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agate
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 Posted: Thu Jan 10, 2013 7:27 pm Post subject: (Abst.) On the sex ratio of MS |
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From Multiple Sclerosis Journal, January 9, 2013:
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On the sex ratio of multiple sclerosis
Giulio Disanto1,2
Sreeram V Ramagopalan1,2,3,4
1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
2Department of Clinical Neurology, University of Oxford, Oxford, UK
3London School of Hygiene and Tropical Medicine, London, UK
4Blizard Institute of Cell and Molecular Science, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK
Dr Sreeram V Ramagopalan, Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK. Email: s.ramagopalan@qmul.ac.uk
An interesting feature that multiple sclerosis (MS) shares with many other immune-mediated diseases is that susceptibility is higher in females than males.1,2 However, the female-to-male ratio (sex ratio) of MS appears to vary significantly in time and space.
A recent meta-analysis of epidemiological studies has shown that the worldwide sex ratio of MS has been substantially increasing over the last century.3 This increase is particularly clear in large population-based studies from Denmark and Canada.3,4 In the latter, the sex ratio of MS patients born in the 1930s was lower than 2 and then increased to more than 3 females for each male patient in the latest birth cohort analysed (1976–1980).4 This intriguing epidemiological phenomenon warrants particular attention since the sex ratio of MS parallels MS incidence and the increasing frequency of MS among females is a key driver for the worldwide increasing prevalence of this devastating disorder.3 A change occurring within a century is too short a time for a genetic cause, suggesting that environmental factor/s are at work in a sex-specific manner.
In this issue of the Multiple Sclerosis Journal, Boström and colleagues investigate sex ratio trends of MS in Sweden using data from several thousand MS patients identified through the National Swedish MS register. Mean sex ratios were 2.62 in the analysis by year of birth (performed between 1931 and 1985) and 2.57 in the analysis by year of onset (performed between 1946 and 2005). In both cases sex ratio figures appeared stable and no increase with time was observed. While these findings appear to be in conflict with those reported by the studies mentioned above, several considerations are warranted.
First, comparing results obtained from different countries is not always straightforward and when assessing temporal trends the baseline characteristics need to be taken into account. Boström and colleagues report sex ratios which are consistently above 2 while in both the Canadian and Danish data baseline sex ratios were considerably lower. Perhaps the environmental factor driving the increasing sex ratio of MS in Canada and Denmark was already present at baseline in Sweden. Alternatively this putative agent may be less able to increase female incidence in a population in which the latter is already relatively high.
Second, even when baseline levels are similar, inter-country differences should not be too surprising since environmental factors can vary substantially between regions and their effect is likely modified by the genetic background of the population. When studies are well performed and statistically powered like that of Boström et al., conflicting results can actually greatly aid the identification of the environmental agent responsible for the investigated phenomenon.
However, what are the environmental agent/s influencing the sex ratio of MS? An interesting hypothesis comes from a recent Australian study which found that a higher number of offspring was inversely associated with the risk of a first clinical demyelinating event among women but not men.5 Although other studies have investigated how pregnancy modifies the risk of MS and reported conflicting results,6⇓⇓–9 older age at birth and reduced offspring number could contribute to the increasing sex ratio of MS. Figure 1 shows temporal trends in fertility rates (average number of children that would be born to a woman of reproductive age) in Canada, Denmark and Sweden in the last century obtained from national statistics agencies. The most remarkable increase in MS sex ratio has been observed in Canada starting from the birth cohort 1941–1945.4 Since these women will be likely to give birth between the 1960s and 1970s, the dramatic increase in sex ratio is parallel to the steep decrease in fertility rates among Canadian women. Similarly in Denmark the increasing sex ratio observed in the second half of the 20th century is associated with a substantial reduction in fertility rates.3 However, fertility rates have also decreased in Sweden but based on Boström and colleagues there has been no concomitant increase in the MS sex ratio. Whilst reproductive history may well have an influence on female susceptibility to MS, this single factor is unlikely to entirely explain temporal trends in the MS sex ratio.
[Figure omitted]
Vitamin D deficiency, Epstein–Barr virus (EBV) infection and smoking history are known to influence MS risk and therefore represent additional plausible candidates.10⇓⇓⇓–14 Unfortunately sex-specific reliable longitudinal data on both vitamin D deficiency and EBV infection are lacking and it would be extremely useful to investigate their secular trends in those countries in which temporal MS sex ratio figures are available. Interestingly, a recent study has shown how trends in sex ratio of smoking behaviour in both Canada and Denmark strongly correlate with sex ratio changes of MS. However this was mainly driven by a decline of smoking among men and cannot therefore fully explain the increased incidence of MS among females.15 Further, the smoking trends in Sweden are similar to Denmark and Canada.15 The sex ratio of MS currently remains an intricate puzzle with no clear solution as yet. Future research is urgently needed to understand the environmental factor/s involved in order to aid disease prevention strategies.
