Replication and meta-analysis of previous genome-wide association studies confirm vezatin as the locus with the strongest evidence for association with endometriosis.

STUDY QUESTION: Is it possible to replicate the genetic association of single nucleotide polymorphisms (SNPs) rs13394619, rs4141819, rs7739264, rs17694933 and rs10859871 in five genetic loci previously identified as associated with endometriosis in an Italian Caucasian population?

SUMMARY ANSWER: SNP rs10859871 near the vezatin (VEZT) gene was found to be significantly associated with endometriosis in general while SNPs rs17694933 and rs4141819 were associated with Stage III/IV and ovarian disease, respectively.

WHAT IS KNOWN ALREADY: Endometriosis represents a complex disease in which the phenotypic manifestations are influenced by both genetic and environmental factors. Recent genome-wide association studies (GWASs) have allowed to identify some SNPs associated with the predisposition to the disease. A meta-analysis published in 2014 combined results from GWAS and replication studies showing that of the nine loci found to be associated with the disease in at least one of the studies, six (rs7521902, rs1270667, rs13394619, rs7739264, rs1537377 and rs10859871) remained genome-wide significant while two others (rs1250248 and rs4141819) showed borderline genome-wide significant association with more severe disease.

STUDY DESIGN, SIZE, DURATION: Allele frequencies of selected SNPs (rs13394619, rs4141819, rs7739264, rs17694933 and rs10859871) were investigated in 305 women with laparoscopically proven endometriosis, 285 laparoscopic controls and 2425 healthy, blood donor controls from the general population. A meta-analysis with previous data was also conducted.

PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 590 women who underwent endoscopic surgery were enrolled in the study and a blood sample was collected. After DNA extraction, genotype was obtained using Taq-Man pre-designed assay. Genotype data from healthy blood donor women were obtained from an existing genotype bank.

MAIN RESULTS AND THE ROLE OF CHANCE: A statistically significant association with endometriosis was found for SNP rs10859871, close to the VEZT gene, compared with both general population [odds ratio (OR) = 1.43, 95% confidence interval (CI): 1.20-1.71, P = 6.9 × 10(-5)] and laparoscopic controls (OR = 1.58, 95% CI: 1.24-2.02, P = 2.1 × 10(-4)). Meta-analysis with previous data confirmed the rs10859871 SNP as that with the strongest evidence for association with endometriosis (OR = 1.19, 95% CI: 1.15-1.24, P = 7.9 × 10(-20)). A further meta-analysis conducted using data from Stage III-IV endometriosis resulted in stronger genome-wide significant effect sizes for four out of the five SNPs tested.

LIMITATIONS, REASONS FOR CAUTION: The inability to confirm all previous demonstrated associations considering all stages of endometriosis may be due to a lack of statistical power and differences in the definition of cases included.

WIDER IMPLICATIONS OF THE FINDINGS: The associations with the SNPs identified so far have been obtained with a relatively small sample size supporting a limited heterogeneity across the various datasets. This represents an important advance in the identification of genetic markers of this disease.

STUDY FINDING/COMPETING INTERESTS: No funding to declare. The authors have no competing financial interests in relation to the content of this research paper.