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Hispanic ethnicity in multiple sclerosis

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Hispanic ethnicity in multiple sclerosis

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Hispanic Ethnicity in Multiple Sclerosis.

Lilyana Amezcua, MD

UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(Clinical and Translational Investigations)

August 2015
2

Acknowledgements
I would like to thank all those affected with multiple sclerosis and those who decided to participate in
this project.
I would like to thank Dr. David Conti for his invaluable guidance and mentorship.
I also want to thank my other committee members, Dr. James Gauderman, Dr. Wendy Gilmore and
Dr. Talat Islam for their thoughtful suggestions and comments to this thesis.
I am also thankful to Dr. Brett Lund, Dr. David Van Den Berg and Mr. Christopher Edlund for making
the GWAS possible from DNA storage and extraction to genotyping and QC.
To Camila and Adel- who are my daily song. Thank you for forgiving all the days I could not play with
you.

3

Table of Contents
Acknowledgements ............................................................................................ 2
List of Tables ....................................................................................................... 4
List of Figures ..................................................................................................... 4
Abstract ............................................................................................................... 5
Background ....................................................................................................7-12
Methods ........................................................................................................12-14
Results ..........................................................................................................15-20
Discussion ....................................................................................................21-23
Addendum ....................................................................................................23-24
References ....................................................................................................25-27

4

List of Tables:
Table 1: Demographics and clinical characteristics of total Hispanic MS cohort (n=136)

Table 2: Clinical characteristics by birth origin in Hispanics (n=136)

Table 3: Ancestral proportions by birth origin in Hispanics (n=136)

Table 4: Association of Asian ancestry by quartiles

Table 5: Disease severity parameters and their association with Asian proportion

Table 6: Clinical characteristics by high and low Asian proportions in Hispanics with MS (n=80)

Table 7: The association of Asian ancestry to severe ambulatory disability (n=80)

Table 8: The association of Asian ancestry to LESCLs (n=80)

List of Figures:
Figure 1: Hispanic patient with longitudinally extensive spinal cord lesions (LESCLs).
A. Sagittal T2frFSE and B. Sagittal STIR images demonstrate a T2 hyperintense spinal cord lesion
extending from cervical spine segment 1/2 to cervical spine segment 5/6.

Figure 2: Distribution of percent Asian background in the Hispanic sample (n=136)

5

Abstract

Background: Multiple sclerosis (MS) is more frequent in individuals of European background, less
common in Hispanics and rare in Asians. Nevertheless, Hispanics and Asians appear to share
characteristics of the disease such as more spinal cord involvement as seen on MRI, a known risk
factor to disease progression. Ethnicity is a biological and a social construct which encompasses
genetic, cultural, geographic and socioeconomic characteristics shared within a population. Thus,
both the genetic and non-genetic components of ethnicity could likely exert influence in the
expression and outcome of MS, including disease severity.
Objective: This study was undertaken to investigate whether Asian global genetic ancestry in
Hispanics increases the risk of spinal cord involvement and disease severity.
Methods: This was a prospective collection of self-identified Hispanics with MS as part of the USC
Hispanic MS Registry. Clinical and demographic information is collected via medical chart review and
structured questionnaire. MRI of spinal cord was collected as standard of care and assessed for
spinal cord involvement and presence of longitudinal extensive spinal cord lesions (LESCLs). Global
genetic ancestry was derived from single-nucleotide polymorphisms (SNPs) informative for ancestry
using the OMNI express chip. Birthplace (US born versus Immigrant) was used to stratify the
samples. We used multiple logistic regression to test the association between Asian ancestry and
disability as measured by EDSS and presence of LESCLs.
Results: For the 136 MS patients, most were relapsing remitting (98%), US born (52%), and female
(56%). Global ancestry estimation showed that both European (60%) and Asian genetic ancestry
proportions (30%) were the most common background in the samples and less by African
background (9%). When stratified, US born Hispanics had significantly less Asian ancestry than
immigrant Hispanics with MS (p=0.03). There was no difference by LESCLs and disability scores.
6

