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Correlation of geographic distributions of haptoglobin alleles with prevalence of multiple sclerosis (MS) – a narrative literature review

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Abstract

We have proposed that the myelin damage observed in multiple sclerosis (MS) may be partly mediated through the long-term release and degradation of extracellular hemoglobin (Hb) and the products of its oxidative degradation [Cellular and Molecular Life Sciences, 71, 1789-1798, 2014]. The protein haptoglobin (Hpt) binds extracellular Hb as a first line of defense, and can serve as a vascular antioxidant. Humans have two different Hpt alleles: Hpt1 and Hpt2, giving either homozygous Hpt1-1 or Hpt2-2 phenotypes, or a heterozygous Hpt1-2 phenotype. We questioned whether those geographic regions with higher frequency of the Hpt2 allele (conversely, lower frequency of Hpt1 allele) would correlate with an increased incidence of MS, because different Hpt phenotypes will have variable anti-oxidative potentials in protecting myelin from damage inflicted by extracellular Hb and its degradation products. To test this hypothesis, we undertook a systematic analysis of the literature on reported geographic distributions of Hpt alleles to compare them with data reported in the World Health Organization Atlas of worldwide MS prevalence. We found the frequency of the Hpt1 allele to be low in European and North American countries with a high prevalence of MS, consistent with our hypothesis. However, this correlation was not observed in China and India, countries with the lowest Hpt1 frequencies, yet low reported prevalence of MS. Nevertheless, this work shows the need for continued refinement of geographic patterns of MS prevalence, including data on ethnic or racial origin, and for new clinical studies to probe the observed correlation and evaluate Hpt phenotype as a predictor of disease variability and progression, severity, and/or comorbidity with cardiovascular disorders.

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Abbreviations

EAE:

Experimental autoimmune encephalomyelitis

Hb:

Hemoglobin

Hpt:

Haptoglobin

HWP:

Hardy-Weinberg principle

MS:

Multiple sclerosis

PD:

Parkinson’s disease

References

  • Adams CWM (1988) Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry 51(2):260–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adams CW, Poston RN, Buk SJ, Sidhu YS, Vipond H (1985) Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 69(3):269–283

    Article  CAS  PubMed  Google Scholar 

  • Ahmad R, Alam A, Fatima F, Hasnain AU (2008) Genetic diversity of serum proteins in some Muslim populations of India. Hum Biol 80(5):501–512. doi:10.3378/1534-6617-80.5.501

    Article  PubMed  Google Scholar 

  • Akkad DA, Lee DH, Bruch K, Haghikia A, Epplen JT, Hoffjan S, Linker RA (2016) Multiple sclerosis in families: risk factors beyond known genetic polymorphisms. Neurogenetics 17(2):131–135. doi:10.1007/s10048-016-0474-4

    Article  PubMed  Google Scholar 

  • Aksoy M, Kutlar A, Kutlar F, Dincol G, Erdem S, Bastesbihci S (1985) Survey on haemoglobin variants, beta thalassaemia, glucose-6-phosphate dehydrogenase deficiency, and haptoglobin types in Turks from western Thrace. J Med Genet 22(4):288–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Albor C, du Sautoy T, Kali VN, Turner BP, Boomla K, Schmierer K (2016) Ethnicity and prevalence of multiple sclerosis in east London. Mult Scler. doi:10.1177/1352458516638746

    PubMed  Google Scholar 

  • Al-Radaideh AM, Wharton SJ, Lim SY, Tench CR, Morgan PS, Bowtell RW, Constantinescu CS, Gowland PA (2013) Increased iron accumulation occurs in the earliest stages of demyelinating disease: an ultra-high field susceptibility mapping study in Clinically Isolated Syndrome. Mult Scler 19(7):896–903. doi:10.1177/1352458512465135

    Article  CAS  PubMed  Google Scholar 

  • Alter M, Kahana E, Zilber N, Miller A (2006) Multiple sclerosis frequency in Israel’s diverse populations. Neurology 66(7):1061–1066. doi:10.1212/01.wnl.0000204194.47925.0d

    Article  PubMed  Google Scholar 

  • Altinoz MA, Ozcan EM, Ince B, Guloksuz S (2016) Hemoglobins as new players in multiple sclerosis: metabolic and immune aspects. Metab Brain Dis 31(5): 983–992. doi:10.1007/s11011-016-9845-7

  • Alvarado-Esquivel C, Delanghe J (2007) Analysis of haptoglobin phenotype polymorphism in a Mennonite population of northern Mexico. Rev Investig Clin 59(6):491–492

    Google Scholar 

  • Amiri AA, Hashemi-Soteh MB, Haghshenas MR, Daneshvar F, Rastegar A, Farazmand T (2013) Haptoglobin polymorphism in individuals with type 2 diabetic microangiopathy. N Am J Med Sci 5(9):529–535. doi:10.4103/1947-2714.118929

    Article  PubMed  PubMed Central  Google Scholar 

  • Ananthakrishnan R (1972) Further studies on the distribution of some serum protein and enzyme groups in South India. Humangenetik 15(2):172–176

    CAS  PubMed  Google Scholar 

  • Ananthakrishnan R, Beck W, Walter H, Arndt-Hanser A, Gumbel W, Leithoff H, Wigand R, Zimmermann W, von BB (1973) A mother-child combination analysis for ABO-Hp interaction. Humangenetik 18 (3): 203-206

  • Ananthakrishnan R, Beck W, Walter H (1974) ABO incompatibility and its interaction with haptoglobins and placental alkaline phosphatase. Humangenetik 23(1):31–43

    Article  CAS  PubMed  Google Scholar 

  • Bagnato F, Hametner S, Yao B, van Gelderen P, Merkle H, Cantor FK, Lassmann H, Duyn JH (2011) Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla. Brain 134(Pt 12):3602–3615

    Article  PubMed  Google Scholar 

  • Baitsch H, Meier G, Schoeller L, Kahlich-Koenner DM (1960) Frequencies of the haptoglobin serum groups among blood donors from Austria and Germany. Nature 186(4729):976–977

    Article  CAS  PubMed  Google Scholar 

  • Bamm VV, Harauz G (2014) Hemoglobin as a source of iron overload in multiple sclerosis: does multiple sclerosis share risk factors with vascular disorders? Cell Mol Life Sci 71(10):1789–1798. doi:10.1007/s00018-014-1570-y

    Article  CAS  PubMed  Google Scholar 

  • Bamm VV, Lanthier DK, Stephenson EL, Smith GST, Harauz G (2015) In vitro study of the direct effect of extracellular hemoglobin on myelin components. Biochim Biophys Acta (Molecular Basis of Disease) 1852(1):92–103. doi:10.1016/j.bbadis.2014.10.009

    Article  CAS  Google Scholar 

  • Bandyopadhyay AR (1993) A parental combination analysis for ABO-HP interaction in a Bengali population. Hum Genet 91(4):377–379

    Article  CAS  PubMed  Google Scholar 

  • Banwell B, Bar-Or A, Arnold DL, Sadovnick D, Narayanan S, McGowan M, O’Mahony J, Magalhaes S, Hanwell H, Vieth R, Tellier R, Vincent T, Disanto G, Ebers G, Wambera K, Connolly MB, Yager J, Mah JK, Booth F, Sebire G, Callen D, Meaney B, Dilenge ME, Lortie A, Pohl D, Doja A, Venketaswaran S, Levin S, Macdonald EA, Meek D, Wood E, Lowry N, Buckley D, Yim C, Awuku M, Cooper P, Grand’maison F, Baird JB, Bhan V, Marrie RA (2011) Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol 10(5):436–445. doi:10.1016/S1474-4422(11)70045-X

