rs2268363 — FSHR FSHR ART Response Variant

FSHR rs2268363 — An FSHR Intronic Tag Variant at the ART-Relevant FSHR Locus

The follicle-stimulating hormone receptor (FSHR) is one of the most important genes in reproductive medicine. Encoded on chromosome 2q16.2 with the gene running on the minus strand, FSHR mediates the action of follicle-stimulating hormone (FSH) in both females — where it drives granulosa cell maturation, folliculogenesis, and ovarian response to exogenous gonadotropin stimulation — and in males, where it supports Sertoli cell function and spermatogenesis. Coding variants in FSHR, particularly rs6165 (Ala307Thr)¹¹ rs6165 (Ala307Thr)
Located in the extracellular hinge region; removes an O-linked glycosylation site and rs6166 (Asn680Ser)²² rs6166 (Asn680Ser)
Located in the intracellular domain; alters cAMP signaling kinetics after FSH binding, are among the most studied pharmacogenomic variants in IVF medicine.

rs2268363 lies in an intron of FSHR at GRCh38 position chr2:48,974,189, approximately 284 base pairs from the closely related intronic variant rs2268361. Its position within the gene means it does not directly alter the FSH receptor protein. Instead, as an intronic tag variant, it may capture information about the underlying haplotype architecture of the FSHR locus — the combination of nearby variants that a given chromosome carries. The G allele occurs at 16% globally, with pronounced ancestry variation: approximately 14% in Europeans, 25% in East Asians, and 42% in African populations.

The Mechanism

As an intronic variant with a CADD score of approximately 11, rs2268363 has no predicted direct functional consequence on the FSH receptor protein. Its biological significance, to the extent it exists, derives from linkage disequilibrium with nearby functional variants across the FSHR locus. The FSHR gene harbors multiple well-characterized regulatory and coding variants — including the promoter SNP rs1394205 (G-29A), which reduces FSHR transcription, and the coding pair rs6165/rs6166 that form the Ala307Thr-Asn680Ser haplotype associated with reduced FSH receptor sensitivity. An intronic variant in close proximity to rs2268361 may partially tag one or more of these haplotypes, particularly in populations where relevant LD patterns are maintained.

The Evidence

The only published genome-wide significant association for rs2268363 is its identification in a 2010 GWAS by Kerns et al.³³ a 2010 GWAS by Kerns et al.
Genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys, 2010 as associated with [erectile dysfunction | Inability to achieve or maintain an erection, here specifically as a late adverse effect of pelvic radiation therapy] after radiotherapy for prostate cancer in African-American men (79 patients total; unadjusted p=5.46×10⁻⁸, Bonferroni p=0.028). The investigators proposed that FSHR expression in penile vascular and neural structures might modify radiation sensitivity in these tissues.

This finding was not validated in a subsequent attempt: Schack et al. 2017⁴⁴ Schack et al. 2017
Validation of genetic predictors of late radiation-induced morbidity in prostate cancer patients. Acta Oncol, 2017 tested rs2268363 among nine radiotherapy-morbidity SNPs in a Danish prostate cancer cohort and could not replicate the original GWAS signal. This is not unusual for GWAS findings from small discovery cohorts — the Kerns 2010 study included only 79 African-American patients, and genomic signals from underpowered studies frequently fail replication.

No direct evidence links rs2268363 specifically to IVF outcomes or ovarian stimulation response. The fertility pharmacogenomics literature on FSHR focuses primarily on rs6165, rs6166, rs1394205, and rs2268361 — all of which are distinct variants. Attributing ART relevance to rs2268363 would require either direct evidence (which is absent) or demonstration of strong linkage disequilibrium with a variant that does have such evidence, which has not been published.

The nearby rs2268361 (284 bp upstream) has been studied in PCOS susceptibility cohorts⁵⁵ cohorts
Saxena et al. 2015, Human Reproduction: rs2268361-T associated with lower FSH levels in European women, P=0.0029 and reproductive phenotypes, but it is a distinct variant and its LD relationship with rs2268363 has not been reported in the published literature.

Practical Implications

For males: the G allele at rs2268363 was associated with a higher risk of erectile dysfunction following pelvic radiotherapy for prostate cancer in one African-American cohort — an association that was not subsequently validated. Men of African ancestry undergoing pelvic radiation therapy may wish to note this result in discussions with radiation oncologists about post-treatment sexual health monitoring, though the evidence does not yet support clinical use of this genotype for decision-making.

For females: there is no published evidence that rs2268363 specifically affects ovarian stimulation response, IVF outcomes, or FSH receptor function in the context of ART. Women who are concerned about their FSH receptor pharmacogenomics profile should prioritize results from rs6165, rs6166, and rs1394205 — the coding and promoter variants with substantial clinical evidence.

The FSHR locus is important for reproductive pharmacogenomics, and rs2268363 is a marker within that locus. As sequencing studies become larger and more ethnically diverse — particularly including African ancestry populations where the G allele is most common — the haplotype contribution of rs2268363 to FSH receptor function may be clarified.

Interactions

rs2268361 (FSHR intronic): The nearest characterized neighbor in FSHR, 284 bp downstream. rs2268361-T is associated with lower basal FSH levels in European women and has been studied in PCOS cohorts across multiple ancestries. The LD relationship between rs2268361 and rs2268363 in different populations has not been characterized in published studies but is likely relevant given their physical proximity.

rs6165 and rs6166 (FSHR coding variants): The primary pharmacogenomic variants at this locus with well-documented effects on ovarian stimulation response in IVF. These coding variants, which form the Ala307Thr-Asn680Ser haplotype, are the actionable variants for ART planning. Their LD relationship with rs2268363 across the full FSHR haplotype block has not been directly reported but is a relevant question for future multi-variant FSHR studies.

rs1394205 (FSHR promoter G-29A): The promoter variant that reduces FSHR transcription; independently studied in additive diplotype analyses alongside rs6165/rs6166. Like rs2268363, it is non-coding, but its mechanistic role (regulating receptor expression level) is established in functional studies.