After adjusting for sex and birthplace, LESCLs (OR 2.96, 95% CIs 1.10- 7.96) and longer disease
duration (OR 1.07, 95% CIs 1.01- 1.12) were found to significantly increase the risk of moderate
ambulatory disability (EDSS≥4) while Asian ancestry could be protective but was did not reach
statistical significance (OR 0.34, 95% CIs 0.01- 6.24). On the other hand, younger age of MS onset
significantly increases the risk (adjusted; OR 0.93 95% CIs 0.88-0.98) of LESCLs, while Asian
ancestry is associated but not statistically significant (adjusted; OR 2.35 95% CIs 0.089-62.37). This
association with disability and LESCLs was also observed when restricting to high and low Asian
quartiles.
Conclusion:
Asian ancestry may modify MS characteristics, including severity of disease and spinal cord
involvement; measures that are important to disease progression. The results presented in this study
provide pilot data that support the use of genetic ancestry in the investigation of MS in Hispanics.
Larger studies should be performed to better understand the clinical implications of Asian ancestry in
disease progression and treatment outcomes.

7

Background:
Multiple Sclerosis and genetics
Multiple Sclerosis (MS) is an immune mediated, progressive, demyelinating, and degenerative
disease. Differences across populations in MS susceptibility, age of onset, central nervous system
site of injury and progression are thought to be the result of a complex interaction between
environmental and genetic risk factors.
1-3
Indeed, MS is associated with the HLA-DR2 allele within the
MHC on chromosome 6 and has been shown to contribute to risk of disease in predominantly
Northern European background.
4
Genome-wide association studies (GWAS) have confirmed the
association with HLA-DR2 and have been helpful in identifying more than 110 additional loci with
moderate effects including interleukin 7 and interleukin 2 receptors (IL-7R & IL-2R) in Europeans.
1,5

While the European population is generally free of major population structure or stratification, and has
the advantage of less genetic heterogeneity, there exists the potential to leverage admixed
populations to help identify genetic variants involved in disease, including disease expression. The
potential advantage comes from using both the genetic diversity within an admixed population, as
well as the differences in MS characteristics.
Admixed populations have been used to identify genes for Alzheimer’s disease, lupus,
diabetes, prostate cancer and MS
6-10
. For example, a recent study identified a novel locus on
Chromosome 1 using admixture mapping in a sample of African Americans and non-Hispanic whites
(NHW) with MS
10
. A more recent study determined that of the 110 non MHC regions that have been
determined to be important in the risk of MS within European populations, only 21 of those had
nominally significant evidence for association. Outside the regions known to be associated in
Europeans, seven are novel. However, none of them reached genome-wide significance. While this
data demonstrates substantial overlap between African American and European multiple sclerosis
8

variants, it also suggest that studies in other race/ethnic groups, such as Hispanics, could facilitate
identification of important regions involved in MS.
2

MS in Latin America
Recent evidence supports that the incidence and prevalence of MS in genetically admix
populations such as African Americans and Hispanic Latinos is increasing.
3, 4
There are a number of
factors that could explain this observation, including improved diagnostic accuracy, increased
availability of Magnetic Resonance Imaging (MRI), and possibly a true increase in prevalence
attributed to environmental factors such as pathogens, vitamin D deficiency or other factors currently
unidentified. This is in contrast where pure indigenous groups such as the Tarahumara, Pima,
Mazahua, and Quarijo Indian groups in Chihuahua, a northern state in Mexico, or other indigenous
groups living in the central regions, of Mexico such as the Nahuatl, Mexica, Huastecos, or Otomies
MS is not reported. This consistent observation is reported among other indigenous groups from
Perú, Brazil, and Chile
5
. A recent epidemiological study among Lacandonians, a pure Amerindian
ethnic group in Mexico, the presence of demyelinating disease, including MS could not be found in
the 10% sampled (population of ~50,000). While environmental factors, such as parasitosis (~20% of
the cohort), a known modifier of immune disease
6
, could explain these findings it also suggests that
genetic factors could also play a role in the maintenance of absence or low prevalence of MS among
populations with predominantly non-European ancestry or recent increase among admix
populations.
7

