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Mindstretcher 2 - genetics and disease

Factor V Leiden
Study
Results
Comment
ACE gene polymorphism
Study
Results
Comment
Overall comment

One of the most unsettling lectures we listen to is given by someone ("pointy-headed academic" is a favourite description of Bandolier readers) who tells us of the changes to be wrought by the tidal wave of new genetic knowledge coming our way. Most of us feel the correct response is to "do an Ostrich" (bury your head in the sand) and hope we retire before this all comes to pass. Too late, because the questions, and some of the answers, may already be upon us.

But there is hope, and part of that hope is that dealing with genetic knowledge may not be so different from dealing with other forms of knowledge. We can cope as long as we are not overawed by the jargon. Two examples are helpful, one on factor V Leiden and the risk of thrombosis [1], the other a study and meta-analysis of the relationship between ACE gene polymorphism and IgA nephropathy [2].

Factor V Leiden


This gene mutation is associated with resistance to activated protein C, a natural anticoagulant and inhibitor of the coagulation system. The mutation can be found in a significant minority of people with documented venous thrombosis, and there is a three to seven-fold increased risk of venous thrombosis in heterozygous carriers of the gene mutation.

This has led to some consideration for screening for factor V Leiden mutation. The problem with this is that we have only limited knowledge of the natural history of thrombosis in people with the mutation, which makes it difficult to balance any benefits of anticoagulation therapy following gene identification with the risks associated with anticoagulation therapy.

Study


A Dutch study [1] helps by looking at the natural history in a large population of gene carriers. In all 470 asymptomatic carriers (458 heterozygotes and 12 homozygotes for the gene mutation, mean age 43 years) who were first-degree relatives of symptomatic patients were followed every six months for an average of 3.3 years, with a range of 1.5 to 4.5 years. People with a history of thromboembolism or on long-term anticoagulation therapy were excluded. Nine withdrew for various reasons and three died, but none developed venous thromboembolism. Thromboembolism was diagnosed appropriately if clinically suspected.

Results


Nine heterozygous carriers had a venous thromboembolism. Four occurred spontaneously, three were associated with use of oral contraceptives (66 women used oral contraceptives), one with hormone replacement therapy (21 women used hormone replacement therapy) and one after surgery despite one week of anticoagulation (29 people had surgery). None occurred in 17 pregnancies.

The overall absolute rate of venous thromboembolism was 0.6% a year (95% CI 0.3% to 1.1%), consistent with smaller studies. This was higher than reported rates in populations free of the mutation, in which it is reported to be about 0.2%.

Comment


If screening and identification of factor V Leiden mutation resulted in warfarin anticoagulation, intracranial haemorrhage might occur in about 0.5% of treated patients and major bleeding in up to 3% every year, though these figures (see Bandolier 24 ) were from older populations. The paper [1] quotes major bleeding with warfarin of 2% to 10% a year. Whatever, the benefits and harms are not importantly balanced towards benefit. Where there are more risks, like surgery or contraception, other criteria may apply, and the paper is thoughtful about them.

ACE gene polymorphism


IgA nephropathy leads to end stage renal disease, more often in men, at older age, and in the presence of hypertension and proteinuria. The angiotensin converting enzyme comes in three genotypes, DD, II and DI. Some small studies have shown high rates of the DD form of ACE in IgA nephropathy patients with progressive deterioration of renal function.

Problems were that the frequency of different genotypes in different populations varied, as well as the small numbers. A large study in a homogenous population plus a meta-analysis of such studies [2] helps answer the question.

Study


The study population was 247 Caucasian patients in Southern Italy with IgA nephropathy diagnosed by renal biopsy and visited the clinic within three years. Two outcomes of renal disease progression were used, either progression of renal damage using creatinine clearance or development of end-stage renal disease treated by dialysis or transplantation. A control population was 140 staff members and blood donors. In addition an extensive search was made for other studies relating to ACE gene polymorphism and renal damage.

Results


In the study, there was no relationship between ACE I/D genotype and renal damage. In the meta-analysis, studies were divided between those in Asians and in Caucasians, because of different genotype frequencies in controls. There was no association between ACE I/D frequencies and IgA nephropathy or progression of renal damage in IgA nephropathy patients.

Comment


A mind-tinglingly complex paper, but one that dissects the problems, examines the answers, and comes up with a probably conclusive lack of relationship.

Overall comment


It might be easy to be put off by these papers, especially when they get into the details of the gene sequences used to identify genotypes, or the unfamiliar notations used in genetics. But genetics aside, the methods used were familiar, and similar to those we are used to from other papers we read. A little stamina meant we found a satisfactory answer, that in neither case do we have to worry about these any more for the moment, though factor V Leiden may be relevant in some situations.

The future may be more challenging. Bandolier hopes that transmission disequilibrium tests that are free of bias due to population stratification can wait till brain cells have a good day.

References:

  1. S Middeldorp et al. A prospective study of symptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Annals of Internal Medicine 2001 135: 322-327.
  2. FP Schena et al. ACE gene polymorphism and IgA nephropathy: an ethnically homogeneous study and a meta-analysis. Kidney International 2001 60: 732-740.
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