    Article  CAS  PubMed  Google Scholar 

  • Beck CA, Metz LM, Svenson LW, Patten SB (2005) Regional variation of multiple sclerosis prevalence in Canada. Mult Scler 11(5):516–519

    Article  PubMed  Google Scholar 

  • Beckman L, Beckman G, Frolander N (1983) Population studies in northern Sweden. XII The haptoglobin polymorphism Hum Hered 33(6):371–376

    Article  CAS  PubMed  Google Scholar 

  • Bessa SS, Hamdy SM, Ali EM (2007) Haptoglobin gene polymorphism in type 2 diabetic patients with and without nephropathy: An Egyptian study. Eur J Intern Med 18(6):489–495. doi:10.1016/j.ejim.2007.02.033

    Article  CAS  PubMed  Google Scholar 

  • Bhasin MK, Walter H, Singh IP, Meena R (1981) Geographic and ethnic distribution of genetic markers in India. 1. Haptoglobin and transferrin polymorphisms. Anthropol Anz 39(1):36–60

    CAS  PubMed  Google Scholar 

  • Blumberg BS, Murray RF Jr, Allison AC, Barnicot NA, Hirschfeld J, Krimbas C (1964) Serum protein polymorphisms in Greek populations. Ann Hum Genet 28(1-3):189–194

    Article  CAS  PubMed  Google Scholar 

  • Bonné B, Godber M, Ashbel S, Mourant AE, Tills D (1971) South-Sinai Beduin. A preliminary report on their inherited blood factors. Am J Phys Anthropol 34(3):397–408. doi:10.1002/ajpa.1330340309

    Article  PubMed  Google Scholar 

  • Bonné-Tamir B, Ashbel S, Bar-Shani S (1978a) Ethnic communities in Israel: the genetic blood markers of the Babylonian Jews. Am J Phys Anthropol 49(4):457–464. doi:10.1002/ajpa.1330490405

    Article  PubMed  Google Scholar 

  • Bonné-Tamir B, Ashbel S, Bar-Shani S (1978b) Ethnic communities in Israel: the genetic blood markers of the Moroccan Jews. Am J Phys Anthropol 49(4):465–471. doi:10.1002/ajpa.1330490406

    Article  PubMed  Google Scholar 

  • Braeckman L, De BD, Delanghe J, Claeys L, De BG (1999) Associations between haptoglobin polymorphism, lipids, lipoproteins and inflammatory variables. Atherosclerosis 143(2):383–388

    Article  CAS  PubMed  Google Scholar 

  • Buckton K, Lai LY, Gibson JB (1981) A search for association between gene markers and serum cholesterol, triglyceride, urate and blood pressure. Ann Hum Biol 8(1):39–48

    Article  CAS  PubMed  Google Scholar 

  • Bush WS, Sawcer SJ, De Jager PL, Oksenberg JR, McCauley JL, Pericak-Vance MA, Haines JL (2010) Evidence for polygenic susceptibility to multiple sclerosis-the shape of things to come. Am J Hum Genet 86(4):621–625. doi:10.1016/j.ajhg.2010.02.027

    Article  PubMed  CAS  Google Scholar 

  • Carter K, Worwood M (2007) Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases. Int J Lab Hematol 29(2):92–110. doi:10.1111/j.1751-553X.2007.00898.x

    Article  PubMed  Google Scholar 

  • Carter K, Bowen DJ, McCune CA, Worwood M (2003) Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis. Br J Haematol 122(2):326–332

    Article  CAS  PubMed  Google Scholar 

  • Cartwright RA, Adib R, Appleyard I, Coxon JG, Glashan RW, Richards B, Robinson MR, Sunderland E, Barham-Hall D (1983) Ten genetic polymorphisms in bladder cancer. J Med Genet 20(2):112–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cendrowski W, Murawski K, Szymanowska Z (1963) [Haptoglobins and blood groups in familial multiple sclerosis] (Article in Polish). Neurol Neurochir Psychiatr Pol 13 (−): 183-188

  • Chapelle JP, Albert A, Smeets JP, Heusghem C, Kulbertus HE (1982) Effect of the haptoglobin phenotype on the size of a myocardial infarct. N Engl J Med 307(8):457–463. doi:10.1056/NEJM198208193070801

    Article  CAS  PubMed  Google Scholar 

  • Christiansen CF (2012) Risk of vascular disease in patients with multiple sclerosis: a review. Neurol Res 34(8):746–753. doi:10.1179/1743132812Y.0000000051

    Article  PubMed  Google Scholar 

  • Cid MC, Grant DS, Hoffman GS, Auerbach R, Fauci AS, Kleinman HK (1993) Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest 91(3):977–985. doi:10.1172/JCI116319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen T, Simhai B, Steinberg AG, Levene C (1981) Genetic polymorphisms among Iranian Jews in Israel. Am J Med Genet 8(2):181–190. doi:10.1002/ajmg.1320080209

    Article  PubMed  Google Scholar 

  • Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517. doi:10.1016/S0140-6736(08)61620-7

    Article  CAS  PubMed  Google Scholar 

  • Costa-Mallen P, Checkoway H, Zabeti A, Edenfield MJ, Swanson PD, Longstreth WT Jr, Franklin GM, Smith-Weller T, Sadrzadeh SM (2008) The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet 147B(2):216–222. doi:10.1002/ajmg.b.30593

    Article  CAS  PubMed  Google Scholar 

  • Costa-Mallen P, Zabetian CP, Agarwal P, Hu SC, Yearout D, Samii A, Leverenz JB, Roberts JW, Checkoway H (2015) Haptoglobin phenotype modifies serum iron levels and the effect of smoking on Parkinson disease risk. Parkinsonism Relat Disord 21(9):1087–1092. doi:10.1016/j.parkreldis.2015.07.006

    Article  PubMed  PubMed Central  Google Scholar 

  • Costa-Mallen P, Zabetian CP, Agarwal P, Hu SC, Yearout D, Samii A, Leverenz JB, Roberts JW, Checkoway H (2016) Response to the letter "Haptoglobin phenotype and Parkinson disease risk" by Delanghe et al. Parkinsonism Relat Disord 22(1):110–111. doi:10.1016/j.parkreldis.2015.10.021

    Article  PubMed  PubMed Central  Google Scholar 

  • Craelius W, Jacobs RM, Jones AO (1980) Mineral composition of brains of normal and multiple sclerosis victims. Proc Soc Exp Biol Med 165(2):327–329

    Article  CAS  PubMed  Google Scholar 

  • Craelius W, Migdal MW, Luessenhop CP, Sugar A, Mihalakis I (1982) Iron deposits surrounding multiple sclerosis plaques. Arch Pathol Lab Med 106(8):397–399

    CAS  PubMed  Google Scholar 

  • Crawford MH, Leyshon WC, Brown K, Lees F, Taylor L (1974) Human biology in Mexico. II. A comparison of blood group, serum and red cell enzyme frequencies, and genetic distances of the Indian populations of Mexico. Am J Phys Anthropol 41(2):251–268. doi:10.1002/ajpa.1330410208

    Article  CAS  PubMed  Google Scholar 

  • Cree BA, Khan O, Bourdette D, Goodin DS, Cohen JA, Marrie RA, Glidden D, Weinstock-Guttman B, Reich D, Patterson N, Haines JL, Pericak-Vance M, DeLoa C, Oksenberg JR, Hauser SL (2004) Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 63(11):2039–2045

