ABH secretor genetic polymorphism: evidence of intrauterine selection

Article Outline

• Abstract
• 1. Introduction
• 2. Materials and methods
  • 2.1. Statistical analyses
• 3. Results
• 4. Comments
• Acknowledgement
• References
• Copyright

Abstract 

Objective

Fucosyltransferase locus 2 (FUT2) controls the presence or absence of blood group substances (A, B, H) in the saliva and other body secretions. Secretor/non-secretor phenotypes are associated with some metabolic and infectious diseases. ABO and FUT2 contribute to build up oligosaccharide structures of the cell surface that are important for blastocyst adhesion and resistance to microbial invasion. We investigated a possible selection on ABH secretor phenotypes during intrauterine life.

Study design

Three hundred and fifty-six consecutive healthy puerperae and their newborn infants from the caucasian population of Rome were studied. Informed consent for study participation was obtained from the mothers to participate and the study was approved by the Institutional Review Board. ABH secretor Se phenotype was determined on saliva by standard laboratory procedure.

Results

Symmetry analysis of mother infant Se phenotype revealed a deficit of mother Se+/newborn Se− with respect to expected values. The asymmetry is present only in infants carrying the A blood group antigen. The asymmetry was dependent on several maternal and neonatal parameters including maternal age, smoke, parity and gestational duration.

Conclusions

The data suggest intrauterine selection against Se− of the embryo carried by a Se+ mother. Such selection is dependent on factors influencing the maternal environment. The study could have practical importance in assessing the risk of infertility and success of artificial insemination.

Keywords: ABH secretor, Intrauterine selection, FUT2

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1. Introduction 

The presence or absence of blood group substances (A, B, H) in the saliva and other body secretions is controlled by a gene on chromosome 19, the fucosyltransferase locus 2 (FUT2). Two alleles are present in this locus: Se and se. Se is dominant on se, resulting in the presence in human populations of two phenotypes: Se+ (secretor) with a frequency around 80% and Se− (non-secretor) with a frequency around 20%. The association of secretor status with several pathological conditions has been observed: in general being non-secretor results in a disadvantage regarding metabolic and immunological functions. Non-secretor phenotype has been associated with insulin resistance, peptic ulcer, immunoglobulin level, resistance to Candida infection, increased susceptibility to ankylosing spondylitis, rheumatoid arthritis, psoriatic arthropathy, multiple sclerosis and Grave's disease, norovirous infection, urinary tract infections, oral pathology, duodenal ulcer and celiac disease [1], [2], [3], [4], [5].

There are several fucosyltransferases (FUT), numbered from 1 to 11 [6]. The majority is located on chromosome 19 (19q13.3). Many of the FUT genes are intimately involved in the development of the embryo, supporting the hypothesis that the primary function of ABO antigens is to act during intrauterine life as a framework for the organisation of embryo development [1]. ABO and FUT2 contribute to the biosynthesis of antigens and work in concert to build up oligosaccharide structures on the cell surface. They play an important role in the organisation of membrane structure and expression of membrane proteins. Such structures are implicated in blastocyst adhesion and may modify the cervical barrier to microbes [7].

Most investigation of ABO selection during intrauterine life has been directed at maternal–fetal incompatibility in this system. Some studies, however, suggest that maternal–fetal interactions not related to incompatibility may also be operating during intrauterine life. These interactions could be related to enzyme differences and/or structural differences between the maternal and fetal parts of the placenta [8], [9]. The role of FUT2 and ABO in the organization of membrane structures and blastocyst adhesion suggests an involvement in the modulation maternal–fetal relationship. Since both systems are polymorphic, selective interactions between the two systems could be operating. In the present study we have investigated ABH secretor selection during intrauterine life and possible interactions with ABO blood groups.

