Journal of the Neurological Sciences 346 (2014) 268–270

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Low familial risks for multiple sclerosis in Buenos Aires, Argentina Mauricio F. Farez a,⁎, María E. Balbuena Aguirre a,b, Francisco Varela a, Alejandro A. Köhler a, Vanesa Nagel a, Jorge Correale a,⁎⁎ a b

Department of Neurology, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina Department of Neurology, Hospital de Clínicas José de San Martín, Buenos Aires, Argentina

a r t i c l e

i n f o

Article history: Received 13 June 2014 Received in revised form 26 July 2014 Accepted 4 September 2014 Available online 16 September 2014 Keywords: Multiple sclerosis Familial risk Argentina South America Recurrence risk Sibling recurrence-risk

a b s t r a c t Background: Multiple sclerosis is a complex disease in which genetic susceptibility plays a role and familial occurrence has long been recognized. To date, no studies of familial occurrence have been conducted in Argentina, a country with low to intermediate prevalence. Methods: As part of a cross-sectional study on multiple sclerosis in Buenos Aires, immediate and extended pedigree details were collected on 219 patients. Crude and age-adjusted recurrence risks for patient relatives were also assessed. Results: Details on age or age of death and disease status were obtained for 4227 relatives. Ten percent of patients reported at least one relative with MS diagnosis, the highest risk (1.54%) was observed in daughters of patients who presented 92-times greater risk than the general population. Sibling recurrence risk ratio was similar to that reported in other locations. Conclusions: Relatives of patients with MS living in Argentina are at greater risk of developing the disease, although not as high as the risk reported for other geographic regions. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Multiple sclerosis (MS) is an inflammatory demyelinating disease caused by an autoimmune response targeted against the central nervous system, which is presumed to result from a complex interplay between genetic and environmental factors [1]. Familial aggregation is one of the most recognized features of MS, and several studies have been published describing the increased risk of developing MS in mono or dizygotic twins, offspring, siblings, half-siblings and even parents of different genetic origin of MS patients [2–5]. Evidence shows that MS is a disease with complex genetic inheritance accounting for 30–35% of the risk of developing the disease in monozygotic twins [6]. The remaining risk is presumed to derive from interactions between several environmental cues such as vitamin D [7], smoking [8], obesity [9] and Epstein Barr virus (EBV) infection [10]. A commonly used measure for genetic susceptibility is sibling recurrence-risk (SRR) [11]. The relative risk or λs, is a simple calculation that divides SRR by risk in the general population, a figure estimated to be between 12–80/100,000 inhabitants in Argentina [12]. Most previous studies in other regions established this value between 12–40 for MS [13].

⁎ Corresponding author. ⁎⁎ Correspondence to: Raúl Carrea Institute for Neurological Research, FLENI, Montañeses 2325, Buenos Aires 1428, Argentina. Tel.: +54 11 5777 3200x2704; fax: +54 11 5777 3209. E-mail address: jcorreale@fleni.org.ar (J. Correale).

http://dx.doi.org/10.1016/j.jns.2014.09.004 0022-510X/© 2014 Elsevier B.V. All rights reserved.

Several studies on familial MS in Europe [2], North America [14] and Australia [13] have been published, but no such study to the best of our knowledge, has been conducted anywhere in South America. Of note, the region has certain demographic peculiarities such as populations with different genetic backgrounds and admixture, with lower overall prevalence of MS compared to most other Caucasian populations [12]. Determining familial MS is of interest to estimate familial recurrence risk, and to advise patients in terms of individual family risk. To this end, local evidence is needed. We therefore set out to establish familial MS prevalence and MS recurrence risk for patients living in Buenos Aires, Argentina. 2. Materials and methods 2.1. Setting This study was conducted at the MS Clinic of the Raúl Carrea Institute for Neurological Diseases, in Buenos Aires, Argentina (location 34°S, 58°W). 2.2. Patients All MS patients defined according to 2010 McDonald criteria [15] attending our center were invited to participate in a cross-sectional survey, the Argentina Case–Control Study on Multiple Sclerosis (Spanish acronym, EMECCA). Patients needed MS diagnosis confirmation from our center, and to be at least 18 years old to participate. If a patient