    Article  CAS  PubMed  Google Scholar 

  • Cristiano E, Patrucco L, Miguez J, Giunta D, Peroni J, Rojas JI (2016) Increasing incidence of multiple sclerosis among women in Buenos Aires: a 22 year health maintenance organization based study. Neurol Sci 37(10):1621–1626. doi:10.1007/s10072-016-2637-3

    Article  CAS  PubMed  Google Scholar 

  • D’haeseleer M, Cambron M, Vanopdenbosch L, De Keyser J (2011) Vascular aspects of multiple sclerosis. Lancet Neurol 10(7):657–666. doi:10.1016/S1474-4422(11)70105-3

    Article  PubMed  Google Scholar 

  • Das SK, Mukherjee BN, Malhotra KC, Majumder PP (1978) Serological and biochemical investigations among five endogamous groups of Delhi, India. Ann Hum Biol 5(1):25–31

    Article  CAS  PubMed  Google Scholar 

  • Delanghe JR, De Buyzere ML, Speeckaert MM, Langlois MR (2016) Haptoglobin phenotype and Parkinson disease risk. Parkinsonism Relat Disord 22(1):108–109. doi:10.1016/j.parkreldis.2015.10.020

    Article  PubMed  Google Scholar 

  • Dhiman SR, Konn M, Singh L, Bansal IJ (1985) Serum proteins among Dusads of Bihar. Anthropol Anz 43(1):87–89

    CAS  PubMed  Google Scholar 

  • Di Lorenzo D, Biasiotto G, Zanella I (2014) Source of iron overload in multiple sclerosis. Cell Mol Life Sci 71(16):3187–3189. doi:10.1007/s00018-014-1641-0

    Article  CAS  PubMed  Google Scholar 

  • Dincol G, Aksoy M, Erdem S, Dincol K (1985) Haptoglobin and transferrin types in Eti-Turks. Hum Hered 35(2):115–116

    Article  CAS  PubMed  Google Scholar 

  • Dumont D, Noben JP, Raus J, Stinissen P, Robben J (2004) Proteomic analysis of cerebrospinal fluid from multiple sclerosis patients. Proteomics 4(7):2117–2124. doi:10.1002/pmic.200300715

    Article  CAS  PubMed  Google Scholar 

  • Ebadian AR, Kadkhodazadeh M, Naghavi SH, Torshabi M, Tamizi M (2014) Haptoglobin gene polymorphisms in peri-implantitis and chronic periodontitis. J Investig Clin Dent 5(2):125–130. doi:10.1111/jicd.12028

    Article  PubMed  Google Scholar 

  • Ebers GC, Sadovnick AD (1993) The geographic distribution of multiple sclerosis: a review. Neuroepidemiology 12(1):1–5

    Article  CAS  PubMed  Google Scholar 

  • Eisele P, Alonso A, Griebe M, Szabo K, Hennerici MG, Gass A (2016) Investigation of cerebral microbleeds in multiple sclerosis as a potential marker of blood-brain barrier dysfunction. Mult Scler Relat Disord 7:61–64. doi:10.1016/j.msard.2016.03.010

    Article  PubMed  Google Scholar 

  • Erdem S, Aksoy M (1975) A note on the distribution of haptoglobin types in Turkey. Hum Hered 25(1):18–19

    Article  CAS  PubMed  Google Scholar 

  • Farhud DD (1980) Haptoglobin polymorphism in the Middle East. Jinrui Idengaku Zasshi (Japanese J Hum Genet ) 25(3):203–206. doi:10.1007/BF01997696

    Article  CAS  Google Scholar 

  • Farias AS, Pradella F, Schmitt A, Santos LM, Martins-de-Souza D (2014) Ten years of proteomics in multiple sclerosis. Proteomics 14(4-5):467–480. doi:10.1002/pmic.201300268

    Article  CAS  PubMed  Google Scholar 

  • Fazeli AS, Nasrabadi D, Sanati MH, Pouya A, Ibrahim SM, Baharvand H, Salekdeh GH (2010) Proteome analysis of brain in murine experimental autoimmune encephalomyelitis. Proteomics 10(15):2822–2832. doi:10.1002/pmic.200900507

    Article  CAS  PubMed  Google Scholar 

  • Ford EB (1971) Ecological Genetics, 3 edn. Chapman and Hall, London

    Google Scholar 

  • Fröhlander N, Johnson O (1989) Haptoglobin groups in acute myocardial infarction. Hum Hered 39(6):345–350

    Article  PubMed  Google Scholar 

  • Galea J, Cruickshank G, Teeling JL, Boche D, Garland P, Perry VH, Galea I (2012) The intrathecal CD163-haptoglobin-hemoglobin scavenging system in subarachnoid hemorrhage. J Neurochem 121(5):785–792. doi:10.1111/j.1471-4159.2012.07716.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galicia G, Maes W, Verbinnen B, Kasran A, Bullens D, Arredouani M, Ceuppens JL (2009) Haptoglobin deficiency facilitates the development of autoimmune inflammation. Eur J Immunol 39(12):3404–3412. doi:10.1002/eji.200939291

    Article  CAS  PubMed  Google Scholar 

  • Germenis A, Babionitakis A, Kaloterakis A, Filiotou A, Fertakis A (1983) Group-specific component and haptoglobin phenotypes in multiple myeloma. Hum Hered 33(3):188–191

    Article  CAS  PubMed  Google Scholar 

  • Giblett ER (1962) Haptoglobins and transferrins in Pacific populations. Eugen Q 9 (−): 45-48

  • Giblett ER, Motusky AG, Fraser GR (1966) Population genetic studies in the Congo. IV Haptoglobin and transferrin serum groups in the Congo and in other African populations Am J Hum Genet 18(6):553–558

    CAS  PubMed  Google Scholar 

  • Giovannoni G, Butzkueven H, Dhib-Jalbut S, Hobart J, Kobelt G, Pepper G, Sormani MP, Thalheim C, Traboulsee A, Vollmer T (2016) Brain health: Time matters in multiple sclerosis. Mult Scler Relat Disord 9(Supplement 1):S5–S48. doi:10.1016/j.msard.2016.07.003

    Article  PubMed  Google Scholar 

  • Gloria-Bottini E, Cosmi E, Nicotra M, Cosmi EV, Bottini E (2005) Is delayed childbearing changing gene frequencies in Western populations? Hum Biol 77(4):433–441

    Article  CAS  PubMed  Google Scholar 

  • Grant SM, Wiesinger JA, Beard JL, Cantorna MT (2003) Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutr 133(8):2635–2638

    CAS  PubMed  Google Scholar 

  • Graversen JH, Madsen M, Moestrup SK (2002) CD163: a signal receptor scavenging haptoglobin-hemoglobin complexes from plasma. Int J Biochem Cell Biol 34(4):309–314

    Article  CAS  PubMed  Google Scholar 

  • Grisi ME, Azevêdo ES (1976) Hypohaptoglobinemia in rural and urban populations of Bahia state, Brazil. Hum Biol 48(4):653–657

    CAS  PubMed  Google Scholar 

  • Guthrie PA, Abdollahi MR, Gaunt T, Lawlor DA, Ben-Shlomo Y, Gallacher J, Davey SG, Day IN, Rodriguez S (2014) Haptoglobin duplicon, hemoglobin, and vitamin C: analyses in the British women’s heart and health study and Caerphilly prospective study. Dis Markers 2014 (Article 529456): 529456-1-5. doi:10.1155/2014/529456

  • Gutteridge JM (1987) The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917(2):219–223