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2. Materials and methods 

We studied 356 consecutive healthy puerperae and their newborn infants from the caucasian population of Rome. Informed verbal consent for study participation was obtained from the mother, and the study was approved by the Institutional Review Board. ABO blood group was determined in all subjects by routine analysis and secretor phenotype was determined on saliva by standard laboratory procedure [10].

2.1. Statistical analyses 

Because neonatal and maternal Se distributions are not independent, symmetry analysis is a useful tool to detect distortions of the joint distribution [11], [12]. Considering the square matrix of the joint mother/infant phenotype distribution (Table 1), the analysis tests whether the probability of falling into the cell of “mother Se−/newborn Se+” group is the same as the probability of falling into the cell of “mother Se+/newborn Se−” group. In this analysis, the secondary diagonal terms (marked by−−and ++ in Table 1) are ignored. The expected values are the average of the frequencies observed for the two cells. Chi-square analysis calculated for the couples with symmetrical entries is evaluated with 1° of freedom.

Table 1. A 2×2 square matrix. Symmetrical enteries (− + and + −) correspond to dissimilar mother–infant pairs, respectively. Similar pairs are located on the secondary diagonal (− − and + +).

The symmetry hypothesis corresponds to the hypothesis that reciprocal mother/infant types have the same frequency. Therefore, the analysis evaluates a class of distortions related to the symmetry of the maternal–fetal joint secretor distribution. The association between maternal and neonatal phenotypes is expected to be symmetrical under Hardy–Weinberg conditions. The presence of asymmetry could be an expression of the differential selective pressure acting on reciprocal joint types during intrauterine life. Independence and goodness of fit were analysed by Pearson's χ² statistics (using SPSS/PC+ Version 5; SPSS, Chicago, IL, USA).

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3. Results 

Table 2 shows the distribution of secretor phenotypes in mothers and newborn infants. No statistically significant difference is observed between the two distributions. Symmetry analysis of the joint mother–infant distribution of secretor phenotype is shown in Table 3. The reciprocal mother Se−/newborn Se+ and mother Se+/newborn Se− are significantly different (p=0.04). Further analysis based on maternal and neonatal secretor phenotype and assuming Hardy–Weinberg expectation has shown that the expected value of the mother Se+/newborn Se− class is very near to 50. This suggests a strong reduction of the mother Se+/newborn Se− class with respect to expected values (31 vs. 50 and not 31 vs. 40.5 as shown in Table) giving a higher chi-square for symmetry analysis (p=0.008).

Table 2. Distribution of secretor phenotype in mothers and newborn infants.

Table 3. Symmetry analysis of the joint mother–infant distribution of secretor phenotype. It should be noted that in this analysis χ² does not refer to a test of independence but to the comparison between observed and expected assuming symmetry.

Table 4 shows the proportion of mother–newborn ABO incompatible couples according to the joint mother–infant secretor phenotype. The class mother Se+/newborn Se− shows a low frequency of ABO incompatibility but the difference with respect to other classes is not statistically significant.

Table 4. Proportion of mother–newborn AB0 incompatible couples according to the joint mother–infant secretor phenotype.

Table 5 shows a symmetry analysis of the joint mother–infant distribution of secretor phenotype in relation to the ABO phenotype of the newborn infant. The asymmetry is present only in infants carrying the A blood group, suggesting an interaction between the two systems. A similar pattern is not observed considering maternal ABO phenotype.

Table 5. Symmetry analysis of the joint mother–infant distribution of secretor phenotype in relation to AB0 phenotype of the newborn infant.

