Genotype-Based Meta-Analysis Suggests Serum Iron Protects Against PD

Though iron gets a bad rap for accumulating in the brains of older people and individuals with neurodegenerative disease, could an abundance of this metal in the blood bode well? Applying an analytical approach that uses genotyping data to strengthen epidemiological observations, scientists report in the June 4 PLoS Medicine that people with high serum iron are less likely to develop Parkinson’s disease. First authors Irene Pichler and Fabiola Del Greco of the European Academy of Bolzano, Italy, led the work with senior author Cosetta Minelli, who has since moved to Imperial College London, U.K. The findings jibe with recent studies in Parkinson’s mouse models that suggest a protective role for plasma iron. However, before you stock up on iron supplements, some scientists questioned how serum iron relates to the metal’s effects in the brain. The authors agree it is too early to make a clinical recommendation and said more research is needed to understand how serum iron lowers PD risk.

Research has long suggested that buildup of iron spells trouble for the brain. Not only is it a sign of aging in general (see ARF related news story), but people with Parkinson's accumulate the metal in neurons of the substantia nigra and in other brain areas vulnerable to disease (Zecca et al., 2004; Dusek et al., 2012). Some studies suggest that free iron, which can act as an oxidant, promotes formation of pathological α-synuclein aggregates (Crichton et al., 2011).

The impact of blood iron on PD risk is less clear, with studies suggesting it protects against or exacerbates the disease. Such inconsistencies muddled a recent meta-analysis of 10 studies covering more than 1,200 people, which found no difference between serum iron levels in PD patients and controls (Mariani et al., 2013).

Pichler and Del Greco turned to “Mendelian randomization” (MR) to circumvent two nagging problems in epidemiological studies—confounding factors and reverse causation. For instance, smoking and coffee drinking, which have been suggested as protective factors for PD, can skew associations between iron and disease because each influences metabolism of the metal. Spurious conclusions can also arise from reverse causation, where the disease affects the factor being measured instead of the other way around. Monoamine oxidase inhibitors, which are used to treat PD, bind tightly to iron, lowering its concentration in the blood. MR steers clear of these shortcomings by focusing on genetic variants that increase or decrease levels of the epidemiological risk factor. Since genetic variants are unaffected by behavioral or environmental confounders, MR offers an advantage over traditional epidemiological analysis (see Davey Smith and Ebrahim, 2005).

For the current study, the researchers correlated PD risk with two genetic polymorphisms in the hemochromatosis (HFE) gene and one in the gene for transmembrane protease 6 (TMPRSS6). Recent genomewide association studies indicated these genes upregulate blood iron (Benyamin et al., 2009; Pichler et al., 2011). The authors found specific variants within those two genes that associate with high serum iron based on an unpublished meta-analysis of 21,567 people from 10 cohorts in the Genetics of Iron Status (GIS) Consortium, Pichler said. The researchers then looked to see if those HFE and TMPRSS6 variants associated with PD in a meta-analysis of a different dataset comprising 20,809 PD cases and 88,892 controls. There were 24 studies in all.

All three polymorphisms associated with high serum iron. The TMPRSS6 variant also correlated with a reduction in PD incidence, while the HFE polymorphisms showed a trend in the same direction. HFE variants are much rarer than the TMPRSS6 polymorphism, which might explain the lower statistical power, the authors note. Crunching the numbers on all three variants, the MR analysis suggests that a 10 mg/dl increase in serum iron lowers PD risk by about 3 percent.

Considering that serum iron levels in men typically land within 65-176 mg/dl range, a 3 percent risk reduction per 10 mg/dl is “very impressive,” Ashley Bush of the University of Melbourne, Australia, wrote in an e-mail to Alzforum. That means serum iron could explain about a third of the risk of PD in people with no other iron abnormality, Bush noted.