    Article  CAS  PubMed  Google Scholar 

  • Haacke EM (2011) Chronic cerebral spinal venous insufficiency in multiple sclerosis. Expert Rev Neurother 11(1):5–9. doi:10.1586/ern.10.174

    Article  PubMed  Google Scholar 

  • Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z, Xuan Y, Khan O, Garbern J, Grossman RI (2009) Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging 29(3):537–544. doi:10.1002/jmri.21676

    Article  PubMed  PubMed Central  Google Scholar 

  • Haacke EM, Garbern J, Miao Y, Habib C, Liu M (2010a) Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol 29(2):149–157

    CAS  PubMed  Google Scholar 

  • Haacke EM, Tang J, Neelavalli J, Cheng YC (2010b) Susceptibility mapping as a means to visualize veins and quantify oxygen saturation. J Magn Reson Imaging 32(3):663–676. doi:10.1002/jmri.22276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Habib Z (1983) Haptoglobin polymorphism in Egyptians. Ann Hum Biol 10(4):385–387

    Article  CAS  PubMed  Google Scholar 

  • Habib CA, Liu M, Bawany N, Garbern J, Krumbein I, Mentzel HJ, Reichenbach J, Magnano C, Zivadinov R, Haacke EM (2012) Assessing abnormal iron content in the deep gray matter of patients with multiple sclerosis versus healthy controls. AJNR Am J Neuroradiol 33(2):252–258. doi:10.3174/ajnr.A2773

    Article  CAS  PubMed  Google Scholar 

  • Hametner S, Wimmer I, Haider L, Pfeifenbring S, Bruck W, Lassmann H (2013) Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 74(6):848–861. doi:10.1002/ana.23974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hardwick RJ, Menard A, Sironi M, Milet J, Garcia A, Sese C, Yang F, Fu B, Courtin D, Hollox EJ (2014) Haptoglobin (HP) and Haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis. Hum Genet 133(1):69–83. doi:10.1007/s00439-013-1352-x

    Article  CAS  PubMed  Google Scholar 

  • Hashem N, Kamel K, Hammoud EI (1966) Haptoglobin phenotypes among Egyptians. J Med Genet 3(4):279–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hauge M, Heiken A, Hoglund C (1970) Studies on the haptoglobin system. II The development and distribution of Hp groups in children Hum Hered 20(5):557–565

    CAS  PubMed  Google Scholar 

  • Hitzeroth HW, Hummel K (1978) Serum protein polymorphisms Hp, Tf, Gc, Gm, Inv and Pt in Bantu speaking South African Negroids. Anthropol Anz 36(2):127–141

    CAS  PubMed  Google Scholar 

  • Hoglund C, Heiken A, Hauge M (1970) Studies on the haptoglobin system. I The distribution of Hp groups in the Swedish population Hum Hered 20(5):549–556

    CAS  PubMed  Google Scholar 

  • Hum S, Lapierre Y, Scott SC, Duquette P, Mayo NE (2016) Trajectory of MS disease course for men and women over three eras. Mult Scler J. doi:10.1177/1352458516655478

  • Hummel K, Pulverer G, Schaal KP, Weidtman V (1970) [Phenotype frequencies in the genetic systems haptoglobin, Gc, erythrocyte acid phosphatase, phosphoglucomutase and adenylate kinase, as well as the genetic properties Gm(1), Gm(2) and Inv(1) in German population (Freiburg i Br and Cologne) and in Turkish people] (Article in German). Humangenetik 8(4):330–333

    CAS  PubMed  Google Scholar 

  • Ibrahim WN, Kamel K, Selim O, Azim A, Gaballah MF, Sabry F, el-Naggar A, Hoerman K (1974) Hereditary blood factors and anthropometry of the inhabitants of the Egyptian Siwa Oasis. Hum Biol 46(1):57–68

    CAS  PubMed  Google Scholar 

  • International MS Genetics Consortium (2013) Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 3,000 controls. Am J Hum Genet 92(5):854–865

    Google Scholar 

  • Jadidi E, Mohammadi M, Moradi T (2013) High risk of cardiovascular diseases after diagnosis of multiple sclerosis. Mult Scler J 19(10):1336–1340. doi:10.1177/1352458513475833

    Article  Google Scholar 

  • Jayanthi M, Habibullah CM, Ishaq M, Ali H, Babu PS, Ali MM (1989) Distribution of haptoglobin phenotypes in oesophageal and gastric cancer. J Med Genet 26(3):172–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, Eaton JW, Balla G (2002) Pro-oxidant and cytotoxic effects of circulating heme. Blood 100(3):879–887

    Article  CAS  PubMed  Google Scholar 

  • Jeney V, Eaton JW, Balla G, Balla J (2013) Natural history of the bruise: formation, elimination, and biological effects of oxidized hemoglobin. Oxidative Med Cell Longev 2013:703571. doi:10.1155/2013/703571

    Article  CAS  Google Scholar 

  • Jiang SF, Lu QY, Hu S, Chen Y, Liu XL, Yang Y, Ding MP (2014) Proteomics comparison of the sera from multiple sclerosis patients and neuromyelitis optica patients. Genet Mol Res 13(4):9292–9299. doi:10.4238/2014.February.14.3

    Article  CAS  PubMed  Google Scholar 

  • Kappus N, Weinstock-Guttman B, Hagemeier J, Kennedy C, Melia R, Carl E, Ramasamy DP, Cherneva M, Durfee J, Bergsland N, Dwyer MG, Kolb C, Hojnacki D, Ramanathan M, Zivadinov R (2016) Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 87(2):181–187. doi:10.1136/jnnp-2014-310051

    PubMed  Google Scholar 

  • Karmon Y, Ramanathan M, Minagar A, Zivadinov R, Weinstock-Guttman B (2012) Arterial, venous and other vascular risk factors in multiple sclerosis. Neurol Res 34(8):754–760. doi:10.1179/1743132812Y.0000000077

    Article  CAS  PubMed  Google Scholar 

  • Kaur H, Sehajpal PK, Shrivastava PK (1981) Distribution of some genetic traits in three populations from Punjab, North India. Anthropol Anz 39(1):66–69

    CAS  PubMed  Google Scholar 

  • Khazaei HA, Teymuri B, Nakhaei A, Mohammadi M, Noura M, Khazaei A, Tofigh N, Rezaei N (2014) Evaluation of haptoglobin phenotypes in association with clinical features of patients suffered from preterm labor disease. Acta Med Iran 52(2):106–110

    CAS  PubMed  Google Scholar 

  • Kirk RL (1968) The Haptoglobin Groups in Man. S. Karger, Basel/New York, pp. 1–77

    Google Scholar 

  • Kirk RL, Kinns H, Morton NE (1970) Interaction between the ABO blood group and haptoglobin systems. Am J Hum Genet 22(4):384–389

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kleisbauer JP, Poirier R, Artinian H, Arnoux A, Laval P (1975) Study of the distribution of haptoglobin groups in Marseilles, in normal and in cancer subjects. C R Seances Soc Biol Fil 169(3 Suppl):811–814

    CAS  PubMed  Google Scholar 

  • Krüger A, Püschel K (1993) Haptoglobin subtypes in northern Germany (Hamburg). Int J Legal Med 106(1):53–54

    Article  PubMed  Google Scholar 

  • Lai LY, Constans J, Archer GT (1986) Isoelectric focusing studies of transferrin and haptoglobin subtypes in an Australian white population. Ann Hum Biol 13(6):555–561

    Article  CAS  PubMed  Google Scholar 

  • Lange V (1992) Haptoglobin polymorphism--not only a genetic marker. Anthropol Anz 50(4):281–302