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reported an affected family member, a contact number was requested and the individual was extended an invitation to participate in the study. If the family member was not being followed at our center, his/ her attending physician was approached to request diagnosis confirmation. In the case of deceased relatives with MS diagnosis, the contact number of the treating physician was requested and diagnosed confirmed. If no records were available, or treating physician was not willing to participate, diagnosis was confirmed through a separate interview by a neurologist obtaining disease course description and treatment information from relatives. If the survey was replied by both a patient and an affected family member, the one with the earlier diagnosis was considered the index case and included in the study. The study was approved by the Institutional Ethics Committee, and all subjects including affected relatives, signed an informed consent form.

with MS. After further investigation, 6 relatives were excluded because of insufficient supporting evidence or because an alternative diagnosis was confirmed by interviewing the relative or their primary care physician. Crude risk and age-adjusted risk for each category of relative are provided in Table 2. Of note, we found a sibling risk of 0.28% (95% CI 0.2–0.4), around 10 times lower than rates previously reported for the northern hemisphere (3.8% in the UK [2], 3.6% in Canada [17]) and in the southern hemisphere (2.13% in Australia [13]). This finding is in agreement with the 10 times lower prevalence reported in our country (17/100,000 vs 111–240/100,000 in abovementioned countries [12,18, 19]). A comparison table with selected studies in the northern and southern hemisphere is provided (see Supplementary Table 2).

2.3. Procedures

Familial clustering of disease is a well known feature of MS [2]. However, no information exists on familial risks in Argentina or South America. Interestingly, we found lower familial recurrence risk compared to Europe or North America, in line with decreased prevalence reported for the region. This study will be of assistance for physicians practicing in the region needing to advise relatives of MS patients on lifetime risk of developing the disease. It also raises new and intriguing questions regarding the interplay between environmental and genetic factors in MS. For example, the relative sibling risk ratio remains strikingly similar to that reported in other parts of the world, reflecting perhaps a similar genetic effect, with environmental factors somehow playing a greater role. Alternatively, although the Argentine population is composed mainly of Italian and Spanish immigrants, and HLA-DRB1 allele frequency in MS patients is similar to those reported in Caucasian populations [20], there is a potential role for native genes providing relative protection [21], a topic which needs to be addressed in future studies. Several reports address familial recurrence rates with significant variations across countries. As an example, familial incidence is approximately 20% in Canada, around 15% in some European countries and surprisingly low in places like Hong Kong, where there is little Caucasian population [2,22,23]. Nevertheless, familial recurrence rates seem to be correlated to disease prevalence, which in turn is a function of genetic composition of the population and local environmental factors. Our study has some limitations: it is a single center study based in Buenos Aires, and one of the features of Latin America is its relative demographic complexity, making extrapolation of these results to other regions, in particular rural or native communities, inappropriate. Future

Demographic and familial data was collected using a structured and standardized questionnaire sent by email. In the case of affected relatives or unclear responses, patients were telephoned and re-interrogated by a trained neurologist (FV, AAK, VN). Information regarding total number of affected relatives, including offspring, siblings, nieces/nephews, aunts/ uncles and first cousins was requested from each proband. Contact details of affected relatives were obtained and used to seek diagnostic confirmation. Adoptees, half-siblings, half-aunts/uncles and half cousins were excluded. Prevalence used to estimate λs was extracted from previously published studies and estimated to be around 12–80/100,000 inhabitants [12]. 2.4. Statistical analysis Crude recurrence risks were calculated for all categories of relatives by dividing the number of affected relatives by the total number of relative in that category. This method may underestimate actual risk of developing MS, since it fails to account for the fact that many relatives have not yet reached the age of maximum risk. Thus, age adjusted lifetime risks were calculated by adjusting the risk of developing MS, taking into account cumulative age at onset distribution in our population (See Supplementary Table 1). This method assumes age of MS onset in relatives is similar to that of probands, a finding supported by previous reported studies [16].

