No association between celiac disease and female infertility: evidence from Mendelian randomization analysis

Several guidelines and reviews recommend screening for celiac disease (CeD) in women with unexplained infertility or suggest an association between CeD and infertility. However, research in this field is contradictory (1Hogen Esch C.E. Van Rijssen M.J.L. Roos A. Koning F. Dekker F.W. Mearin M.L. et al.Screening for unrecognized coeliac disease in subfertile couples.Scand J Gastroenterol. 2011; 46: 1423-1428Crossref PubMed Scopus (0) Google Scholar). We conducted this Mendelian randomization (MR) study to strengthen the causal assessment of CeD-infertility association. Figure 1 shows the study design. Single-nucleotide polymorphisms (SNPs) strongly associated with CeD were extracted from a genome-wide meta-analysis including 12,041 CeD cases and 12,228 controls (2Trynka G. Hunt K.A. Bockett N.A. Romanos J. Mistry V. Szperl A. et al.Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.Nat Genet. 2011; 43: 1193-1201Crossref PubMed Scopus (627) Google Scholar). We pruned these genetic variants to reduce influence of linkage disequilibrium, leaving 58 SNPs as instrumental variables. We found no weak instruments (Fminimum >30 and Faverage = 233). Given the complexity of major histocompatibility complex (MHC) gene in health, we used secondary genetic instruments comprising 37 SNPs not within MHC. The 58 and 37 SNPs included explained approximately 45.3% and 6.5%, respectively, of the genetic variance of CeD (3Yuan S. Jiang F. Chen J. Lebwohl B. Green P.H.R. Leffler D. et al.Phenome-wide Mendelian randomization analysis reveals multiple health comorbidities of coeliac disease.EBioMedicine. 2024; 101: 105033Abstract Full Text Full Text PDF Scopus (3) Google Scholar).Detailed information on SNPs is shown in online supplements. Summary-level data on female infertility were obtained from FinnGen (14,759 cases and 111,583 controls) and the UK Biobank (3,038 cases and 194,024 controls). Female infertility was defined according to the International Classification of Diseases codes (ICD-10 N97, excluding N97.4; ICD9 628.0,2-4,8-9; ICD8 628). Single-nucleotide polymorphisms-infertility associations were computed using regenie method and adjusted for age, 10 principal components, and genotyping batch in both studies. The inverse variance weighted method under the multiplicative random effects was used as the primary analysis and supplemented by the weighted median, MR-Egger, and MR-PRESSO methods. We used Cochran's Q values to assess heterogeneity and MR-Egger intercept test to assess horizontal pleiotropy. The analyses were performed with TwoSampleMR package in R (version 4.1.1). The association with a 2-sided P<.05 was deemed significant. Genetic predisposition to CeD was not associated with risk of infertility among women in either FinnGen or UK Biobank (Fig. 2). The null association persisted in the sensitivity analyses and the analysis using SNPs not within MHC gene region (Fig. 2). We found low heterogeneity in either of the analyses (Cochran's Q < 51), no indication of horizontal pleiotropy (PMR-Egger intercept>.71), or no SNP outliers. The lack of association between genetic liability to CeD and infertility in our study is consistent with 2 large case series of women with unexplained infertility (1Hogen Esch C.E. Van Rijssen M.J.L. Roos A. Koning F. Dekker F.W. Mearin M.L. et al.Screening for unrecognized coeliac disease in subfertile couples.Scand J Gastroenterol. 2011; 46: 1423-1428Crossref PubMed Scopus (0) Google Scholar, 4Grode L.B. Agerholm I.E. Humaidan P. Parkner T. Bech B.H. Ramlau-Hansen C.H. et al.Unrecognised coeliac disease among men and women undergoing fertility treatment: a screening study.United European Gastroenterol J. 2018; 6: 1477-1484Crossref PubMed Scopus (0) Google Scholar). When Grode et al. (4Grode L.B. Agerholm I.E. Humaidan P. Parkner T. Bech B.H. Ramlau-Hansen C.H. et al.Unrecognised coeliac disease among men and women undergoing fertility treatment: a screening study.United European Gastroenterol J. 2018; 6: 1477-1484Crossref PubMed Scopus (0) Google Scholar) screened 453 women referred for infertility treatment, only 1 (0.22%) was positive for CeD. In a similar screening study of infertile couples in the Netherland (2Trynka G. Hunt K.A. Bockett N.A. Romanos J. Mistry V. Szperl A. et al.Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.Nat Genet. 2011; 43: 1193-1201Crossref PubMed Scopus (627) Google Scholar), 6 of 1038 women (0.58%) were positive for CeD, a proportion consistent with the general population. Together, these studies argue against screening for CeD in women with infertility.