    CAS  PubMed  Google Scholar 

  • Langlois MR, Delanghe JR (1996) Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem 42(10):1589–1600

    CAS  PubMed  Google Scholar 

  • Larkin MF (1967) Serum haptoglobin type and cancer. J Natl Cancer Inst 39(4):633–638

    CAS  PubMed  Google Scholar 

  • Lassmann H (2013) Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci 333(1-2):1–4. doi:10.1016/j.jns.2013.05.010

    Article  CAS  PubMed  Google Scholar 

  • Lassmann H, van Horssen J (2011) The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett 585(23):3715–3723. doi:10.1016/j.febslet.2011.08.004

    Article  CAS  PubMed  Google Scholar 

  • Lassmann H, Bruck W, Lucchinetti C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 7(3):115–121

    Article  CAS  PubMed  Google Scholar 

  • Latner AL, Zaki AH (1960) Clinical uses of starch gel electrophoresis with special reference to leukaemia. Clin Chim Acta 5(1):22–25

    Article  CAS  PubMed  Google Scholar 

  • Law M, Saindane AM, Ge Y, Babb JS, Johnson G, Mannon LJ, Herbert J, Grossman RI (2004) Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology 231(3):645–652. doi:10.1148/radiol.2313030996

    Article  PubMed  Google Scholar 

  • Lehmann H, Ala F, Hedeyat S, Montazemi K, Nejad HK, Lightman S, Kopec AC, Mourant AE, Teesdale P, Tills D (1973) XI. The hereditary blood factors of the Kurds of Iran. Philos Trans R Soc Lond Ser B Biol Sci 266(876):195–205

    Article  CAS  Google Scholar 

  • Levene C, Steinberg AG, Friedlander Y, Brautbar C, Cohen T (1984) Genetic polymorphisms among Bukharan and Georgian Jews in Israel. Am J Med Genet 19(4):623–641. doi:10.1002/ajmg.1320190402

    Article  CAS  PubMed  Google Scholar 

  • LeVine SM (2016) Albumin and multiple sclerosis. BMC Neurol 16(1) 47-1-47-12. doi:10.1186/s12883-016-0564-9

  • Levy AP, Roguin A, Hochberg I, Herer P, Marsh S, Nakhoul FM, Skorecki K (2000) Haptoglobin phenotype and vascular complications in patients with diabetes. N Engl J Med 343(13):969–970. doi:10.1056/NEJM200009283431313

    Article  CAS  PubMed  Google Scholar 

  • Liang CC, Qi ZB, Ying QL, Wang LF (1983) Types and Subtypes of Haptoglobin in the Chinese Population. Hum Genet 63(2):175–177

    Article  CAS  PubMed  Google Scholar 

  • Lisker R, Pérez-Briceño R, Granados J, Babinsky V, de RJ, Armendares S, Buentello L (1986) Gene frequencies and admixture estimates in a Mexico City population. Am J Phys Anthropol 71 (2): 203–207. doi:10.1002/ajpa.1330710207

  • Lisker R, Pérez-Briceño R, Granados J, Babinsky V (1988) Gene frequencies and admixture estimates in the state of Puebla, Mexico. Am J Phys Anthropol 76(3):331–335. doi:10.1002/ajpa.1330760307

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Bai S, Qin Z, Yang Y, Cui Y, Qin Y (2009) Quantitative proteomic analysis of the cerebrospinal fluid of patients with multiple sclerosis. J Cell Mol Med 13(8A):1586–1603. doi:10.1111/j.1582-4934.2009.00850.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lumsden CE (1971) The immunogenesis of the multiple sclerosis plaque. Brain Res 28(3):365–390

    Article  CAS  PubMed  Google Scholar 

  • MacLean CH, Adams MS, Leyshon WC, Workman PL, Reed TE, Gershowitz H, Weitkamp LR (1974) Genetic studies on hybrid populations. 3. Blood pressure in an American black community. Am J Hum Genet 26(5):614–626

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maes M, Delanghe J, Scharpe S, Meltzer HY, Cosyns P, Suy E, Bosmans E (1994) Haptoglobin phenotypes and gene frequencies in unipolar major depression. Am J Psychiatry 151(1):112–116

    Article  CAS  PubMed  Google Scholar 

  • Maes M, Delanghe J, Bocchio CL, Bignotti S, Tura GB, Pioli R, Zanardini R, Altamura CA (2001) Haptoglobin polymorphism and schizophrenia: genetic variation on chromosome 16. Psychiatry Res 104(1):1–9

    Article  CAS  PubMed  Google Scholar 

  • Mahmud SM, Koushik A, Duarte-Franco E, Costa J, Fontes G, Bicho M, Coutlee F, Franco EL (2007) Haptoglobin phenotype and risk of cervical neoplasia: a case-control study. Clin Chim Acta 385(1-2):67–72. doi:10.1016/j.cca.2007.06.020

    Article  CAS  PubMed  Google Scholar 

  • Mandato VD, Magnani E, Abrate M, Casali B, Nicoli D, Farnetti E, Formisano D, Pirillo D, Ciarlini G, De IP, Strada I, Zamagni C, La Sala GB (2012) Haptoglobin phenotype and epithelial ovarian cancer. Anticancer Res 32(10):4353–4358

    CAS  PubMed  Google Scholar 

  • Marchesi VT (2014) Alzheimer’s disease and CADASIL are heritable, adult-onset dementias that both involve damaged small blood vessels. Cell Mol Life Sci 71(6):949–955. doi:10.1007/s00018-013-1542-7

    Article  CAS  PubMed  Google Scholar 

  • Marrie RA (2004) Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 3(12):709–718. doi:10.1016/S1474-4422(04)00933-0

    Article  PubMed  Google Scholar 

  • Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T (2010) Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology 74(13):1041–1047. doi:10.1212/WNL.0b013e3181d6b125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marrie RA, Yu BN, Leung S, Elliott L, Caetano P, Warren S, Wolfson C, Patten SB, Svenson LW, Tremlett H, Fisk J, Blanchard JF (2012) Rising prevalence of vascular comorbidities in multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and hyperlipidemia. Mult Scler 18(9):1310–1319. doi:10.1177/1352458512437814

    Article  PubMed  Google Scholar 

  • Maza I, Miller-Lotan R, Levy AP, Nesher S, Karban A, Eliakim R (2008) The association of Haptoglobin polymorphism with Crohn’s disease in Israel. J Crohns Colitis 2(3):214–218. doi:10.1016/j.crohns.2008.03.005

    Article  PubMed  Google Scholar 

  • Miller YI, Altamentova SM, Shaklai N (1997) Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin. Biochemistry 36(40):12189–12198. doi:10.1021/bi970258a

    Article  CAS  PubMed  Google Scholar 

  • Mitchell RJ, Carzino R, Janardhana V (1988) Associations between the two serum proteins haptoglobin and transferrin and leukaemia. Hum Hered 38(3):144–150

    Article  CAS  PubMed  Google Scholar 

  • Mitchell RJ, Hale CB, Kahwagi M (1993) Genetic polymorphisms in the white population of Victoria, Australia. Ann Hum Biol 20(5):411–422

    Article  CAS  PubMed  Google Scholar 

  • Moral P, Panadero AM (1983) Haptoglobin subtypes in Barcelona (Spain). Hum Hered 33(3):192–194

    Article  CAS  PubMed  Google Scholar 

  • Moullec J, Reuge C, Linhard J, Nguyen-van-Cong, Diebolt G (1965) Haptoglobin levels in blood donors of Paris and Dakar. Transfusion (Paris) 8(4):277–292

