**5.3.4 Low comorbidity between schizophrenia and rheumatoid arthritis**

The hypothesis predicts that diseases predisposed by facilitating genes, if present, would be negatively associated with schizophrenia. Rheumatoid arthritis could be one of such candidates.

(< 21 years) (Malaspina et al., 2001; El-Saadi et al., 2004; Sipos et al., 2004) as well as in the offspring of younger women (< 20 years) (El-Saadi et al., 2004). Therefore, major roles of

Indeed, no available data can exclude the possibility that the 'paternal age effect' has a 'maternal origin'; while women in many countries today may be usually supposed to bear children after the age of 20 years and not to marry much older men or too young men unless the men have special socio-economic benefits, a certain proportion of predisposed women

It should be noted that in the famous twin study by Gottesman and Bertelsen (1989) which included almost equal number of male and female monozygotic twins, most schizophrenic twins whose offspring are affected are females (12 out of 14), implying that the transmission

gender effect might be due to non-genetic factors such as stronger psychological interactions between mother and child, we must also consider the possibility that it is due to the closer

The hypothesis predicts that endogenous antioxidants exhibit a protective effect against

A consistent and specific finding for schizophrenia is that the age at onset is significantly lower in males than in females (Jablensky, 1995; Kulkarni & Fink, 2000); schizophrenia starts earlier on average in males and reaches its peak between 15 and 25 years of age, whereas in females it occurs almost between 20 and 30 years of age and shows a less steep curve after that age. It also appears that women are vulnerable to relapses or first episode of schizophrenia in the perimenoposal period (the second peak of onset for females) (Kulkarni & Fink, 2000), when estrogen production diminishes. A close association between premenstrual or menstruation phase and exacerbation of the illness in females has been well documented (Kulkarni & Fink, 2000). In addition, less negative symptoms, less brain morphological changes, and better response to neuroleptic medication are relatively consistent finding in female patients with schizophrenia (Jablensky, 1995; Goldstein &

These observations lead to the concept that estrogen protects predisposed females (Kulkarni & Fink, 2000), which seems to accord with the hypothesis; estrogen has been shown to have antioxidant activity due to its intrinsic antioxidant structure that lies in the phenolic moiety of the steroidal compound (Behl, 2002), to increase antioxidant enzyme activities (Strehlow et al., 2003; Pajović et al., 2003), and to have neuroprotective effect against oxidative stress (Behl, 2002; Brann et al., 2007). Furthermore, mitochondrion has estrogen binding sites (Monje & Boland, 2001; Chen et al., 2004) and estrogen increases mitochondrial efficiency

The hypothesis predicts that diseases predisposed by facilitating genes, if present, would be negatively associated with schizophrenia. Rheumatoid arthritis could be one of such

schizophrenia, and may give a plausible explanation for sex difference of the disease.

14 12 14 13 14 14 *pC C C* 0.5 0.5 0.5 0.007 ). While this

paternally derived mutations in schizophrenia seem to remain unsubstantiated.

was mainly via females ( <sup>14</sup> <sup>14</sup> <sup>14</sup>

**5.3.3 Sex difference and a protective effect of estrogen in schizophrenia** 

genetic relationship between mother and child, i.e. the mtDNA.

and reduces intracellular oxidative stress (Stirone et al, 2005).

**5.3.4 Low comorbidity between schizophrenia and rheumatoid arthritis** 

might behave differently.

Lewine, 2000).

candidates.

A role of oxidative stress in the pathogenesis of rheumatoid arthritis has been suggested by several lines of evidence (for review, see Hitchon et al, 2004). In addition, it has been shown that chronic oxidative stress in the synovial T lymphocytes is not secondary to exposure to environmental free radicals but originates from intracellularly produced reactive oxygen species (Remans et al, 2005). Therefore, a presumptive susceptibility gene for rheumatoid arthritis, which may cause intracellular oxidative stress in several cell lines, could be a facilitating gene for schizophrenia in this model and is likely to be subject to a negative selection in the predisposed matrilineal pedigrees.

Indeed, robust evidence shows a negative association between schizophrenia and rheumatoid arthritis while the exact mechanism is still unknown (Vinogradov et al., 1991; Jablensky, 1995; Rubinstein, 1997; Oken 1999). According to the nuclear genome model, several hypotheses have been proposed such that pathogenic genes for schizophrenia may be protective genes for rheumatoid arthritis and vice versa.

Thus the mitochondrial genome model may offer a new explanation for the low comorbidity between schizophrenia and rheumatoid arthritis and the additional prediction: most of patients with both of the diseases would be females because the survival rate of males in early life stage must be remarkably reduced due to lack of the antioxidant defense by estrogen, and show more negative symptoms, poorer response to neuroleptic medication, and/or more morphological changes in the brain.
