Chronic lymphocytic leukaemia (CLL) is a slowly-progressing form of the disease and affects around 2,750 people in the UK every year.
While anecdotal evidence has led to the suspicion that inherited factors play a part in the development of CLL, no genetic basis had previously been discovered.
In new research by carried out at the Institute of Cancer Research in London, scientists have discovered that a variation in certain genes may explain to some extent the inherited susceptibility for developing the disease.
The scientists say the discovery could lead to improved treatment for CLL patients.
The team led by Professor Richard Houlston compared DNA from CLL patients with DNA from a healthy group and found six genes with variations in their genetic sequences that are strongly associated with the development of CLL.
Professor Houlston says each of these variations, by itself, has a very small effect on the risk of developing CLL, but when all of them are present there is a significantly increased risk of leukaemia.
CLL accounts for roughly a quarter of all leukaemia cases and the variants occur in genes that play a role in the proliferation of so-called B cells, a type of white blood produced in the bone marrow.
Professor Houlston says the evidence they now have will mean research can now be carried out to determine exactly how the different genes contribute to this risk.
Experts say the study's findings are intriguing and are particularly useful because all previous attempts to identify a gene responsible for CLL have failed, even though scientists have long suspected there might be a genetic link to the disease.
They say CLL is more common among certain ethnic groups and some families have a strong history but warn that the information is too novel to be used as yet to screen groups of patients for CLL.
Cancer Research UK and Leukaemia Research who funded the research, say they are pleased that investment in genome wide scanning technology is paying dividends and enabling important discoveries to be made.
They hope in the long term they will be able help more people at increased risk of the developing CLL, through the development of tailored screening and treatment programmes.
The research is published in the journal Nature Genetics.
Mutations or polymorphisms in several genes have been associated with altered plasma HDL-C levels. Mutations in the cholesteryl ester transfer protein (CETP) gene are associated with increases in HDL-C whereas mutations in the apolipoprotein (apo) AI gene (the major apolipoprotein of HDL particles), or the lecithin:cholesterol acyl transferase (LCAT) gene cause a low HDL-C. Of the approximately 46 mutations affecting the structure of apo AI, not all are associated with CAD. Mutations in the lipoprotein lipase (LPL) and hepatic lipase (HL) genes also affect HDL-C levels. The identification of the ATP binding cassette A1 gene (ABCA1) as the cause of Tangier disease and familial HDL deficiency has led to a better understanding of the role of cellular cholesterol and phospholipid transport in the metabolism of nascent HDL particles. Based upon the analysis of a selected group of subjects, we estimate that approximately 10-20% of subjects with severe HDL deficiency have mutations of the ABCA1 gene. Other genes have been found in animal models to have a profound impact on HDL-C levels, although no human counterpart disorders have yet been identified.
Heritability of HDL-C
To examine the genetic contribution to the determination of HDL-C levels, there have been at least nine published studies in twins and 14 family studies. Estimates for the heritability of plasma HDL-C levels varies between 0.24 to 0.83 and is most often quoted as approximately 0.5.
Genetics of HDL and risk of cardiovascular disease
The inverse epidemiological association between serum levels of HDL-C and risk of CAD is graded and has been validated in multiple studies. However, there is remaining controversy whether a low HDL-C should not predominantly be considered a marker of poor lifestyle (obesity, lack of exercise, hypertriglyceridemia, diet, etc.), rather than a primary causal agent for atherosclerosis in the majority of the population. Specific mutations in genes affecting HDL-C levels have had considerable discordant effects on CAD risk. For instance, mutations in the apo AI gene affecting HDL-C levels can be strongly associated with premature CAD, but apo AIMilano and apo AIParis are notable exceptions. Mutations in the LCAT gene cause a marked decreased level of HDL-C but are not considered to be associated with CAD. While loss-of-function mutations in the CETP gene cause an elevated HDL-C, cardiovascular risk does not seem decreased and may in fact be increased. Mutations in ABCA1 are associated with very low HDL-C and increase cardiovascular risk 3.5 fold in one study, but more recent data from the Copenhagen Heart Study suggests that ABCA1 mutations are not associated with increase cardiovascular risk, despite being associated with a low HDL-C. Important questions therefore remain which genetic forms of HDL deficiency confer cardiovascular risk. This has implications for the identification and treatment of patients with HDL deficiency. It remains to be determined whether a genetic form of HDL deficiency confers cardiovascular risk.
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