Newborn infant AB0 phenotype		Newborn Se phenotype
		−	+
A
Maternal Se	−	14	17
Phenotype	+	5	89
B
Maternal Se	−	7	6
Phenotype	+	6	28
AB
Maternal Se	−	3	3
Phenotype	+	0	8
0
Maternal Se	−	18	24
Phenotype	+	20	107
Symmetry analysis (mother+ newborn− vs. mother− newborn+)

Mother	+	−	χ2	df	p
Newborn	−	+
Newborn AB0 phenotype
A+AB
Obs	5	20	9.00	1	0.003
Exp	12.5	12.5
B
Obs	6	6	0.00	1	1.00
Exp	6	6
0
Obs	20	24	0.36	1	0.65
Exp	22	22

Table 6 shows the symmetry analysis of the joint mother–infant distributions of secretor phenotype in relation to some neonatal and maternal parameters. Only the reciprocal classes are reported in Table. The asymmetry is present only in young mothers and in first-born offspring; it is more evident in females than in males; and it is much more evident in smokers than in non-smokers. The asymmetry is present only when gestational duration is equal to or greater than 39 weeks. Thus, ABH selection seems to be dependent on several environmental variable, suggesting an important role of ABH genetic polymorphism in embryo adaptability. No differences were observed in relation to birth weight (<2500 vs. ≥2500) or history of spontaneous abortion (data not shown).

Table 6. Symmetry analysis of the joint mother–infant distribution of secretor phenotype in relation to neonatal and maternal parameters.

	Mother Se−	Mother Se+	Significance of difference between observed and expected
	Newborn Se+	Newborn Se−	χ2	df	p
Maternal age
≤28 years	Obs. 31 Exp. 23	15 23	5.57	1	0.025
>28 years	Obs. 19 Exp. 18.5	16 18.5	0.67	1	0.400
Sex
Females	Obs. 27 Exp. 20	13 20	4.90	1	0.030
Males	Obs. 23 Exp. 20.5	18 20.5	0.61	1	0.450
Order of birth
1st	Obs. 27 Exp. 18.5	10 18.5	7.81	1	0.006
Others	Obs. 23 Exp. 22	21 22	0.09	1	0.750
Number of pregnancies
1	Obs. 21 Exp. 14.5	8 14.5	5.45	1	0.024
2 or more	Obs. 29 Exp. 26	23 26	0.69	1	0.410
Smoke
No	Obs. 31 Exp. 27.5	24 27.5	0.89	1	0.370
Yes	Obs. 19 Exp. 12.5	6 12.5	6.76	1	0.013
Gestational duration
Less than 39 weeks	Obs. 6 Exp. 5.5	5 5.5	0.09	1	0.750
39 or more weeks	Obs. 44 Exp. 35	26 35	4.63	1	0.035

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4. Comments 

Symmetry analysis appears very useful for the investigation of intrauterine selection. The present analysis suggests the occurrence of prenatal selection against non-secretor fetuses carried by secretor mothers. The deficit of the “newborn−/mother+” class as compared to the reciprocal class “newborn+/mother−” indicates that in the biological mother–embryo competition at implantation the secretor phenotype prevails over the non-secretor phenotype. The selection against non-secretor embryos carried by a secretor mother is especially evident in A-phenotype newborns suggesting a strong interaction with the ABO system with possible involvement in maternal–fetal immunological interaction.

The fact that the class “mother Se+/infant Se−” is less represented among ABO incompatible infants may suggest an involvement of maternal–fetal incompatibility. Although with the size of the present sample the difference is not statistically significant this possibility cannot be excluded. There is also a slight indication that the involvement of ABO incompatibility may be specific to A blood group, but again the size of the sample is not sufficient to draw reliable conclusions.

The maternal–fetal selection is dependent on maternal age and on gestational order, being present only in first-born offspring. A positive smoking history seems to enhance the phenomenon. Overall it seems that intrauterine selection of the Se genotype is dependent on several factors influencing the maternal environment that controls zygote development. The exact mechanism underlying the pattern described is not known at present, but the observations support the notion that ABO and secretor loci are important for the control of membrane structures implicated in blastocyst implantation and intrauterine survival. Further studies are necessary to confirm and clarify the patterns we have observed. These studies may have practical importance in assessing the risk of infertility and the success of artificial insemination.

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Acknowledgement 

We thank Prof. James MacMurray, Los Angeles, CA, for editing the manuscript.

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References 

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