    Article  CAS  Google Scholar 

  • Mukherjee BN, Das SK, Sharma PD (1975) Serum protein and red cell enzyme polymorphisms in Oraon tribe, India. Ann Hum Biol 2(2):201–204

    Article  CAS  PubMed  Google Scholar 

  • Muralidhar B, Goud JD, Murty JS (1989) Genetic structure of three Naikpod subpopulations of Andhra Pradesh, India. Am J Phys Anthropol 80(1):41–47. doi:10.1002/ajpa.1330800106

    Article  CAS  PubMed  Google Scholar 

  • Nagel R, Etcheverry R (1963) Types of haptoglobins in Araucanian Indians of Chile. Nature 197(4863):187–188

    Article  CAS  PubMed  Google Scholar 

  • Nagel R, Etcheverry R, Guzman C (1964) Haptoglobin types in inhabitants of Easter Island. Nature 201(4915):216–217

    Article  CAS  PubMed  Google Scholar 

  • Nagy E, Eaton JW, Jeney V, Soares MP, Varga Z, Galajda Z, Szentmiklosi J, Mehes G, Csonka T, Smith A, Vercellotti GM, Balla G, Balla J (2010) Red cells, hemoglobin, heme, iron, and atherogenesis. Arterioscler Thromb Vasc Biol 30(7):1347–1353. doi:10.1161/ATVBAHA.110.206433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakhaee A, Hashemi M, Rezaeifar A, Kaykhaei MA (2015) Evaluation of haptoglobin genotypes in patients with metabolic syndrome: A preliminary report. ARYA Atheroscler 11(3):167–172

    PubMed  PubMed Central  Google Scholar 

  • Napolioni V, Gianni P, Carpi FM, Concetti F, Lucarini N (2011) Haptoglobin (HP) polymorphisms and human longevity: a cross-sectional association study in a Central Italy population. Clin Chim Acta 412(7-8):574–577. doi:10.1016/j.cca.2010.12.006

    Article  CAS  PubMed  Google Scholar 

  • Nevo SS, Sutton HE (1968) Association between response to typhoid vaccination and known genetic markers. Am J Hum Genet 20(5):461–469

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nevo S, Tatarsky I (1986) Serum haptoglobin types and leukemia. Hum Genet 73(3):240–244

    Article  CAS  PubMed  Google Scholar 

  • Ozcan ME, Ince B, Karadeli HH, Gedikbasi A, Asil T, Altinoz MA (2016) Higher minor hemoglobin A2 levels in multiple sclerosis patients correlate with lesser disease severity. Neuropsychiatr Dis Treat 12:2033–2038. doi:10.2147/NDT.S109954

    Article  PubMed  PubMed Central  Google Scholar 

  • Padma T, Murty JS (1983) Association of genetic markers with some eye diseases. Acta Anthropogenet 7(1):1–12

    CAS  PubMed  Google Scholar 

  • Palmer AJ, Hitchens PL, Simpson S Jr, O’Leary B, Colman S, Taylor BV (2013) A novel method for calculating prevalence of multiple sclerosis in Australia. Mult Scler 19(13):1704–1711. doi:10.1177/1352458513479841

    Article  PubMed  Google Scholar 

  • Palsson JO, Walter H, Bajatzadeh M (1970) Sero-genetical studies in Ireland. Hum Hered 20(2):231–239

    Article  CAS  PubMed  Google Scholar 

  • Papiha SS, Roberts DF (1976) Haptoglobin distribution in north-east England. Ann Hum Biol 3(4):387–390

    Article  CAS  PubMed  Google Scholar 

  • Papiha SS, Jones AL, Thompson B, Carr D (1974) Haptoglobins in chronic lymphatic leukemia. J Med Genet 11(4):349–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papiha SS, Roberts DF, Gulati PD (1976) Some erythrocyte enzyme and serum protein systems in two communities of North-West India. Hum Biol 48(2):323–336

    CAS  PubMed  Google Scholar 

  • Papma JM, de Groot M, de Koning I, Mattace-Raso FU, van der Lugt A, MW V, WJ N, van Swieten JC, Koudstaal PJ, Prins ND, Smits M (2014) Cerebral small vessel disease affects white matter microstructure in mild cognitive impairment. Hum Brain Mapp 35(6):2836–2851. doi:10.1002/hbm.22370

    Article  PubMed  Google Scholar 

  • Parker WC, Bearn AG (1961) Haptoglobin and transferrin gene frequencies in a Navajo population: A new transferrin variant. Science 134(3472):106–108. doi:10.1126/science.134.3472.106

    Article  CAS  PubMed  Google Scholar 

  • Patzelt D, Schröder H (1985) Haptoglobin subtypes in Berlin, GDR. A simple procedure for haptoglobin purification and subtyping. Z Rechtsmed 94(3):207–212

    Article  CAS  PubMed  Google Scholar 

  • Poser CM (1995) Viking voyages: the origin of multiple sclerosis? An essay in medical history. Acta Neurol Scand Suppl 161:11–22

    Article  CAS  PubMed  Google Scholar 

  • Ramot B, Duvdevani-Zikert P, Kende G (1962) Haptoglobin and transferrin types in Israel. Ann Hum Genet 25(4):267–271

    Article  CAS  PubMed  Google Scholar 

  • Rantapää-Dahlqvist S, Fröhlander N (1985) Haptoglobin groups and rheumatoid arthritis. Hum Hered 35(4):207–211

    Article  Google Scholar 

  • Rantapää-Dahlqvist S, Beckman G, Beckman L (1988) Serum protein markers in systemic lupus erythematosus. Hum Hered 38(1):44–47

    Article  PubMed  Google Scholar 

  • Rickards O, Martinez-Labarga C, Scano G, De Stefano GF, Biondi G, Pacaci M, Walter H (1998) Genetic history of the population of Sicily. Hum Biol 70(4):699–714

    CAS  PubMed  Google Scholar 

  • Rifkind JM, Mohanty JG, Nagababu E (2014) The pathophysiology of extracellular hemoglobin associated with enhanced oxidative reactions. Front Physiol 5 (1): 500-1-500-6 doi:10.3389/fphys.2014.00500

  • Robinson SR, Dang TN, Dringen R, Bishop GM (2009) Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke. Redox Rep 14(6):228–235. doi:10.1179/135100009X12525712409931

    Article  CAS  PubMed  Google Scholar 

  • Robotti A, Natale M, Albo AG, Lis K, Perga S, Marnetto F, Gilli F, Bertolotto A (2010) Acute-phase proteins investigation based on lectins affinity capture prior to 2-DE separation: application to serum from multiple sclerosis patients. Electrophoresis 31(17):2882–2893. doi:10.1002/elps.201000171

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez S, Williams DM, Guthrie PA, McArdle WL, Smith GD, Evans DM, Gaunt TR, Day IN (2012) Molecular and population analysis of natural selection on the human haptoglobin duplication. Ann Hum Genet 76(5):352–362. doi:10.1111/j.1469-1809.2012.00716.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosati G (2001) The prevalence of multiple sclerosis in the world: an update. Neurol Sci 22(2):117–139

    Article  CAS  PubMed  Google Scholar 

  • Rothämel T, Krüger HJ, Tröger HD (1989) Haptoglobin subtyping by isoelectric focusing in ultrathin-layer polyacrylamide gels. Population genetic data for Hanover and Lower Saxony. Z Rechtsmed 102(6):391–397

