Genetic association of HMS in Kumasi, Ghana

1
Genetic association of HMS in Kumasi, Ghana
Ruby Martin-Peprah a, Dominic Kwiatkowski b,
George Bedu-Addo c, Imelda Bates d a. Komfo
Anokye Teaching Hospital, Kumasi, b. Wellcome
Trust Centre for Human Genetics, Oxford, c. Kwame
Nkrumah University of Science and Technology
School of Medical Sciences and Komfo Anokye
Teaching Hospital, Kumasi, d. Liverpool School
of Tropical Medicine, Liverpool

• Aim
• To Identify the segregational pattern of
  splenomegaly in family members of patients with
  HMS in Kumasi, Ghana
• To determine the association of HMS to known
  malaria resistance genes

• Introduction
• HMS is a disease of persistent splenomegaly in
  adult inhabitants of many malaria endemic
  tropical countries, and diagnosed by a set
  criteria (Box 1)
• HMS is believed to have a genetic basis because
  it has
• Tribal associations
• Familial predisposition
• Female preponderance
• Related to certain genetic markers such as HLA
  DR2 and IGHG3 G

• Diagnostic criteria for HMS
• Spleen 10cm below the left sub-costal margin
• Long term residence in malaria endemic area
• A splenic reduction of to 40 after four
  months malarial therapy
• PCR for immunoglobulin gene rearrangement (to
  exclude lymphoma)
• These were supported by high immunoglobulin and
  malaria antibody titres and low malaria
  parasitaemia

• Methods
• Confirm HMS in patients with massive splenomegaly
• Determine segregational patterns of splenomegaly
  in family members of patients and sex matched
  controls of similar socio-economic background
• Association studies with known malaria
  susceptibility and resistance, and B-cell
  development genes

Location of HMS
Fig a Pedigree of patient A
Fig b Pedigree of patient B
HMS patient with spleen outlined

• Results
• 6/22 patients had 11 family members with
  splenomegaly and 1/15 controls had a family
  member with splenomegaly (p0.04)
• No definite pattern of segregation (see example
  of pedigree of families with splenomegaly in
  figs. a and b)
• No association with HbS, ICAM, G6PD, IL4, CD36,
• 63 of HMS patients and 20 of controls had
  haemoglobin levels below 12g/dl (?26.8 p0.009)
• 50 of HMS patients and 15 of controls had IgM
  values more than 2SD above the local mean
  (p0.005)
• Mean malaria antibody titres were significantly
  higher in patients (p0.001) than that of local
  mean
• Malaria parasitaemia identified by malaria PCR in
  3 patients and 2 controls, and not by blood film
  microscopy

• Conclusion
• HMS is not associated with a single gene, but may
  be related to a complex interaction between many
  different genetic and environmental factors
• Low levels of malaria parasitaemia in HMS are not
  associated with malaria resistant genes and genes
  of B-cell development and antibody production

• Discussion
• Relatives of HMS patients are more likely to have
  splenomegaly than population controls
• No clear pattern of familial segregation to
  indicate the involvement of a single gene
• No association of HMS with malaria resistant and
  B-cell development genes
• HMS was associated with low haemoglobin levels,
  high malaria antibody and immunoglobulin M titres
• Low malaria parasitaemia in HMS