Population heterogeneity may help to explain why results among genetic studies of rs1800795 and PTB association were inconsistent. Indeed, HapMap data showed that the frequency of the derived C allele of rs1800795 is 0 in the YRI, CHB, and JPT populations, while it is 0.53 in the CEU population . In other population samples, the C allele frequency is consistently high in people of European descent, ranging from 0.35 in Tuscans from Italy to 0.65 in a European-American sample ascertained for coronary artery disease. In contrast, the C allele frequency is consistently low in East Asian (highest in Chinese in Metropolitan Denver, Colorado, 0.006) and African (highest in Maasai in Kinyawa, 0.049) populations. The frequency in admixed populations varies. The Programs for Genomic Applications' African-American panel reported a frequency of 0, a population with African ancestry in Southwest USA had a frequency of 0.092, while a population with Mexican ancestry in Los Angeles had a frequency of 0.16 . The allele frequency difference of 0.53 between people of European descent and populations in other continents falls within the 5% tail of continental allele frequency differences for a large panel of common SNPs (see Additional file 2) and is thus statistically significant. This variation suggests that population heterogeneity could have strong effects for this polymorphism. After stratification by population, our subgroup analysis showed that the rs1800795 CC genotype is significantly protective against PTB in women of European descent, but not in other heterogeneous populations (Figure 1). In the latter group of populations, ancestral diversity is likely to obscure any potential genotype-phenotype association, emphasizing the importance of addressing underlying population structure in genetic studies.
A regression analysis reveals a negative relationship between OR and CC genotype frequency (see Additional file 3). The result is significant in maternal studies. This matches the finding that in European populations, which have high CC genotype frequencies, the CC genotype has a protective effect against PTB; while in ethnically heterogeneous populations, which have low or zero CC genotype frequencies, no protective effect could be observed.
In all these studies, all ancestry was self-reported. Unfortunately, genetic admixture data confirming self-reported ancestry are not available. However, previous studies have demonstrated nearly 100% concordance between self-reported race/ethnicity and specific genetic ancestry markers among pregnant women enrolled in clinical studies . Although we cannot exclude the possibility of misclassification of some women, we infer a similar high rate of concordance between self-reported race/ethnicity and genotyped race/ethnicity among women enrolled in this meta-analysis.
It is intriguing that rs1800795 has such large frequency differences across different populations. In addition to its association with PTB, this SNP has been shown to be associated with many other diseases, such as juvenile rheumatoid arthritis , susceptibility to Kaposi sarcoma , metabolic syndrome [50–54], and inflammatory bowel disease . However, there is no strong evidence of natural selection near rs1800795 [56–58].
Methodological differences may have contributed to the inconsistent results among prior studies. Most studies compared CC vs. CG+GG, but some reported GG vs. CG+CC and others compared individual alleles rather than genotypes. Because of the evidence that CC genotypes cause significantly lower serum IL-6 concentrations than do the CG or GG genotypes , we uniformly meta-analyzed CC versus CG+GG for all studies, providing a consistent approach to the genotype-phenotype correlation.
Another goal of our meta-analysis was to increase statistical power by increasing the sample size. For women of European descent, we pooled 790 PTB cases and 2,324 controls, which significantly increased the sample size relative to any previous individual study. With this sample size, we have 97.72% power to detect an OR of 0.68 at the 0.05 significance level. Under the same conditions, the single study with the largest case sample size  had only 51.38% power.
The purpose of this meta-analysis is to pool peer-reviewed published studies that qualify our inclusion criteria (see Additional file 1). Even though there is no evidence of publication bias (Figures 3 and 4), a potential limitation of our study is that some findings of no association between rs1800795 and PTB may not have been reported in the literature and therefore could not be included in our meta-analysis.
In addition to population structure, phenotypic heterogeneity is another problem that may undermine studies of any complex diseases. In this meta-analysis, we stratified by population, included the data from earlier GA cutoffs, and selected earlier PTB cases. Therefore, our conclusion that the CC genotype of rs1800795 in the IL6 promoter is protective against PTB is limited to European women with early PTB. Our sensitivity test showed that PPROM may be a confounding factor. Besides early PTB and PPROM, further refinement of PTB phenotype, such as a sub-classification by placenta abruption, cervical insufficiency, and other factors, may also help to reduce phenotype heterogeneity.