Other polymorphisms

Haemochromatosis gene polymorphisms

Iron metabolism is known to impact on mitochondrial function and oxidative stress (increased oxidant production characterised by the release of free radicals and resulting in cellular degeneration).

A polymorphism linked to haemochromatosis, a condition that causes perturbations of the body's ability to regulate iron levels, has been linked to the risk of peripheral neuropathy in patients taking nucleoside reverse transcriptase inhibitors (NRTIs). Patients with higher iron levels due to heterozygosity at this position were less likely to experience this side-effect.1

The same haemochromatosis gene variant, HFE 187C/G, was also found in one study to be protective against subcutaneous fat loss. In 94 patients, those who were heterozygous for this variant (24%) gained a median of over 6% in limb fat. Those patients homozygous (variant inherited from both parents) for HFE 187C/G lost a median of over 12% limb fat.2

Stavudine (d4T, Zerit) is the NRTI found to be most strongly associated with fat loss. If it could be determined which patients were genetically protected against lipoatrophy, it would widen their range of available therapies.

Other polymorphisms have been associated with the side-effects of HIV treatment in numerous studies. Examples include an association between the polymorphism -G238A in the promoter region of the gene for tumour necrosis factor alpha and the speed of development of fat loss from under the skin, although this association was not found in another study.3 4 5 6 Tumour necrosis factor alpha is involved in the metabolism of fat cells (adipocytes). Another polymorphism in this promoter region is more common in patients with neuropathy as a side-effect of HIV treatment.7

Lipoatrophy has also been linked to a polymorphism in the gene for FAS-670 that is involved in the death and metabolism of fat cells.8

A polymorphism in the gene for resistin, a hormone released by fat tissue, has also been linked to an increased risk of elevated blood triglyceride levels or unfavourable changes in cholesterol levels, as well as alterations in insulin in an exploratory study that screened 285 polymorphisms in 137 candidate genes.9

Although they do retain some biological plausibility, determining whether these isolated observations reflect true biological phenomena or are the result of chance associations requires confirmation in larger studies.

References

  1. Kallianpur AR et al. Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. AIDS 20: 1503-1513, 2006
  2. Huldan T et al. Hemochromatosis gene polymorphisms, mitochondrial haplogroups and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis 197: 858-866, 2008
  3. Tarr PE et al. Modeling the influence of APOC3, APOE, and TNT polymorphisms on the risk of antiretroviral therapy-associated lipid disorders. J Infect Dis 191: 1419-1426, 2005
  4. Maher B et al. TNF-alpha promoter region gene polymorphisms in HIV-positive patients with lipodystrophy. AIDS 16: 2013-2018, 2002
  5. Nolan D et al. Tumour necrosis factor-alpha gene -238G/A promoter polymorphism associated with a more rapid onset of lipodystrophy. AIDS 17: 121-123, 2003
  6. Sethi J et al. The role of TNF alpha in adipocyte metabolism. Semin Cell dev Biol 10: 19-29, 1999
  7. Cherry C et al. Cytokine genotypes establish a role for inflammation in antiretroviral toxic neuropathy and redict an individual's risk. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 344, 2006
  8. Cossarizza A et al. FAS-670 and APOC3 polymorphisms as predictors of lipoatrophy in patients receiving antiretroviral therapy. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 767, 2006
  9. Ranade K et al. A single nucleotide polymorphism in the resistin gene is associated with adverse metabolic changes on HAART: an exploratory pharmacogenetic association study of A5005s, the metabolic sub-study of ACTG 384. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 763, 2006
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

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We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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