Recent work seems consistent with the new findings. Analyzing postmortem brain tissue from sporadic PD patients, Bush and colleagues found that substantia nigral neurons lost ceruloplasmin activity. This enzyme removes excess iron from tissues, loading it onto the plasma iron transporter protein, transferrin (Ayton et al., 2012). They also reported that ceruloplasmin knockout mice develop PD pathology, but that injecting the enzyme intraperitoneally rescues symptoms. “Loss of ceruloplasmin activity can explain elevated nigral iron and lowered plasma iron, which fits with the findings by Pichler et al.,” Bush noted.

However, while other scientists found the PLoS Medicine data intriguing, they said they still leave much about iron’s role in PD open for debate. “Iron regulation is complex and, like most critical biological pathways, has multiple redundancies and contributing factors,” wrote Caroline Tanner of the Parkinson’s Institute and Clinical Center, Sunnyvale, California, in an e-mail to Alzforum. “I worry that it is a gross oversimplification to assume that a single gene variant (or the combination of three variants) that regulates serum iron levels would be key to explaining iron metabolism in the central nervous system (CNS).” Research suggests that serum iron is inversely correlated with iron levels in the substantia nigra (Walter et al., 2012), though the current study did not assess whether the HFE and TMPRSS6 alleles influence brain iron.

Pichler said they are planning to use the MR approach to see if transferrin and ferritin levels associate with PD risk. Meanwhile, Bush and others are gearing up for an MR analysis of HFE and TMPRSS6 alleles in AD patients in the Australian Imaging, Biomarkers & Lifestyle (AIBL) Flagship Study of Ageing cohort and other datasets.

MR could prove useful for identifying causal factors in other disorders, note the authors, though the approach depends on gene variants strongly affecting intermediate phenotypes. Pleiotropy, which is a situation in which polymorphisms influence disease risk through multiple mechanisms, can also be problematic.—Esther Landhuis

Comments

  1. My overall impression of this paper is that it adds an interesting piece of evidence, but that the story of iron is not a simple one. Iron regulation is complex and, like most critical biological pathways, has multiple redundancies and contributing factors. The crucial assumption of this paper is that the three single nucleotide polymorphisms (SNPs) the authors selected are critical determinants of serum iron levels. However, the data for this are not published, so that assumption has not been peer reviewed. But, assuming it is correct, while I am not an expert by any means, I worry that it is a gross oversimplification to assume that a single gene variant (two did not have statistically significant associations) that regulates serum iron levels would necessarily be key to explaining iron metabolism in the central nervous system.

    We have looked at features potentially related to peripheral iron metabolism and PD risk in the period before the development of the disease (see Abbott et al., 2010). The authors cite two other studies (Logroscino et al., 2008, and Savica et al., 2009) that indirectly support the idea put forth in this paper that higher serum iron protects against PD. Our finding runs somewhat counter, as we found higher normal hemoglobin in elderly men was associated with a higher incidence of PD. In these studies the relationship between peripheral iron and central iron homeostasis, and how the latter might relate to PD pathogenesis, remains an open question. But because these three papers include information collected before PD diagnosis, they avoid the confounding due to disease or treatment that makes other studies so hard to interpret.

    Regarding the analytic approach of Mendelian randomization, I think it is an interesting one and adds an additional tool to our scientific armamentarium, but there are also significant limitations, namely the necessary assumptions regarding the effect of the SNPs, which in most cases will not be met, since biologic processes generally have more than one determinant. Using this approach when the assumptions can be met with confidence would be very helpful in understanding mechanisms for disease.

    References:

    Abbott RD, Ross GW, Tanner CM, Andersen JK, Masaki KH, Rodriguez BL, White LR, Petrovitch H. Late-life hemoglobin and the incidence of Parkinson's disease. Neurobiol Aging. 2012 May;33(5):914-20. PubMed.

    Logroscino G, Gao X, Chen H, Wing A, Ascherio A. Dietary iron intake and risk of Parkinson's disease. Am J Epidemiol. 2008 Dec 15;168(12):1381-8. PubMed.

    Savica R, Grossardt BR, Carlin JM, Icen M, Bower JH, Ahlskog JE, Maraganore DM, Steensma DP, Rocca WA. Anemia or low hemoglobin levels preceding Parkinson disease: a case-control study. Neurology. 2009 Oct 27;73(17):1381-7. PubMed.

