Scand J Haernatol 1985;34:68-70

Key words: acute leukaemia - HLA genotypes

Distribution of HLA genotypes in sibs of patients with acute leukaemia

Pieter de Moor i3 Andries Louwagie Lab. Exp. Gen. & Endo (Legendo) Onderwijs en Navorsing, Gasthuisberg, 3030 Leuven, Belgium

More unaffected sibs than expected have the same HLA genotypes as their sib with acute leukaemia. This seems not to be due to the restricted heterogeneity in HLA antigens described in the parents of sibs with acute leukaemia.

Accepted for publication August 7, 1984

Recently, Chan et a1 (1) showed that the HLA genotype of both ALL and AML leukaemic patients is found more frequently than the expec- ted 25% among their siblings. They suggested that an HLA-linked factor(s) conferring suscepti- bility to leukaemia may also be associated with increased gametic survival.

Material and methods The patients were ascertained by one of us (A.L., Haematology clinic, A.Z. Sint Jan at Bruges). Conse- cutive patients were HLA typed at the time of diagno- sis. Their sibs, volunteering to give blood, were also typed. The patients were not candidates for bone marrow transplantation.

HLA-A, B and C antigens were typed by the stan- dard 2-stage microlymphocyte toxicity procedure using a large battery of well-defined antisera.

Results Comparison was made of sick/healthy pairs of sibs with healthy/healthy pairs of sibs in families

of patients with acute leukaemia comprising at least 4 sibs available for study.

HLA-identity was studied in pairs of sibs made up of a sick sib with acute leukaemia and a healthy sib taken from the same sibship. The sick sib was paired with the healthy sib who was, closest in age to the sick sib. The pair of healthy sibs was made up of healthy sibs of the same family not involved in the sick/healthy pair. If more than 3 healthy sibs were available, the oldest healthy sib was paired with the youngest one.

3 groups of sibships were studied (Table 1). The 1st group comprised 33 sibships ascertained through a sib with acute leukaemia. The 2nd group comprised 19 sibships ascertained through a sib presenting another haematological disor- der. The 3rd group of 23 sibships was made up either from uncles or aunts of the leukaemia patients or of children from these patients.

For each of the pairs ye selected the pairs sharing 2 haplotypes as well as the pairs having 1 or no haplotypes in common (Table 2). As can be seen the patient with acute leukaemia has a 3.32 times (P=0.03) higher risk of having an HLA-identical healthy sib than the oldest of the

HLA GENOTYPES IN ACUTE LEUKEMIA 69

TABLE 1 Diagnosis, number of patients and number of sibs available for study

number of number of sibs patients in each of

the sibships

(A) Leukaemia - acute undifferentiated 1 4

-acute lymphoid leukaemia 8 4,4,4,4,4, 6,6,6 - acute monomyeloid 8 4,4,5,5,6,?,?,8

-acute promyeloid leukaemia 3 5 , 6 , 8 -acute myeloid leukaemia 10 4,4,4,5,5,6,7,7,8,9

leukaemia

leukaemia

-hairy cell leukaemia 3 4,4,4 ~

33

(B) Other haematological disc - refractory anaemia with

exsess of blasts - multiple myeloma - chronic myeloid leukaemia - aplastic anaemia - agranulocytosis - pancytopenia - thrombocytopenia - haemolytic anaemia

wders 1 8

1 4 3 5,5,8 3 8,8, 8 4 4,4, 5 , 6 1 7 1 5 5 4,4,4,5,? 19 -

number of sibships

(C) Aunts and uncles or 23 4,4,4,4,4,4,4,4,4, children of patients 4,4,4,5,5,5,5,5,

6,6,7,7,7, 10

healthy sibs. Such was not the case in the sib pairs ascertained by a patient with a non-acute leukae- mic haematological disorder. Moreover, no ab- normal distribution of haplotypes was found in sibships made up of either aunts and uncles or of children from the leukaemia patients.

It is known that parents of patients with acute leukaemia have more HLA antigens or haplo- types in common than parents of normal subjects (2). This implies that sibships of patients with acute leukaemia often have a resticted heteroge- neity of HLA genotypes (Table 3). In order to eliminate restricted heterogeneity as the cause of the excess of healthy sibs HLA-identical with the sick propositus, we studied separately the 22 (out of 33) sibships of leukaemia patients who each expressed 4 different haplotypes (Table 2), I bis). The distribution of these haplotypes was still ab- normal. A sick sib with acute leukaemia had 3.62 times (P=0.08;ns) more chance of finding an HLA-identical sib than a healthy sib.

TABLE 2 Distibution of H L A genotypes in families of patients with acute leukaemia

Discussion Chan et a1 (1) have reported that the HLA geno- types found in patients with acute leukaemia are also found more frequently than the expected 25% among their sibling. This was not'so in 40

Sibships Sick/Healthy pairs: HealthyiHealthy pairs: 2' 1 0 2 1 0

(1) acute leukaemia (n = 33) 14 14 5 6 20 7 (1 bis) acute leukaemia expressing 4 different 8 10 4 3 13 6

haplotypes per sibship (n = 22)

acute leukaemia (n = 19)

- children of patients with acute leukaemia(n = 23)

(2) haematological disorders besides 6 9 4 4 11 4

(3) -aunts or uncles 6* * 13 4 7 I 1 5

* Number of HLA haplotypes the pair has in common. * * Since there are no sick sibs in this group the pair comprising the 2 oldest sibs was compared with the pair comprising the 2

youngest.

70 DE MOOR & LOUWAGIE

TABLE 3 Restricted heterogeneity in parents and patients: a and b are the paternai HLA haplotypes and c and d the maternal hapiofypes

% of sibs expected to be HLA-identi-

bb cal versus propositus

Phenotypes in offspring Restricted (R) HLA heterogeneity and eventually sharing (S) of HLA haplotypes in parents

Maximum no of expressed pheno- types in offspring

ac ad bc bd ab aa

Normal a c b d

4 1 1 1 1 0 0 0 25

R 2 1 1 0 0 0 0 0 50 Homozygosity a c a d

in parents R a c a c

1 1 0 0 0 0 0 0 100

R + S 4 0 1 0 1 1 1 0 25 Sharing of a a b d

HLA haploptypes a a b b

in parents a a a c

R + S 3 0 0 0 0 2 1 1 25-50

R + S 2 1 0 0 0 0 1 0 50

families with 106 siblings used as controls. The size of the families did not influence the distribu- tion of HLA haplotypes. The authors (1) postula- te that the union of gametes expressing particular parental HLA haplotypes were favoured. We could confirm these findings and show that this is probably not due to restricted heterogeneity in the parents of these patients.

Acknowledgements We wish to thank Dr. I. Vande Putte for the HLA typing. Mrs. B. Minten and Mrs. M. P. Vander Auwera typed the manuscript with diligent care.

References 1. Chan Ka-WAH, Pollack MS, Brown D Jr, O’Reilly RJ,

Dupont B. Distribution of HLA genotypes in families of patients with acute leukemia. Transplantation 1982;33: 6&5.

2. Werner-Favre Ch, von Fliedner W, Jeannet M. Similitude des antigknes HLA chez les parents de patients atteints de leucemie aigue ou d’anernie aplastique. Schweiz Med Wochenschr 1979;109: 1399.

Correspondence to: P. De Moor Lab. Exp. Gen. & Endo (Legendo) Onderwijs en Navorsing Gasthuisberg 3030 Leuven Belgium