Funding:
GD is funded by a research fellowship Fondazione Italiana Sclerosi Multipla (Cod. 2010/B/5) and SVR receives research support from the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.
Conflict of interest:
The authors declare no conflicts of interest in preparing this article.
References omitted.
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| Posted: Thu Mar 07, 2013 10:26 pm Post subject: (Abst.) Fog lifting in MS gender enigma |
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Another abstract of an article on this topic, from MedPage Today, March 6, 2013:
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Fog Lifting in MS Gender Enigma
By Kathleen Struck, Senior Editor, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Recent discoveries in the laboratory have provided strong clues to the reasons why multiple sclerosis now afflicts mainly women, two prominent MS researchers said.
Differences in how the female and male immune systems are "tuned" are the most striking among these findings, but not the only ones, according to Shannon Dunn, PhD, of the University of Toronto, and Lawrence Steinman, MD, of Stanford University, in a "Viewpoint" article published online in JAMA Neurology.
"These discoveries illuminate the pathogenesis of MS, with applications and benefits for both men and women," the authors wrote. "These breakthroughs potentially allow for the repurposing of certain approved drugs for potential use as treatments of MS."
Currently, close to three-quarters of new MS cases occur in women. The biological basis for the gender imbalance has been one of the stubborn mysteries surrounding the disease -- in no small part because it is of relatively recent origin. When MS was first described in the late 19th century, about as many men as women had the condition.
"Over the past 50 years, [the female:male] ratio has been steadily increasing," Dunn and Steinman wrote.
Fewer and later pregnancies, vitamin D3 and sunlight, and the female sex hormone estradiol are other notable factors in understanding how the autoimmune disease works and impacts three times as many women as men, the authors said.
"Something in the environment" must be at work besides genetic changes, then authors explained, because the 50-year trend of increasing female preponderance in MS is not enough time for mutations to present, they said.
Because pregnancy is a known "major protective factor" against MS relapses, fewer pregnancies and a later age for pregnancy and childbearing might allow the hormones involved in MS pathogenesis to flourish.
Vitamin D3 and sunlight -- or lack of them -- are other suspects in the rapid increase in MS among women. Vitamin D3 has been effective in reducing proinflammatory Th1 immune activity in MS, the authors wrote.
A sterol, vitamin D3 thwarts interleukin-17. It and similar cytokines are involved in molecular inflammation in MS. Vitamin D regulates the inflammation by eliminating those cells that attack myelin, the protein coating that protects nerve fibers. Demyelination is the root pathology in MS.
"Surprisingly, vitamin D3 has a greater modulatory effect in women with MS than in men with MS, where it inhibits both Th1 and Th17 pathways to a greater extent," the authors wrote. "This may be due in part to a deficiency in females of the inactivating enzyme, CYP24A1 for vitamin D3, leading to accumulation of more vitamin D3 in target cells."
In experimental autoimmune encephalomyelitis (EAE), the standard animal model of MS, vitamin D3 reduced paralysis in females, "again to a much greater extent than in males," they said.
Estradiol, the authors said, has a great impact on the immune system and is naturally more prevalent in women. The authors cited earlier studies that showed estradiol protects against EAE. Much interest is focused on mediating B cells, "a major target of interest in MS therapy," Dunn and Steinman wrote.
A phase II clinical trial with estriol is now active with an aim to preserve cognition, they wrote.
Another influence of sex hormones is on peroxisome proliferator–activated receptors (PPARs), which in turn control Th1 responses as well as levels of fatty acids and lipids that play roles in MS.
One PPAR type that controls TH1 is much more highly expressed in T cells from men, the researchers indicated.
"This may have practical significance as medicines like the widely used lipid-lowering drug gemfibrozil ... are effective in reducing paralytic signs in [EAE]," they wrote. "Clinical trials with approved PPAR modulators in MS should be considered."
"The worrisome increase in the incidence of MS in women is the subject of intense scrutiny. Analysis of this dichotomy in incidence between men and women is yielding insights into the differential regulation of the immune response between males and females," the researchers wrote.
"The research is uncovering key therapeutic pathways that may ultimately add to the growing armamentarium of drugs that can ameliorate MS. This would be an example of turning a disturbing problem into a scientific and medical success story."
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The authors reported no conflicts of interest.
Primary source: JAMA Neurology
Source reference:
Dunn S, et al "The Gender gap in multiple sclerosis" JAMA Neurology 2013 |
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