Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin

Abstract

Multiple sclerosis (MS) is a demyelinating disease that affects about one in 500 young Europeans. In order to test the previously proposed influence of the A PO E and SC A 2 loci on susceptibility to MS, we studied these loci in 243 Portuguese patients and 192 healthy controls and both parents of 92 patients. We did not detect any significant difference when A PO E and SC A 2 allele frequencies of cases and controls were compared, or when we compared cases with different forms of the disease. Disequilibrium of transmission was tested for both loci in the 92 trios, and we did not observe segregation distortion. To test the influence of the A PO E o4 and SC A 2 22 C AGs alleles on severity of disease, we compared age at onset and progression rate between groups with and without those alleles. We did not observe an association of the o4 or the 22 C AG s alleles with rate of progression in our total patient population; allele o4 was associated with increased rate of progression of MS in a subset of patients with less than 10 years of the disease. However, globally in the Portuguese population, the A PO E and SC A2 genes do not seem to be useful in the clinical context as prognostic markers of this disorder.

Keywords

allelic asso ciation demyelinating disease genetics linkage disequilibrium prognostic markers spinocerebellar ataxia

Get full access to this article

View all access options for this article.

References

Compston A , Ebers G , Lassmann H , McDonald I , Matthews B , Wekerle H. Multiple sclerosis. London: McAlpine’s Churchill Livingstone , 1998: 101-142.

Ebers GC , Bulman DE , Sadovnick AD , Paty DW , Warren S , Hader W et al. A population-based study of multiple sclerosis in twins . N Engl J Med 1986; 315: 1638-1642 .

Mumford CJ , Wood NW , Kellar-Wood H , Thorpe JW , Miller DH , Compston DA. The British Isles survey of multiple sclerosis in twins . Neurology 1994; 44: 11-15 .

Sadovnick AD , Armstrong H , Rice GP , Bulman D , Hashimoto L , Paty DW et al. A population-based study of multiple sclerosis in twins: update . Ann Neurol 1993; 33: 281-285 .

Rasmussen HB , Clausen J. Genetic risk factors in multiple sclerosis and approaches to their identification . J Neurovirol 2000; 6 (suppl 2): S23-S27 .

Rasmussen HB , Kelly MA , Clausen J. Additive effect of the HLA-DR15 haplotype on susceptibility to multiple sclerosis . Mult Scler 2001; 7: 91-93 .

Marrosu MG , Muntoni F , Murru MR , Spinicci G , Pischedda MP , Goddi F et al. Sardinian multiple sclerosis is associated with HLA-DR4: a serologic and molecular analysis . Neurology 1988; 38: 1749-1753 .

Sawcer S , Jones HB , Feakes R , Gray J , Smaldon N , Chataway J et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22 . Nat Genet 1996; 13: 464-468 .

Chataway J , Feakes R , Coraddu F , Gray J , Deans J , Fraser M et al. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen . Brain 1998; 121: 1869-1887 .

10.

Ebers GC , Kukay K , Bulman DE , Sadovnick AD , Rice G , Anderson C et al. A full genome search in multiple sclerosis . Nat Genet 1996; 13: 472-476 .

11.

Haines J , Pericak-Vance M , Seboun E , Hauser S and the Multiple Sclerosis Genetics Group . A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex . Nat Genet 1996; 13: 469-471 .

12.

Kuokkanen S , Gschwend M , Rioux JD , Daly MJ , Terwilliger JD , Tienari PJ et al. Genomewide scan of multiple sclerosis in Finnish multiplex families . Am J Hum Genet 1997; 61: 1379-1387 .

13.

Sawcer S , Maranian M , Setakis E , Curwen V , Akesson E , Hensiek A et al. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility . Brain 2002; 125: 1337-1347 .

14.

Goedde R , Sawcer S , Boehringer S , Miterski B , Sindern E , Haupts M et al. A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers . Hum Genet 2002; 111: 270-277 .

15.

Imbert G , Saudou F , Yvert G , Devys D , Trottier Y , Garnier JM et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats . Nat Genet 1996; 14: 285-291 .

16.

Pulst SM , Nechiporuk A , Nechiporuk T , Gispert S , Chen XN , Lopes-Cendes I et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 . Nat Genet 1996; 14: 269-276 .

17.

Sanpei K , Takano H , Igarashi S , Sato T , Oyake M , Sasaki H et al. identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT . Nat Genet 1996; 14: 277-284 .

18.

Chataway J , Sawcer S , Coraddu F , Feakes R , Broadley S , Jones HB et al. Evidence that allelic variants of the spinocerebellar ataxia type 2 gene influence susceptibility to multiple sclerosis . Neurogenetics 1999; 2: 91-96 .

19.