4. Discussion

3. Results 3.1. Clinical and demographic characteristics of study participants Clinical and demographic characteristics of study participants are presented in Table 1. A total of 237 patients were invited to participate, of which 219 were finally included (92%). Patients were excluded either when not reachable (10), or when MS was not confirmed (8). Proband pedigree mean size was 19 (range 2–67). Twenty nine probands (13.2%) initially reported the possibility of a family member diagnosed Table 1 Baseline and clinical characteristics of study participants. Patients

219

Males Females Female:Male ratio Age (mean ± SD) Disease duration in years (median, range) EDSS (median, range) Patients with affected relatives (n, %) Total affected relatives/total relatives (n, %)

59 (27%) 160 (73%) 2.71:1 40.03 ± 10.4 6 (0–35) 1 (0–8.5) 23 (10,5%) 23/4227 (0.54%)

Table 2 Crude and age-adjusted risk in MS relatives. Relative

Affected/total (n)

Crude risk (%)

AAR (%, 95% CI)

Mother Father Parents Sister Brother Sibling Daughter Son Offspring Aunt Uncle Female cousin Male cousin Niece Nephew Aunt/uncle Cousin Niece/nephew

2/188 1/175 3/363 1/178 0/193 1/371 2/130 1/129 3/259 1/501 2/504 6/858 5/849 2/252 0/270 3/1005 11/1707 2/522

1.06 0.57 0.83 0.56 0.00 0.27 1.54 0.78 1.16 0.20 0.40 0.70 0.59 0.79 0.00 0.30 0.64 0.38

1.51 (1.3–1.7) 0.59 (0.4–0.7) 1.07 (0.9–1.3) 0.56 (0.4–0.7) – 0.28 (0.2–0.4) 1.57 (1.3–1.8) 0.81 (0.6–1) 1.19 (1–1.4) 0.21 (0.1–0.4) 0.41 (0.2–0.5) 1.21 (1–1.4) 1.19 (1–1.4) 0.83 (0.7–1) – 0.31 (0.2–0.4) 1.20 (1–1.4) 0.40 (0.3–0.5)

Estimates of λs based on sibling recurrence risk were 16.5 (range from 3.5 to 23.3), similar to results published for MS in other locations [13].

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studies should be conducted in multi-centric fashion to address exact incidence of familial MS in other regions of South America. Many potential causes exist to explain differences between results in Buenos Aires, located in a mild weather region (at latitude 34S), and other countries. Vitamin D is among them, as one may expect greater exposure to sunlight in our region. However, and to our surprise, this was not the case, vitamin D deficiency was common among MS patients and controls alike, with up to 50% presenting suboptimal vitamin D levels during the winter (JC, personal communication for MS patients, reference [24] for controls). Parasite infections may be another factor explaining lower prevalence. As we have previously shown, parasite infections decrease disease activity in MS patients [25]. Epstein–Barr virus infection is another putative environmental factor linked to MS development, as risk of MS is low in EBV sero-negative individuals but rises sharply after infectious mononucleosis [26]. Since EBV-seronegative prevalence is unknown in our country, this could be another potential explanation for the aforementioned differences.

4.1. Conclusions In conclusion, our study shows that genetic contribution to MS in Buenos Aires seems to be equal to that of other parts of the world, with environmental factors perhaps accounting for the lower prevalence observed in our region. Patients can be advised that familial recurrence risk is increased overall, with daughters at greater risk, 1.54% (92-times greater than the general population).

Funding This study was supported by a funding from Raúl Carrea Institute for Neurological Research, FLENI and Novartis Argentina.

Conflict of interest Mauricio F. Farez has received professional travel/accommodations stipends from Merck-Serono Argentina. María E. Balbuena Aguirre has received professional travel/accommodations stipends from Novartis Argentina. Francisco Varela has nothing to disclose. Alejandro A. Köhler has nothing to disclose. Vanesa Nagel has nothing to disclose. Jorge Correale is a board member of Merck-Serono Argentina, BiogenIdec LATAM, and Merck-Serono LATAM. Dr. Correale has received reimbursement to develop educational presentations for MerckSerono Argentina, Merck-Serono LATAM, Biogen-Idec Argentina, and TEVA-Tuteur Argentina as well as professional travel/accommodations stipends.

Acknowledgments We would like to thank Dr. Sergio Baranzini and Dr. Romina Flores for the critical appraisal of the manuscript.

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Low familial risks for multiple sclerosis in Buenos Aires, Argentina.

Multiple sclerosis is a complex disease in which genetic susceptibility plays a role and familial occurrence has long been recognized. To date, no stu...
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