    View all comments by Caroline M. Tanner

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References

News Citations

  1. Aging Primates—Brain Iron Up, Motor Skills and Plastic Synapses Down

Paper Citations

  1. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004 Nov;5(11):863-73. PubMed.
  2. Dusek P, Jankovic J, Le W. Iron dysregulation in movement disorders. Neurobiol Dis. 2012 Apr;46(1):1-18. PubMed.
  3. Crichton RR, Dexter DT, Ward RJ. Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm. 2011 Mar;118(3):301-14. PubMed.
  4. Mariani S, Ventriglia M, Simonelli I, Donno S, Bucossi S, Vernieri F, Melgari JM, Pasqualetti P, Rossini PM, Squitti R. Fe and Cu do not differ in Parkinson's disease: a replication study plus meta-analysis. Neurobiol Aging. 2013 Feb;34(2):632-3. PubMed.
  5. Davey Smith G, Ebrahim S. What can mendelian randomisation tell us about modifiable behavioural and environmental exposures?. BMJ. 2005 May 7;330(7499):1076-9. PubMed.
  6. Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP, Hottenga JJ, Henders AK, Campbell MJ, Wallace L, Frazer IH, Heath AC, de Geus EJ, Nyholt DR, Visscher PM, Penninx BW, Boomsma DI, Martin NG, Montgomery GW, Whitfield JB. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet. 2009 Nov;41(11):1173-5. PubMed.
  7. Pichler I, Minelli C, Sanna S, Tanaka T, Schwienbacher C, Naitza S, Porcu E, Pattaro C, Busonero F, Zanon A, Maschio A, Melville SA, Grazia Piras M, Longo DL, Guralnik J, Hernandez D, Bandinelli S, Aigner E, Murphy AT, Wroblewski V, Marroni F, Theurl I, Gnewuch C, Schadt E, Mitterer M, Schlessinger D, Ferrucci L, Witcher DR, Hicks AA, Weiss G, Uda M, Pramstaller PP. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Hum Mol Genet. 2011 Mar 15;20(6):1232-40. PubMed.
  8. Ayton S, Lei P, Duce JA, Wong BX, Sedjahtera A, Adlard PA, Bush AI, Finkelstein DI. Ceruloplasmin dysfunction and therapeutic potential for parkinson disease. Ann Neurol. 2012 Nov 24; PubMed.
  9. Walter U, Witt R, Wolters A, Wittstock M, Benecke R. Substantia nigra echogenicity in Parkinson's disease: relation to serum iron and C-reactive protein. J Neural Transm. 2012 Jan;119(1):53-7. PubMed.

Further Reading

Papers

  1. Kristinsson J, Snædal J, Tórsdóttir G, Jóhannesson T. Ceruloplasmin and iron in Alzheimer's disease and Parkinson's disease: a synopsis of recent studies. Neuropsychiatr Dis Treat. 2012;8:515-21. PubMed.
  2. Ayton S, Lei P, Duce JA, Wong BX, Sedjahtera A, Adlard PA, Bush AI, Finkelstein DI. Ceruloplasmin dysfunction and therapeutic potential for parkinson disease. Ann Neurol. 2012 Nov 24; PubMed.
  3. Mariani S, Ventriglia M, Simonelli I, Donno S, Bucossi S, Vernieri F, Melgari JM, Pasqualetti P, Rossini PM, Squitti R. Fe and Cu do not differ in Parkinson's disease: a replication study plus meta-analysis. Neurobiol Aging. 2013 Feb;34(2):632-3. PubMed.

Primary Papers

  1. Pichler I, Del Greco M F, Gögele M, Lill CM, Bertram L, Do CB, Eriksson N, Foroud T, Myers RH, , Nalls M, Keller MF, Benyamin B, Whitfield JB, Pramstaller PP, Hicks AA, Thompson JR, Minelli C. Serum iron levels and the risk of Parkinson disease: a mendelian randomization study. PLoS Med. 2013 Jun;10(6):e1001462. PubMed.

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