Cytokine SNPs: Comparison of allele frequencies by race and implications for future studies☆
Introduction
Differences by race in incidence for diseases associated with inflammation suggest that there may be underlying racial differences in inflammatory pathway genes. For example, there is racial variation in the incidence of several autoimmune diseases such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS), and infectious diseases such as tuberculosis, septicemia, and HIV/AIDs [1]. The incidence of several types of cancer associated with inflammation and/or chronic infection, including colorectal, liver and bile, lung and bronchus, prostate, and stomach, is also elevated in African Americans relative to Caucasians, especially among men [2]. Finally, several markers of inflammation, including C-reactive protein and homocysteine, have been shown to be associated with cardiovascular disease and to be elevated in African Americans [3].
One set of markers of inflammatory pathways are cytokines and cytokine receptors. Differences in protein expression of IL-6 SR between healthy, older African Americans and Caucasians have been shown in at least one study [4]. While few studies have examined the relationship between cytokine protein expression and race, studies investigating the association between cytokine single nucleotide polymorphisms (SNPs) and race have been previously published [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. These studies have focused on SNPs in only a few cytokines including tumor necrosis factor (TNF), IL1A, IL1B, IL6, IL2, IFNG, IL18, and IL10.
The consensus from these published reports is that among African Americans there is an increase in the frequency of alleles associated with high production of pro-inflammatory T helper type I (TH1) cytokines and low production of anti-inflammatory T helper type II (TH2) cytokines. These results suggest the potential for systemic inflammatory upregulation in African Americans. Specifically, IL1A −889T, IL1B −3957C and −511A, IL6 −174G, IL18 −137G, TNFA −308A, and IFNG −874 alleles are associated with an increase in cytokine production and are found more frequently among African Americans [7], [9], [11], [13]. IL10 −592A, −819T, and −1082A alleles, associated with decreased IL-10 production, are also found more frequently among African Americans [7], [9], [13], [15]. In contrast, another study reported that the pro-inflammatory IL2 −330G allele, associated with increased IL-2 production, was found less frequently among African Americans than among Caucasians [9]. Furthermore, some studies have found no relationship between allele frequency of the TNFA −308 polymorphism and race [7], [9], [11].
To expand this research, we examined the association between race and 70 cytokine and cytokine receptor polymorphisms in 26 inflammation-related genes among African American and Caucasian women in a large, population-based study.
Section snippets
Study participants
Subjects were population-based healthy controls obtained through a study comparing controls frequency matched on age and self-reported race to women with non-small cell lung cancer (NSCLC) [19]. Control participants were women without a history of NSCLC between the ages of 18 and 74 living in the Detroit metropolitan area and were identified through random-digit dialing. Of the households that completed the eligibility screening questionnaire, 69.6% (N = 575) participated in the interview. 209
Sample
Our sample included 103 population-based African American women (21.3%) and 380 Caucasian (78.7%) women.
Cytokine and cytokine receptor SNPs
Five (IL3-rs40401; IL12B-rs730690; TNF-rs3093661; IL10RA-rs9610; TGFB1-rs1800471) and two (IL8RB-rs1126579; IFNGR1-rs11914) out of 83 cytokine and cytokine receptor SNPs on the cancer SNP panel were not in Hardy–Weinberg equilibrium for African Americans and Caucasians, respectively. For an additional six SNPs (IL8-rs2227549; IL8RB-rs1126579; IFNGR1-rs3799488; TNF-rs3093661; LTA-rs3093546,
Discussion
We observed allelic frequency differences by race for 52 of the 70 SNPs meeting criteria for analysis. General genotypic frequency differences between African Americans and Caucasians were observed for 49 of these 52 SNPs. Significant trends in genotypic frequency by race were found for all of these 52 SNPs. While the same haplotypes were constructed for African Americans and Caucasians for all genes for which multiple SNPs were analyzed, there was marked variation in haplotype frequency by
Conclusions
We found that cytokine and cytokine receptor SNP allelic, genotypic and haplotype frequencies varied significantly by race. These results suggest that future analyses of the associations between cytokine and cytokine receptor SNPs and disease risk and prognosis should at least consider self-reported race, if not more complex measures such as race and socioeconomic status or genetic ancestry. Additionally, the conclusion by Ness et al. [13] that African Americans have an increased allele
Conflict of interest
None.
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This research was funded by NIH Grant R01-CA87895 and Contracts N01-PC35145 and P30CA22453.