Siegel GJ , Agranoff BW , Alberts RW , Fisher SK , Uhler MD. Basic neurochemistry. molecular, cellular and medical aspects, sixth edition. Philadelphia, PA: Lippincott Williams & Wilkins , 1999.

20.

Hallman DM , Boerwinkle E , Saha N , Sandholzer C , Menzel HJ , Csazar A et al. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations . Am J Hum Genet 1991; 49: 338-349 .

21.

Gerdes LU , Klausen IC , Sihm I , Faergeman O. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world . Genet Epidemiol 1992; 9: 155-167 .

22.

Kamboh MI , DeKosky ST. Apolipoprotein E genotyping in the diagnosis of Alzheimer’s disease . Ann Neurol 1995; 38: 967-970 .

23.

Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology . Science 1988; 240: 622-630 .

24.

Nicoll JA , Roberts GW , Graham DI. Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury . Nat Med 1995; 1: 135-137 .

25.

Roses AD , Saunders AM. APOE, Alzheimer’s disease, and recovery from brain stress . Ann N YAcad Sci 1997; 826: 200-212 .

26.

Basun H , Corder EH , Guo Z , Lannfelt L , Corder LS , Manton KG et al. Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more . Stroke 1996; 27: 1310-1315 .

27.

Slooter AJ , Tang MX , van Duijn CM , Stern Y , Ott A , Bell K et al. Apolipoprotein E epsilon 4 and the risk of dementia with stroke. A population-based investigation . JAMA 1997; 277: 818-821 .

28.

Chapman J , Vinokurov S , Achiron A , Karussis DM , Mitosek-Szewczyk K , Birnbaum M et al. APOE genotype is a major predictor of long-term progression of disability in MS . Neurology 2001; 56: 312-316 .

29.

Hogh P , Oturai A , Schreiber K , Blinkenberg M , Jorgensen OS , Ryder L et al. Apolipoprotein E and multiple sclerosis: impact of epsilon-4 allele on susceptibility, clinical type and progression rate . Mult Scler 2000; 6: 226-230 .

30.

Fazekas F , Strasser-Fuchs S , Schmidt H , Enzinger C , Ropele S , Lechner A et al. Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis . J Neurol Neurosurg Psychiatry 2000; 69: 25-28 .

31.

Fazekas F , Strasser-Fuchs S , Kollegger H , Berger T , Kristoferitsch W , Schmidt H et al. Apolipoprotein E o4 is associated with rapid progression of multiple sclerosis . Neurology 2001; 57: 853-857 .

32.

Evangelou N , Jackson M , Beeson D , Palace J. Association of the APOE o4 allele with disease activity in multiple sclerosis . J Neurol Neurosurg Psychiatry 1999; 67: 203-205 .

33.

Poser CM , Paty DW , Scheinberg L , McDonald WI , Davis FA , Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 1983; 13: 227-231 .

34.

Amato MP , Ponziani G. Quantification of impairment in MS: discussion of the scales in use . Mult Scler 1999; 5: 216-219 .

35.

Weinshenker BG , Santrach P , Bissonet AS , McDonnell SK , Schaid D , Moore SB et al. Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study . Neurology 1998; 51: 742-747 .

36.

Hixson JE , Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I . J Lipid Res 1990; 31: 545-548 .

37.

Ferri C , Sciacca FL , Veglia F , Martinelli F , Comi G , Canal N et al. APOE o2-4 and -491 polymorphisms are not associated with MS . Neurology 1999; 53: 888-889 .

38.

Gervais A , Gaillard O , Plassart E , Reboul J , Fontaine B , Schuller E. Apolipoprotein E polymorphism in multiple sclerosis . Ann Clin Biochem 1998; 35: 135-136 .

39.

Weatherby SJ , Mann CL , Fryer AA , Strange RC , Hawkins CP , Stevenson VL et al. No association between the APOE o4 allele and outcome and susceptbility in primary progressive multiple sclerosis . J Neurol Neurosurg Psychiatry 2000; 68: 532-532 .

40.

Chapman J , Sylantiev C , Nisipeanu P , Korczyn A. Preliminary observations on APOE o4 allele and progression of disability in MS . Arch Neurol 1999; 56: 1484-1487 .

41.

Reunanen K , Finnila S , Laaksonen M , Sumelahti ML , Wik-strom J , Pastinen T et al. Chromosome 19q13 and multiple sclerosis in Finland: a linkage and two-stage association study . J Neuroimmunol 2002; 126: 134-142 .

42.

Miterski B , Eppelen JT , Poehlau D , Sindern E , Haupts M. SCA2 alleles are not general predisposition factors for multiple sclerosis . Neurogenetics 2000; 2: 235-236 .

43.

Oliveri RL , Cittadella R , Sibilia G , Manna I , Valentino P , Gambardella A et al. APOE and risk of cognitive impairment in multiple sclerosis . Acta Neurol Scand 1999; 100: 290-295 .