prevalence of porphyria-associated pathogenic mutations should be regarded as "minimal." Since porphyria has an extremely low penetrance, determining its prevalence in the population by using predicted carrier and prevalence rates necessitates taking into account the penetrance of different types of porphyria. Unfortunately, no available data on the penetrance of porphyria applicable to the Chinese population was found. As a result, the carrier and disease rates for porphyria that we calculated are purely theoretical genetic values. To accurately predict the prevalence in the Chinese population, we require support from large-scale epidemiological study data.