Genetic and environmental backgrounds responsible for the changes in the phenotype of MS in Japanese subjects

Abstract

There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as opticospinal (OSMS) and conventional (CMS) forms. In Japan, the results of four nationwide surveys of MS conducted between 1972 and 2004 have revealed a four-fold increase in the estimated number of clinically definite MS patients in 2003 compared with 1972; a shift in the peak age at onset from the early 30s in 1989 to the early 20s in 2003; a successive proportional decrease in optic-spinal involvement in clinically definite MS patients; an increase in the number of CMS patients with Barkhof brain lesions with advancing birth year and a decrease in the number of OSMS patients with LESCLs. These findings suggest that MS phenotypes are drastically altered by environmental factors such as latitude and “Westernization”. Helicobacter pylori infection rates, reflecting sanitary conditions in infancy, are significantly different between CMS and OSMS patients. Both phenotypes show distinct HLA class II gene associations. Therefore, changes in environmental factors may have differentially influenced susceptibility to each disease subtype, given that disease susceptibility is only partly genetically determined.

Introduction

Multiple sclerosis (MS) is rare in Asians, but when it does occur, selective and severe involvement of the optic nerve and spinal cord is characteristic (Kira, 2003). There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as opticospinal (OSMS) and conventional (CMS) forms. CMS involves multiple sites of the central nervous system (CNS) including the cerebrum and cerebellum, while OSMS selectively affects the optic nerve and spinal cord (Kira et al., 1996). OSMS shows similar features to the relapsing form of neuromyelitis optica (NMO) in Westerners. Because NMO-IgG, a specific marker for NMO, targeting aquaporin-4 (AQP4) (Lennon et al., 2004, Lennon et al., 2005), was also detected in a fraction of Japanese OSMS patients (Nakashima et al., 2006, Matsuoka et al., 2007), OSMS is now postulated to be the same disease as the relapsing form of NMO (Weinshenker et al., 2006).

Relapsing NMO or OSMS is relatively frequently encountered in East-Asians, such as Japanese, Koreans, Chinese and Taiwanese (Kira, 2003), and NMO is also a major form of demyelinating disease in Africans (Osuntokun, 1971, Cree et al., 2004). Such a difference in phenotypes among races is assumed to result from genetic differences (Compston, 1997); however, studies on migrants have revealed changes in not only the prevalence but also the phenotype of MS, which are attributable to the early-life environment (Kurtzke et al., 1971, Detels et al., 1978, Elian et al., 1990, Dean and Elian, 1997, Hammond et al., 2000, Sánchez et al., 2001, Cabre et al., 2005). Asian and African descendants in the United Kingdom (Elian et al., 1990, Dean and Elian, 1997) and returning migrants from France to the French West Indies (Cabre et al., 2005) demonstrated the emergence of classical MS in place of NMO, whereas Caucasian descendants in tropical Colombia showed more frequent optic-spinal involvement (Sánchez et al., 2001). These migration studies imply the influence of exogenous factors on MS phenotypes as well as susceptibilities to different forms of the disease; however, such interpretations must be made with caution since the admixture of genes could be equally influential (Compston, 1997), as observed in a genetic study on Mexican Mestizos which revealed that patients who presented with classical MS also harbored more Caucasian genes (Alvarado-de la Barrera, 2000).

Japanese populations are genetically homogeneous and geographically isolated. Interracial marriage with Caucasians remains exceptional among Japanese, who have experienced rapid environmental changes. Therefore, Japanese are a suitable population in which to investigate phenotypic changes over time to clarify whether genetic or environmental factors are responsible for the manifestation of MS. Here, I review the results of the nationwide epidemiological studies, as well as recent genetic and environmental studies in Japan.