Despite this recent increase, Hispanics are significantly less likely to develop MS than whites
of European background and African Americans.
3, 8, 9
Epidemiological data regarding MS in Latin
America have indicated a preponderance of combined optic nerve and motor deficits in countries
such as Colombia, Brazil, Cuba and recently Mexico suggesting that this population presents more
like opticospinal MS independent of detectable aquaporin-4 antibody; a known antibody to be strongly
9

associated with neuromyelitis optica spectrum disorders.
11-15
This observation has been referred to
MS having characteristics of Asian MS.
10,16
These similarities between Hispanics and Asians provide
an ideal backdrop for studying the genetic ancestry in Hispanics with MS while taking advantage of
shared characteristics of the disease.
MS in Hispanics living the United States
While limited data exists in the United States about Hispanics with MS, our studies suggest
that Hispanics develop MS at an earlier age compared to non-Hispanic Whites, in particular Hispanics
born and raised in the United States.
3, 11, 12
Optic neuritis is a common clinical presentation at onset of
MS with a reported prevalence of 14-20%
13-15
while in Hispanics it has been reported to be the most
common characteristic at presentation ranging from 32-54%.
8, 10, 11
In addition, we previously
reported that greater spinal cord involvement, with neuromyelitis like lesions (LESCLs) can be seen in
close to 20% of Hispanics with longer standing MS.
16
LESCLs were also associated with greatest risk
to disability (OR 7.3, 95 % CIs 1.9–26.5; p=0.003) compared to absence of spinal cord involvement.
These results mirror Asian reports where 14-31% are reported to have LESCLs
17, 18
and are in
contrast to that reported in non-Hispanic whites (1-3%).
19, 20
The underlying nature of these
differences or disparity has not been defined and differences in sociocultural and genetic factors have
been proposed:
Genetic: Hispanics and global ancestry in MS
Hispanics are a complex ethnic group where both genetic and cultural admixture derives
mostly from the original indigenous inhabitants of America and its European settlers and to some
degree Africans.
21
However, most studies have relied on self-reported ethnicity which may not be
sufficient to describe the underlying characteristics or to control for the potential confounding effect
that stem from this ethnic variability. The contribution of each parental population and the degree of
admixture vary across regions in the Americas. For example, Mexican Americans, the largest
10

minority Latino in the US, contains primarily a mixture of European and Native American ancestry.
22

The use of genetic ancestry through ancestry informative markers, used to estimate the average
ancestral proportions for major source populations in admixed population stratification, may be a way
to better understand how genetic, environmental and cultural factors each contribute to the risk of MS
and disability in MS.
In a recent cross-sectional study of genome-wide analysis, genetic European ancestry in
patients living in Mexico and of Mexican ancestry with MS were found to significantly differ from
Mexican controls (33.1 vs 25.6, respectively; p = 0.0045).
23
While no phenotypic aspect or clinical
characteristics of the disease were investigated, individual ancestry proportions of each chromosome
showed that the main enrichment of European ancestry proportion in MS patients was found across
chromosome 6 (0.3983 vs 0.2341; p = 0.00035). Interestingly the enrichment proportion of indigenous
or Amerindian ancestry was higher in controls as compared with MS patients (0.7158 vs 0.5516;
p=0.00031).
In a small pilot study (n=45), we investigated global individual admixture and clinical
characteristics of MS in Hispanics. An increasing proportion of non-European ancestry was
associated with an increased risk of LESCLs (p=0.03; unadjusted) in addition to greater disability
(p=0.05; unadjusted). This association suggests that the recent admixture within the Hispanic
population could facilitate future projects aiming at localizing genetic variants that may play a role in
disability. Whether the relationship of such variation in genetic/ancestral involvement in disability and
spinal cord involvement exists and is independent of other MS factors remains unknown. Taken
together, these studies suggest that ancestral genetics could be important in the development of
specific disease characteristics in MS in Hispanics and thus may contribute to the varying risk of
disability and spinal cord involvement across groups.
11

