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New genetic link to inflammatory bowel diseases discovered

August 12, 2015

Inflammatory bowel disease (IBD) is a group of common inflammatory conditions affecting the large and small intestine involving both genetic and environmental triggers.

Crohn's disease can affect any part of the gastrointestinal tract, from mouth to anus, while UC affects only the colon and the rectum, but they are sometimes confused as the symptoms for both are similar - abdominal pain, vomiting, diarrhea, bright red blood in stools, weight loss and various associated complaints and both can lead to liver problems, arthritis, skin and eye problems.

Treatment usually depends on the severity of IBD and may call for immunosuppressing drugs to control the symptoms or some form of anti-inflammatory medication.

Steroids too are sometimes used to control disease flare ups and in severe cases surgery may be needed.

IBD can affect and limit the quality of life because of the pain, vomiting, diarrhea, and other socially unacceptable symptoms it causes; it is rarely fatal on its own and the goal of treatment is to achieve some form of remission.

Depending on the circumstances, flare ups may go away on their own or require medication and the time between attacks may be anywhere from weeks to years, and vary greatly between patients.

The study led by Professor Subra Kugathasan from the Medical College of Wisconsin has found two new genes that are linked with IBD in children.

The researchers say previous studies had already identified a genetic variation which accounted for a small portion of the overall genetic susceptibility for CD and an even smaller contribution to UC.

They suspected that examining the disease early on in children might identify additional genes associated with IBD.

They carried out a search in a group of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls and compared their results and two new genes linked to IBD were revealed.

They believe their discovery will open the way for new diagnostic tools to help identify people at risk from the ailment and also lead to drugs able to block or reverse the genes malfunction.

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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