Genetic Associations with Outcomes after Letrozole or Clomiphene Citrate Treatment in Women of European Ancestry with PCOS

Presentation Number: LB SAT 82
Date of Presentation: April 1st, 2017

M. Geoffrey Hayes1, Frederick TJ Lin2, Michael P Diamond3, Christos Coutifaris4, William D Schlaff5, Peter Raymond Casson6, Gregory M Christman7, Nanette Santoro8, Heping Zhang9, Esther Eisenberg10, Margrit Urbanek1, Andrea Dunaif1 and Richard S Legro*11
1Northwestern University Feinberg School of Medicine, Chicago, IL, 2Northwestern University, 3Augusta University, Augusta, GA, 4Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 5Jefferson University, Philadelphia, PA, 6University of Vermont, Burlington, VT, 7Shands Hospital, University of Florida, Gainesville, FL, 8University of Colorado School of Medicine, Aurora, CO, 9Yale University, New Haven, CT, 10Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, 11Penn State College of Medicine, Hershey, PA

Abstract

The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (1) is a randomized trial to compare treatment efficacy of letrozole and clomiphene citrate for infertility in women with polycystic ovary syndrome (PCOS). We performed a genomewide association study (GWAS) in 236 PPCOS II participants (117 letrozole and 119 clomiphene citrate) of European ancestry who were included in a previously performed GWAS for PCOS (2), to identify genetic associations for ovulation, conception, ovulation rate, live birth, and treatment side effects (hot flashes, fatigue, or dizziness) as well as treatment specific associations with these measures. Genotyping was performed on the MetaboChip, imputed to 1000Genomes Phase 2. Linear (ovulation rate) or logistic regression (all other traits) were adjusted for BMI and principal components of ancestry. Four loci were associated with ovulation at a genomewide level of significance: rs114745536, 1p34.3, p=1.78E-08 in MEAF6 which has previously shown association with endometrial stromal sarcoma; rs75807444, 11q13.3, p=3.55E-08 in LOC338694; chr3:180210845:I, 3q26.33, p=4.08E-08 upstream of LINC02053; and rs17065032, 6q16.3, p=4.66E-08 between LOC100129694 and HACE1. Several loci were associated with the remaining traits approaching genomewide significance (P<5E-06): rs11055737, 12q13.1, between GRIN2B and LOC644693 with conception; rs10427418, 20q13.13, in a H3K27Ac histone modification mark between SULF2 and SRMP1, and rs7243010, 18p11.22, in a H3K27Ac histone modification mark between TXNDC2 and VAPA, the former of which regulates sperm development, with live birth; rs2151282, 9p21.3, in a H3K27Ac histone modification mark between CDKN2B-AS1 and DMRTA1, the former of which has been associated with type 2 diabetes and endometriosis, with ovulation rate; and chr15:51096622:D, 15q21.2, between TNFAIP8L3 and CYP19A1, the latter of which catalyzes the last steps of estrogen biosynthesis, with treatment side effects. After stratifying by treatment protocolmultiple loci approaching genomewide significance (P<5E-06) were associated with treatment protocol: 4 loci with ovulation, 4 loci with conception, 1 locus with live birth, and 4 with treatment side effects. Of these RBFOX1 (with ovulation) is a plausible candidate gene since it stimulates transcription of androgen receptor regulated genes KLK2 and KLK3. Collectively, these associations identify a number of genes and pathways for follow-up studies to elucidate the etiology of reduced fertility in PCOS and/or the treatment response in these traits due to letrozole and clomiphene citrate.

Reference: (1) Legro et al., N Eng J Med 2014, 371(15):1463-4. (2) Hayes et al., Nat Commun 2015 6:7502.

 

Disclosure: NS: Principal Investigator, Bayer, Inc., Ad Hoc Consultant, Menogenix. Nothing to Disclose: MGH, FTL, MPD, CC, WDS, PRC, GMC, HZ, EE, MU, AD, RSL