    Article  PubMed  Google Scholar 

  • Rothhammer F, Spielman RS (1972) Anthropometric variation in the Aymara: genetic, geographic, and topographic contributions. Am J Hum Genet 24(4):371–380

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rudduck C, Franzen G, Frohlander N, Lindstrom L (1985) Haptoglobin and transferrin types in schizophrenia. Hum Hered 35(2):65–68

    Article  CAS  PubMed  Google Scholar 

  • Sadovnick AD, Ebers GC (1993) Epidemiology of multiple sclerosis: a critical overview. Can J Neurol Sci 20(1):17–29

    Article  CAS  PubMed  Google Scholar 

  • Saha N, Tsoi WF (1990) Serum protein markers in Chinese schizophrenics--haptoglobin types and transferrin and group-specific component subtypes. Clin Genet 37(1):54–58

    CAS  PubMed  Google Scholar 

  • Salvatore A, Cigliano L, Carlucci A, Bucci EM, Abrescia P (2009) Haptoglobin binds apolipoprotein E and influences cholesterol esterification in the cerebrospinal fluid. J Neurochem 110(1):255–263. doi:10.1111/j.1471-4159.2009.06121.x

    Article  CAS  PubMed  Google Scholar 

  • Sammour RN, Nakhoul FM, Levy AP, Miller-Lotan R, Nakhoul N, Awad HR, Gonen R, Ohel G (2010) Haptoglobin phenotype in women with preeclampsia. Endocrine 38(2):303–308. doi:10.1007/s12020-010-9392-7

    Article  CAS  PubMed  Google Scholar 

  • Santoro C, Olivetti E, Carbonara AO (1983) Distribution of haptoglobin subtypes in Continental Italy and Sardinia. Hum Hered 33(3):195–198

    Article  CAS  PubMed  Google Scholar 

  • Sati P, Thomasson D, Li N, Pham D, Biassou N, Reich D, Butman J (2014) Rapid, high-resolution, whole-brain, susceptibility-based MRI of multiple sclerosis. Mult Scler 20(11):1464–1470. doi:10.1177/1352458514525868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sawcer S, Franklin RJ, Ban M (2014) Multiple sclerosis genetics. Lancet Neurol 13 (7): 700-709. (S1474-4422(14)70041-9 doi:10.1016/S1474-4422(14)70041-9

  • Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM (2013) Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 121(8):1276–1284. doi:10.1182/blood-2012-11-451229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schiess N, Huether K, Fatafta T, FitzGerald KC, Calabresi PA, Blair I, Alsaadi T, Szolics M (2016) How global MS prevalence is changing: A retrospective chart review in the United Arab Emirates. Mult Scler Relat Disord 9(1):73–79. doi:10.1016/j.msard.2016.07.005

    Article  PubMed  Google Scholar 

  • Schmidt RM, Diessner H (1975) [Studies on protein genetic factors in multiple sclerosis and psychoses] (Article in German). Psychiatr Neurol Med Psychol (Leipz ) 27(4):219–224

    CAS  Google Scholar 

  • Scott EM, Duncan IW, Ekstrand V, Wright RC (1966) Frequency of polymorphic types of red cell enzymes and serum factors in Alaskan Eskimos and Indians. Am J Hum Genet 18(4):408–411

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sehajpal PK, Khanna AK, Singh G, Sharma VK (1981) Genetic studies among Ramgarhias and Ramdasias of Punjab, North India. Anthropol Anz 39(1):61–65

    CAS  PubMed  Google Scholar 

  • Seth S, Berndt H (1973) Distribution of enzyme groups and serum proteins in a North German population. Humangenetik 20(2):147–150

    Article  CAS  PubMed  Google Scholar 

  • Shi X, Sun L, Wang L, Jin F, Sun J, Zhu X, Tang L, Qu Y, Yang Z (2012) Haptoglobin 2-2 genotype is associated with increased risk of type 2 diabetes mellitus in northern Chinese. Genet Test Mol Biomarkers 16(6):563–568. doi:10.1089/gtmb.2011.0246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shim BS, Bearn AG (1964) The distribution of haptoglobin subtypes in various populations, including subtype patterns in some nonhuman primates. Am J Hum Genet 16 (−): 477-483

  • Siegel M, Paperna T, Lejbkowicz I, Petrou P, Shahien R, Karussis D, Lavi I, Dishon S, Rawashdeh H, Miller A (2012) Multiple sclerosis in diverse populations: characteristics in distinct Arab ethnicities in Israel. Mult Scler 18(12):1737–1744. doi:10.1177/1352458512445059

    Article  PubMed  Google Scholar 

  • Simpson S Jr, Taylor BV, van der Mei I (2015) The role of epidemiology in MS research: Past successes, current challenges and future potential. Mult Scler 21(8):969–977. doi:10.1177/1352458515574896

    Article  PubMed  Google Scholar 

  • Singh S, Sareen KN, Goedde HW (1974) Investigation of some biochemical genetic markers in four endogamous groups from Panjab (N. W. India). I. Protein and enzyme polymorphisms in serum. Humangenetik 21(4):341–346

    CAS  PubMed  Google Scholar 

  • Singh SK, Sunderland E, Woolley V (1984) Genetic polymorphisms in the Kuwaiti Arabs. Hum Hered 34(5):303–307

    Article  Google Scholar 

  • Singh V, van Pelt D, Stoop M, Stingl C, Ketelslegers I, Neureboom R, Luider T, and Hintzen R (2014) Grey matter related proteins in derebrospinal fluid differentiate between multiple sclerosis and other acquired demyelinating syndromes in childhood (Poster P246). ACTRIMS-ECTRIMS MSBoston 2014. Mult.Scler.J. 20(S1):177

  • Singh V, van Pelt ED, Stoop MP, Stingl C, Ketelslegers IA, Neuteboom RF, Catsman-Berrevoets CE, Luider TM, Hintzen RQ (2015) Gray matter-related proteins are associated with childhood-onset multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2(5):e155. doi:10.1212/NXI.0000000000000155

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith A, McCulloh RJ (2015) Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders. Front Physiol 6 (1): 187-1-187-20 doi:10.3389/fphys.2015.00187

  • Smithies O (1959) An improved procedure for starch-gel electrophoresis: further variations in the serum proteins of normal individuals. Biochem J 71(3):585–587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephenson E, Nathoo N, Mahjoub Y, Dunn JF, Yong VW (2014) Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat Rev Neurol 10(8):459–468. doi:10.1038/nrneurol.2014.118

    Article  CAS  PubMed  Google Scholar 

  • Su YC, Chen YC, Li SC, Lee CC, Tung YT (2009) Detection of Hpdel in healthy individuals and cancer patients in Taiwan. Clin Chem Lab Med 47(6):745–749. doi:10.1515/CCLM.2009.156

    Article  CAS  PubMed  Google Scholar 

  • Sutton HE, Neel JV, Livingstone FB, Binson G, Kunstadter P, Trombley LE (1958) The frequencies of haptoglobin types in 5 populations. Ann Hum Genet 23(2):175–183

    Article  Google Scholar 

  • Sutton HE, Matson GA, Robinson AR, Koucky RW (1960) Distribution of haptoglobin, transferrin, and hemoglobin types among Indians of southern Mexico and Guatemala. Am J Hum Genet 12 (−): 338-347

  • Takeoka T, Shinohara Y, Furumi K, Mori K (1983) Impairment of blood-cerebrospinal fluid barrier in multiple sclerosis. J Neurochem 41(4):1102–1108