Sociocultural: Hispanics and acculturation
Migration patterns and age at migration are reported to primarily influence MS disease
susceptibility,
24-26
and age of onset.
11, 27
Increased disease severity has also been reported among
non-European immigrants to Norway, France, and United Kingdom compared with natives, despite
similar access to health care and biological markers in some.
27-29
While biological differences could
be responsible, immigration can come at the expense of health concerns and proper care that could
be playing a role in MS disease progression.
Hispanics in the United States (US) represent a complex population of US-born and foreign-born
immigrants, where immigration patterns have been noted to be influential in chronic inflammatory
diseases.
30
Data indicate that these changing patterns among Hispanics may be related to
acculturation, the process of cultural and psychological change that results following meeting
between cultures.
31
Obesity, Type 2 diabetes risk, smoking, and cardiovascular disease in Hispanics
are often observed more often with higher acculturated Hispanics paralleling their age of immigration
or time in the US.
32-35
On the other hand less acculturated Hispanics are reported to eat healthier
foods, but yet experience more barriers to healthcare and are less likely to seek preventive
services.
36, 37
Thus, it is possible that being born in the US as oppose to immigrating could influence
MS disease severity and progression among Hispanics living in the US.
In our recent cross-sectional assessment of Hispanics with MS we also found that increase
ambulatory disability is more common among the late immigrant compared to the US born (28% vs.
18%, p=0.04).
38
Being late-immigrant was independently associated with increased disability
(adjusted OR 2.3 95% CIs 1.07–4.82; p=0.03) compared to US-born. These results suggest that in
addition to the likely genetic factors playing a role in disease characteristics and disability, non-
biological factors such as acculturation, need to be incorporated into the examination of disability.

12

Goals of this study:
In this study, we investigated whether the genetic diversity of Hispanics, in particular Asian
ancestry, is responsible for spinal cord differences and disease severity measures and how may they
differ by place of birth, as a proxy to acculturation.
Methods
Study population
Participants. All participants met the criteria for multiple sclerosis according to McDonald Criteria and
the diagnosis of MS was verified by medical records review. These MS patients were previously
enrolled in the MS Hispanic Registry of the University of Southern California (USC). Participants were
recruited from two settings, including academic MS Comprehensive Care Center private clinic and the
outpatient Los Angeles county hospital MS clinic (LAC+USC Medical center). The MS
Comprehensive Care center where private payer individuals are seen and the publicly funded
specialty MS clinic at the Los Angeles County medical center serving uninsured/underinsured
individuals; both of which are served by the same MS specialist neurologists. Hispanic was defined
using the NIH criteria for minority inclusion in research as a person who self-identifies as Hispanic or
Latino of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or
origin, regardless of race. Initial Hispanic self-identification was collected along with identification of
country of origin, and later verified by a comprehensive, self-administered questionnaire. A
neurological history, exam and an expanded disability status scale (EDSS)
39
was assigned by an MS
specialist. Hispanic ancestral background dating back to grandparent origin was completed for 100%
of participants. The Institutional Review Board at USC approved this study and all patients provided
informed consent prior to participation.

