Prevalence Of The JAK2V617F Mutation and Associated Risk Haplotype and Determination Of Demographic and Lifestyle Risk Factors In The US Population, Nhanes 1999-2002

In 2008, the WHO released new diagnostic criteria for polycythemia vera (PV), which included testing for the JAK2V617F mutation. The JAK2V617F mutation is associated with PV and other myeloproliferative neoplasms (MPN) and is present in approximately 97% of all PV cases. A germ-line haplotype, referred to as 46/1, has been reported to be associated with acquisition of JAK2V617F. The exact hierarchical position of JAK2V617F and the risk haplotype in the pathogenesis and phenotypic variability of the MPNs remains unclear. Since the current literature on the prevalence of the JAK2V617F mutation in non-MPN populations is limited, the objective of our study was to determine the JAK2V617F prevalence and the 46/1 risk haplotype in the general, non-institutionalized US population. We evaluated demographic information, lifestyle factors, and body burden levels of environmental contaminants to determine if they correlated with JAK2-status.

The NHANES surveys are conducted by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC). In order to obtain a representative sample of the civilian non-institutionalized US population, the surveys consisted of a complex multistage sampling design including questionnaire and examination components, as well as the use of blood specimens for a wide variety of analytical purposes. Consent for use of blood specimens for genetic research purposes is permitted in participants aged 20 years and greater. DNA was collected from 7,839 participants (NHANES, 1999-2002). To detect JAK2V617F, real-time quantitative polymerase chain reaction (qPCR) was used for screening. All JAK2V617F(+) samples were confirmed by an independent laboratory. Two tagged single-nucleotide polymorphism (SNPs), rs12340895 and rs12343867, were genotyped using allelic discrimination. The risk haplotype was empirically determined in JAK2V617F(+) specimens using mutation specific amplification followed by single allele sequence based typing. The mutation and risk haplotype prevalence was determined and frequencies calculated using race/ethnicity, age, and sex as variables.

The JAK2V617F mutation prevalence was 0.62% in the US general population. Age was the only demographic factor that was significantly associated with the JAK2V617F mutation (p-value = 0.0015). Of the 65 participants who tested positive for JAK2V617F, 10% were between the ages 20-39, 32% were 40-59, and 58% were 60 years and older. Diagnosis of a blood cancer, leukemia, or other related cancer was not reported in any of the JAK2V617F(+) participants. However, PV and other MPNs were not designated as reportable cancers until 2001, and the questionnaire was administered in 1999-2002. After adjusting for race/ethnicity and age, exposure to environmental contaminants was not found to be associated with the JAK2V617F mutation. The haplotype tagging SNP analysis showed a significant association with JAK2V617F(+) participants versus the JAK2V617F (-) participants. However, when the haplotype was empirically determined with single allele sequencing of the informative heterozygous JAK2V617F(+) participants (N=40), the mutation was detected on the 46/1 haplotype in only 55% of the JAK2V617F(+) chromosomes, which was lower than previously reported in MPN populations. The JAK2V617F mutation was also detected on the common non-risk haplotype (T-C) in 25% of the chromosomes and on less common haplotypes (C-C, T-G) in 21% of the chromosomes.

This is the only study to examine the prevalence of JAK2V617F in the US general population. When analyzing a large population-based data set, the analysis showed that the JAK2V617F mutation is present in persons who did not report having an MPN. The incidence of the JAK2V617F was directly correlated with age, and was consistent with the known age of onset of MPNs. Whether this group of individuals has a pre-clinical form of an MPN or the detection of JAKV617F is a transient phenomenon remains unknown. The frequency of the two haplotype-tagging SNPs in the normal population was similar to that previously reported. The risk haplotype however, was not more commonly seen associated with JAK2V617F, indicating that the JAK2V617F may not arise preferentially on the 46/1 risk haplotype. These studies provide important epidemiological information about the occurrence of JAK2V617F in “normal” individuals.

No relevant conflicts of interest to declare.