    Article  CAS  PubMed  Google Scholar 

  • Tettey P, Simpson S Jr, Taylor BV, van der Mei IA (2014) Vascular comorbidities in the onset and progression of multiple sclerosis. J Neurol Sci 347(1-2):23–33. doi:10.1016/j.jns.2014.10.020

    Article  PubMed  Google Scholar 

  • Tiburcio V, Romero A, De Garay AL (1978) Gene frequencies and racial intermixture in a Mestizo population from Mexico City. Ann Hum Biol 5(2):131–138

    Article  CAS  PubMed  Google Scholar 

  • Tumani H, Lehmensiek V, Rau D, Guttmann I, Tauscher G, Mogel H, Palm C, Hirt V, Suessmuth SD, Sapunova-Meier I, Ludolph AC, Brettschneider J (2009) CSF proteome analysis in clinically isolated syndrome (CIS): candidate markers for conversion to definite multiple sclerosis. Neurosci Lett 452(2):214–217. doi:10.1016/j.neulet.2009.01.057

    Article  CAS  PubMed  Google Scholar 

  • Valenzuela CY, Pastene CS, Perez CM (1998) Intelligence and genetic markers in Chilean children. Biol Res 31(2):81–92

    CAS  PubMed  Google Scholar 

  • van Rensburg SJ, Kotze MJ, van Toorn R (2012) The conundrum of iron in multiple sclerosis--time for an individualised approach. Metab Brain Dis 27(3):239–253. doi:10.1007/s11011-012-9290-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vasconcelos CCF, Aurencao JCK, Thuler LCS, Camargo S, Alvarenga MP, Alvarenga RMP (2016) Prognostic factors associated with long-term disability and secondary progression in patients with multiple sclerosis. Mult Scler Relat Disord 8(1):27–34. doi:10.1016/j.msard.2016.03.011

    Article  PubMed  Google Scholar 

  • Vercellino M, Fenoglio C, Galimberti D, Mattioda A, Chiavazza C, Binello E, Pinessi L, Giobbe D, Scarpini E, Cavalla P (2015) Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis. Mult Scler 22(8):1007–1012. doi:10.1177/1352458515610646

    Article  PubMed  Google Scholar 

  • Walter H, Palsson J (1963) On the distribution of haptoglobin types in Iceland. Am J Phys Anthropol 21(1):49–52

    Article  CAS  PubMed  Google Scholar 

  • Walter H, Kellermann G, Bajatzadeh M, Kruger J, Chakravartti MR (1972) Hp, Gc, Cp, Tf, Bg and Pi phenotypes in leprosy patients and healthy controls from West Bengal (India). Humangenetik 14(4):314–325

    CAS  PubMed  Google Scholar 

  • Wang Y, Bos SD, Harbo HF, Thompson WK, Schork AJ, Bettella F, Witoelar A, Lie BA, Li W, McEvoy LK, Djurovic S, Desikan RS, Dale AM, Andreassen OA (2016) Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors. Mult Scler J in press online (−): 1-11 doi:10.1177/1352458516635873

  • Waschbisch A, Manzel A, Linker RA, Lee DH (2011) Vascular pathology in multiple sclerosis: mind boosting or myth busting? Exp Transl Stroke Med 3(1):7. doi:10.1186/2040-7378-3-7

    Article  PubMed  PubMed Central  Google Scholar 

  • Weigel KJ, Lynch SG, LeVine SM (2014) Iron chelation and multiple sclerosis. ASN Neuro 6 (1): e00136-43-63 doi:10.1042/AN20130037

  • Wens I, Dalgas U, Stenager E, Eijnde BO (2013) Risk factors related to cardiovascular diseases and the metabolic syndrome in multiple sclerosis - a systematic review. Mult Scler 19(12):1556–1564. doi:10.1177/1352458513504252

    Article  PubMed  Google Scholar 

  • Williams R, Buchheit CL, Berman NE, LeVine SM (2012) Pathogenic implications of iron accumulation in multiple sclerosis. J Neurochem 120(1):7–25. doi:10.1111/j.1471-4159.2011.07536.x

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (2008) ATLAS - Multiple sclerosis resources in the world. World Health Organization, Geneva

    Google Scholar 

  • Xie Y, Li Y, Zhang Q, Stiller MJ, Wang CL, Streilein JW (2000) Haptoglobin is a natural regulator of Langerhans cell function in the skin. J Dermatol Sci 24(1):25–37

    Article  CAS  PubMed  Google Scholar 

  • Zamboni P (2006) The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 99(11):589–593. doi:10.1258/jrsm.99.11.589

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Song S, Sun G, Strong R, Zhang J, Grotta JC, Aronowski J (2009) Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 29(50):15819–15827. doi:10.1523/JNEUROSCI.3776-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Song S, Sun G, Zhang J, Strong R, Zhang L, Grotta JC, Aronowski J (2011) Cytoprotective role of haptoglobin in brain after experimental intracerebral hemorrhage. Acta Neurochir Suppl 111(1):107–112. doi:10.1007/978-3-7091-0693-8_17

    Article  PubMed  Google Scholar 

  • Zhou BY, Yan SY, Shi WL, Qu Z, Zhao X, Liu ZM, Pu XP (2014) Serum proteomic analysis reveals high frequency of haptoglobin deficiency and elevated thyroxine level in heroin addicts. PLoS One 9(4):e95345. doi:10.1371/journal.pone.0095345

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zivadinov R, Weinstock-Guttman B, Pirko I (2011) Iron deposition and inflammation in multiple sclerosis. Which one comes first? BMC Neurosci 12 (1): 60-1-60-3 doi:10.1186/1471-2202-12-60

  • Zivadinov R, Alexander SJ, Minagar A (2012) Vascular pathology of multiple sclerosis. Neurol Res 34(8):735–737. doi:10.1179/0161641212Z.000000000114

    Article  PubMed  Google Scholar 

  • Zivadinov R, Ramasamy DP, Benedict RR, Polak P, Hagemeier J, Magnano C, Dwyer MG, Bergsland N, Bertolino N, Weinstock-Guttman B, Kolb C, Hojnacki D, Utriainen D, Haacke EM, Schweser F (2016) Cerebral microbleeds in multiple sclerosis evaluated on susceptibility-weighted images and quantitative susceptibility maps: a case-control study. Radiology in press online. doi:10.1148/radiol.2016160060

    Google Scholar 

  • Zou Q, Lin X, Chen Y, Lin Y (2008) Genetics analysis of haptoglobin gene in Fujian Han nationality. Frontiers of Medicine in China 2 (1): 105-107

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Acknowledgments

Our research program is supported by the Natural Sciences and Engineering Research Council of Canada (RG121541 to G.H.), and by the Canada Research Chairs Program (G.H. is a Tier 1 CRC in Myelin Biology).

Author Contributions

VVB and AMG contributed equally to this investigation; VVB and GH conceived of, designed, and guided the study; AMG performed all literature searches and compiled raw data; VVB analyzed aggregated data; all authors contributed to manuscript preparation.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, ON, N1G 2W1, Canada

    Vladimir V. Bamm, Arielle M. Geist & George Harauz

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  1. Vladimir V. Bamm
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  2. Arielle M. Geist
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  3. George Harauz
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Correspondence to George Harauz.

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Vladimir V. Bamm and Arielle M. Geist contributed equally to this work.

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Bamm, V.V., Geist, A.M. & Harauz, G. Correlation of geographic distributions of haptoglobin alleles with prevalence of multiple sclerosis (MS) – a narrative literature review. Metab Brain Dis 32, 19–34 (2017). https://doi.org/10.1007/s11011-016-9923-x

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