13

2.2 Measurements
Clinical Characteristics. Clinical MS characteristics such as type of MS, type of first symptom,
spinal cord involvement via MRI were extracted from the medical record system and registry
database.
Outcome variables. Our primary outcome variable was the presence of ambulatory disability, which
was defined using the Expanded Disability Status Scale (EDSS). The EDSS is an ordinal scale in 0.5
increments ranging from 0, being normal neurological exam to 10, being death. An EDSS of 4.0 is
equivalent to some
ambulatory impairment
and can be reliably
estimated from self-
reported ambulation
index.
40
An EDSS of
≥6 is consistent with
severe ambulatory
disability requiring at
least unilateral
assistance to walk.
A secondary outcome of interest was the presence of radiological spinal cord involvement.
Evidence of spinal cord involvement was found in 61% of Hispanics. We defined spinal cord
involvement by the presence (yes/no), location and extent of spinal cord lesions (<3, and ≥ 3 vertebral
segments: LESCLs, Figure 1) on MRI sagittal and axial planes (Figure 1). Most MRI’s were
performed with a 1.5 Tesla unit and collected as standard of care. For spinal MRI multi-sequence
multi-planar imaging is obtained utilizing the following sequences: Sagittal T1, sagittal T2, sagittal T2
14

STIR, sagittal T1 post-contrast, axial T1post-cotnrast and axial T2. Images were analyzed
retrospectively for the present study blinded to the studies’ clinical data.
Covariates. Covariates included gender, birthplace, lagtime, and disease duration. Disease duration
was defined as the time from formal diagnosis of MS until entry into the USC MS Hispanic Registry.
Lagtime was defined as the time between age of first symptom and age of diagnosis. To characterize
acculturation, we examined birthplace and age of immigration. We dichotomized this variable into US
born and non-US born as “immigrant” from a Latin American country.
Genotyping. DNA was extracted from peripheral blood leukocytes and stored at the lab of Dr. Brett
Lund. Samples were genotyped in groups of 48 at the Epigenome Center directed by Dr. David Van
Den Berg. The Illumina Omni Express 700k SNP array chip was used to genotype 144 self-identified
Hispanics. For quality control (QC) a rigorous 30+ step quality control process that we have utilized in
previous GWA studies which resulted in 135 samples.
21
This process is for the identification and
comparison of inter- and intra-plate controls, stratified SNP and sample call rate investigations for
center and case status, confirmation of strand, concordance comparisons to additional genotyping
performed via the Illumina Golden Gate assay, intensity checks, identification of chromosome X and
Y anomalies, stratification by stripe, and tests of Hardy-Weinberg equilibrium. SNPs were excluded
from the analysis if they were invariant or missing in the study population. From this cleaned data we
estimated global ancestry.
Global Ancestry estimation. We used a comprehensive set of 2,193 SNPs. These SNPs provide
information about participants’ genetic ancestry; ancestry informative markers (AIMs). These AIMS
have shown to capture between and within continental heterogeneity.
41, 42
Global ancestry was
estimated using STRUCTURE (available in the public domain at
(http://pritchardlab.stanford.edu/structure.html), a Bayesian clustering approach using a Markov
Chain Monte Carlo method.

The STRUCTURE output of interest included the estimated proportions
15

of European, Asian, and African ancestry, the sum of
which equals 1, for each study subject.
Statistical analysis. We used descriptive statistics,
including mean values and proportions, to
characterize the demographic and clinical
characteristics of the study population as a whole and
stratified the sample by US born followed by a
restricted stratification by Asian proportions.
Differences in demographic and clinical
characteristics among self-identified Hispanics were
assessed using the chi-square test and the Kruskal-Wallis test. Univariate analysis and logistic
regression were used to test the association between Asian ancestry and disability and spinal MRI
characteristics.
Results
This study included 136 cases for analysis that were mostly of relapsing remitting forms of MS (Table
1). Genotype data for
ancestry analysis were
available for all participants.
The majority of participants
(56%) were female. Mean
disease duration was 7.7
years (SD 7.2). Among the
participants, mean EDSS was
2.9.
16

