Human Reproduction, Vol. 15, No. 11, 2447,
November 2000
© 2000 European Society of Human Reproduction and Embryology
Letters to the editor |
HLA-DR4 and pre-eclampsia
Blood Transfusion Service Laboratories, 2 Foreest Road, Edinburgh EH1 2QN, UK
Dear Sir,
Takukuwa et al. (1999) recently reported HLA-DR data from a group of Japanese pre-eclampsia patients. The finding that was emphasized was a higher frequency of DR ß1*04 genotypes in the small sub-group of patients positive for anti-cardiolipin antibodies (ACA) compared to normal fertile women. Nevertheless, a similar trend is apparent with ACA-negative patients, and the strengths of the associations are fairly similar (odds ratios of 2.9 and 1.9 for ACA-positive and ACA-negative patients respectively).
We and others have independently reported a positive association between HLA-DR4 and pre-eclampsia which was not confirmed by several other investigators (Kilpatrick, 1999
). Since the putative DR4 association is a prior hypothesis, it would be appropriate to analyse Takukuwa et al.'s data by a one-sided Fisher's exact test without correction for the total number of genes tested for. By such means, it can be calculated that the DR4-inclusive gene frequency was significantly higher in both the ACA-negative patients (P = 0.04) and the total group of patients (P = 0.01) compared with the normal fertile controls. These results are in excellent agreement with our serological data, and, futhermore, lend some support to the conjecture that only certain HLA-DRß1*04 alleles are over-represented in pre-eclampsia. The distribution of DRß1*04 genotypes differed between patients (especially those with ACA) and controls, a finding consistent with the possible existence of some immunogenetic factor in common between pre-eclampsia, intra-uterine growth retardation, spontaneous abortion and autoimmunity (Kilpatrick, 1999).
Nevertheless, the literature is inconsistent and it is unclear why several, but not the majority of, studies report a positive association between HLA-DR4 and pre-eclampsia. Most puzzlingly, this same group now reporting a positive association by genotyping 54 patients and 81 controls previously reported a significant inverse association by serological typing of 35 patients and 112 controls (Takakuwa et al, 1997)! Clearly, there is a need for a large-scale (probably multi-centre) investigation determining HLA-DR4 status both by serological and by DNA-based methods.
References
Kilpatrick, D.C. (1999) Influence of human leukocyte antigen and tumour necrosis factor genes on the development of pre-eclampsia. Hum. Reprod. Update, 5, 94–102.
Takakuwa, K., Arakawa, M., Tamura, M. et al. (1997) HLA antigens in patients with severe preeclampsia. J. Perinat. Med., 25, 79–83.[Web of Science][Medline]
Takakuwa,K., Honda, K., Ishii, K. et al. (1999) Studies on the HLA-DRß1 genotypes in Japanese women with severe pre-eclampsia positive and negative for cardiolipin antibody using a polymerase chain reaction-restriction fragment length polymorphism method. Hum. Reprod., 14, 2980–2986.
Department of Obstetrics and Gynecology, Niigata University School of Medicine, 1-757 Asahimachi-dori, Niigata 951-8510, Japan
Dear Sir,
I greatly appreciate the comments of Dr Kilpatrick concerning my work on HLA-DR genotypes and pre-eclampsia (Takakuwa et al., 1999). Dr Kilpatrick pointed out that a significantly higher frequency of HLA-DRß1*04 genotypes was observed in patients with pre-eclampsia negative for anti-cardiolipin antibody (ACA) in our series. However, the P value calculated by comparing the frequency of HLA-DRß1*04 in the patient group with that in the control population was 0.054 (by 
2 test), and the odds ratio with 95% confidence interval was 1.89 with 0.98–3.63. Thus, we could not conclude that the frequency of HLA-DRß1*04 in the patient population was significantly higher than that in the control population, although the tendency was observed.
The discrepancy between the results of the serological assay (Takakuwa et al., 1996) and genotyping assay is considered to be due to the ambiguity of the serological method as I noted in the Discussion of my paper referring to the report by Opelz et al. (1991). They reported that up to 25% of serological HLA-DR typing assignments were incorrect when compared with a more precise DNA-RFLP method. We are now applying only the genotyping method when analysing the HLA-class II types (HLA-DR, -DQ, and -DP).
I am in complete agreement with the proposal of Dr Kilpatrick that a multi-centre analysis should be done for elucidating the association of HLA-class II antigen systems and the diversity of reproductive failure such as pre-eclampsia, unexplained recurrent abortion, and ACA-positive abortion.
References
Opelz, G., Mytilineos, J., Scherer, S. et al. (1991) Survival of DNA HLA-DR typed and matched cadaver kidney transplants. Lancet, 338, 461–463.[Web of Science][Medline]
Takakuwa, K., Arakawa, M., Tamura, M. et al. (1996) HLA antigens in patients with severe preeclampsia. J. Perinat. Med., 25, 79–83.
Takakuwa, K., Honda, K., Ishii, K. et al. (1999) Studies on the HLA-DRß1 genotypes in Japanese women with severe pre-eclampsia positive and negative for cardiolipin antibody using a polymerase chain reaction-restriction fragment length polymorphism method. Hum. Reprod., 14, 2980–2986.
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