Implications of Blood Type for Ovarian Reserve

Edward J. Nejat; Sangita Jindal; Dara Berger; Erkan Buyuk; Maria Lalioti; Lubna Pal

Disclosures

Hum Reprod. 2011;26(9):2513-2517. 

In This Article

Discussion

Our findings relate blood group antigens with biochemical evidence of DOR in women seeking fertility treatment. We demonstrate that blood type O relates to biochemical evidence of DOR, a relationship that is independent of age. Women with blood type O were observed to be twice as likely to have elevated baseline FSH levels compared with those with blood types A or AB. We additionally observed that the A blood group antigen (blood types A or AB) was associated with a reduced likelihood for DOR, an association independent of age. Our findings relating blood type in infertile women to ovarian reserve correspond with a study by Binder et al., who reported OHSS was more likely to be observed during the course of ovarian stimulation in infertile women with blood type A. Our observation that the A antigen relates to reduced likelihood for DOR is thus in agreement with Binder et al., given that the authors describe blood type A as being prognostic of a robust ovarian response, i.e. a parameter considered as diametrically opposite to DOR.

The ABO gene locus has three main allelic forms: A, B and O. The H antigen is an essential precursor to the ABO blood group antigens. The gene products of the A and B alleles are glycosyltransferases that catalyze the transfer of carbohydrates to the H antigen, forming the A and B antigens, respectively (Yamamoto et al., 1990; Palcic et al., 2001). The A allele encodes for a glycosyltransferase (A transferase) that catalyzes the transfer of N-acetylgalactosamine to the H antigen, producing the A antigen. Similarly, the B allele encodes for a glycosyltransferase (B transferase) that catalyzes the transfer of galactose to the H antigen, producing the B antigen. The O allele has a single base deletion, 258-guanine, in the coding region close to the N terminus of the protein. The deletion shifts the reading frame, resulting in translation of an entirely different protein. The product of the O allele is an enzymatically inactive protein leaving the H antigen unchanged on the red blood cells of those with blood type O (Yamamoto et al., 1990). Though traditionally considered red blood cell antigens, the A and B antigens can be found on the cell membranes of a variety of cell types, including epithelial cells (Mandel et al., 1990). It is unknown whether the H antigen is present in ovarian cells.

Considering the protective effect blood group A transferase appears to exhibit against DOR, one may speculate that this enzyme may be relevant to processes of gamete accrual and/or attrition, and the absence of A transferase activity, as in the case of blood type O, may be detrimental to these processes. Several proteins crucial for follicle development and maturation, such as FSH-receptor (FSH-R) and LH-receptor (LH-R) are heavily glycosylated proteins. Of interest in this context are the observed decreased rates of ovulation in mice with oocyte-specific deletion of a glycosyltransferase, N-acetylglucosaminyltransferase I (Williams and Stanley, 2009).

Another possible explanation for the observed relationship between blood type and ovarian reserve may include genetic inheritance. Specific genes (known or predicted from the genome sequence) relevant to ovarian reserve may be linked with the ABO gene, which is located on chromosome 9 (9q34). Nearby unknown variants close to ABO and associated with ovarian function could theoretically explain the observed correlation with blood type. For example, if alleles or genes related to ovarian reserve are inherited with ABO, this may potentially explain how blood type may predict ovarian reserve, as suggested in our study. Notable is a single candidate gene, NR5A1, which is in proximity to the ABO locus and recognized as relevant to ovarian reserve (Lourenco et al., 2009). However, the recombination distance between NR5A1 and ABO loci (NR5A1 is located 9 Mb and 14.7 cM proximal to the ABO locus, Genome Reference Consortium Assembly GRCh37/hg19) allows for a relatively high probability of recombination between NR5A1 and blood type genes (14% chance of recombination per meiosis), rendering linkage disequilibrium as an unlikely phenomenon for explaining the observed relationship of FSH level with blood type O. An alternative explanation for the observed associations may lie within DNA variation in haplotype that can alter the folding and stability of a protein and thereby allow certain allele combinations to be more commonly inherited together (Clark, 2004; Schaid, 2004). Haplotype variations are impacted by ethnicities however, and hence ABO blood types and ovarian reserve need to be evaluated within specific populations for informative linkage and recombination analyses.

Our study design limits exploration of parameters that may relate to elevated FSH, such as smoking history, prior pelvic surgery or fragile X permutation carriage (El-Nemr et al., 1998; Wittenberger et al., 2007; Padhy et al., 2010). Given the study population, being exclusively comprised of infertile women, our observations may not be generalized to the female population at large. Racial variations in blood type are recognized (Mourant et al., 1976; Garratty et al., 2004) as are racial variations in ovarian reserve parameters (Randolph et al., 2004). Although we did not collect information regarding the race and ethnicity for the study population, we have attempted to at least partly address this latter concern by including patients from two study sites, thereby allowing a broader ethnic and racial representation. The lacking information relating to the exact timing of serum sampling in relation to the menstrual cycle also introduces a potential for bias resulting from spurious 'normalization' of FSH values for samples collected beyond the early follicular phase of the cycle. However, we have attempted to minimize such an occurrence by restricting analyses to FSH data where the concomitant E2 level was <80 pg/ml. Given the known inter-cycle variability in early follicular phase FSH, our strategy to diagnose DOR based on a single FSH value may have yielded 'false reassurance' regarding ovarian reserve status in some participants. Ovarian reserve parameters are recognized to be influenced by the body mass (Freeman et al., 2007; Binder et al., 2008a) and this parameter is similarly unavailable for the study population. Despite the identified limitations, the relatively large sample size, the adjusted analytic approach and the consistency in our observations to findings reported by Binder et al., add credence to our work.

In summary, our findings suggest that in subfertile women, the A blood group antigen is protective against DOR while blood type O relates to an increased likelihood of DOR. While the exact mechanisms that tie blood type to ovarian reserve are unclear at this juncture, the possibilities that glycosyltransferases may play an important role in ovarian function, or that the presence of a gene that co-segregates with blood group antigens and may be associated with DOR, are both enticing and constitute an area of further investigation.

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