Stratified by birth, US
born compared to immigrant
were significantly younger at
age of first symptom
(p=0.0005) and diagnosis
(p=0.004) (Table 2). No
difference was seen by
disability status, type of
symptom onset, or lagtime to
diagnosis. There was no
difference also by spinal cord
presentation or spinal cord
involvement, in particular LESCLs (Figure 1). We estimated the global ancestries for the Hispanic MS
patients using STRUCTURE
43
. Global ancestry estimation is highly heterogeneous among each
individual: individual located towards the left on the horizontal axis has relative higher proportion of
European ancestry and lower proportion of Asian ancestry, while the individuals located more
towards the right on the horizontal axis have decreasing proportion of European ancestry and
increasing proportion of Asian ancestry (Figure 2A and 2). But on average global ancestry was 60%
European, 9% African, 30%
Asian (Table 3). US born
Hispanics had significant
less Asian ancestry than
immigrant Hispanics with MS
(p=0.03) while no difference
17

was observed by African ancestry.
Using univariate analysis, the
distribution of Asian ancestry by quartiles
was examined. We categorized Asian
ancestry into 4 quartiles (0, 1, 2, 3) to
examine the association to our two
outcomes of interest (EDSS≥6 and
LESCLs) (Table 4). Using logistic
regression, with each rising category of Asian ancestry compared to the lowest quartile, there is a
decrease risk of severe ambulatory disability. As for LESCLs it did not show a specific trend. This is
likely the result of our small sample size.
Because the clinical parameter of spinal cord
presentation is a known predictor of long term
disability,
44
we explored the association of
Asian ancestry by quartiles as well. In this
model, for each increase in quartile of Asian
ancestry the risk of presenting with spinal cord
syndrome increases despite large confidence
intervals (Table 4). This suggests that the
effect of Asian ancestral proportion on our
outcomes of interest could be linear.
We then performed logistic regression
analysis with both EDSS and LESCLs
(separately) as the outcome variable and Asian
18

genetic ancestry as the
independent variable and as
continuous variable without
adjustment of other variables
(Table 5). Asian ancestry at
this time is not significantly
associated as seen by the wide confidence intervals.
Global Asian ancestry estimation and test of association with disability
Research supports that male sex and longer disease duration places an individual at higher
risk of ambulatory disability. In addition, we have shown that the presence of LESCLs and
immigrating to the US at a later age increases the risk of severe ambulatory disability.
2, 11, 16, 38
Thus,
including these variables in our model as we investigate Asian ancestry as a risk factor in the
development of ambulatory disability is important.
After adjusting for sex and birthplace, LESCLs (OR 2.96, 95% CIs 1.10- 7.96) and longer
disease duration (OR 1.07, 95% CIs 1.01- 1.12) were found to significantly increase the risk of
moderate ambulatory disability (EDSS≥4). Interestingly, higher Asian background was found to be
possibly protective in developing moderate ambulatory disability (OR 0.34, 95% CIs 0.01- 6.24)
without reaching statistical significance.
Global Asian ancestry estimation and test of association with LESCLs
Because the risk of developing LESCLs is less clear, we first investigated the distribution of
LESCLs by birth. The proportion of LESCLs in this sample was no different (p=0.64). However,
when we examine the characteristics of individuals with LESCLs we find that individuals with LESCLs
for continuous variables were significantly younger at age of diagnosis (p=0.002) and age of first
symptom (p=0.003). In previous investigations of a larger sample, LESCLs were more common in
19

individuals with longer disease duration too.
16
As for categorical variables, neither sex, EDSS, or MS
type was significantly associated with LESCLs in this small sample. This data shows that individuals
that start with MS at a younger age could be at risk of developing LESCLs which may in turn be a risk
factor for disability progression.
Thus, in the investigation of LESCLs age of onset of MS needs to be included. Because age
of first symptom is likely to be closest to age of onset of MS, age of first symptom was kept in the
model. Younger age of MS onset significantly increases the risk (adjusted; OR 0.93 95% CIs 0.88-
0.98; p=0.0034) of LESCLs. Asian ancestry on the other hand does not reach statistical significance
(adjusted; OR 2.35 95% CIs 0.089-62.37; p=0.61).
Restricted analysis by high and low Asian ancestry estimations
To further assess the distribution of Asian ancestry using univariate analysis we restricted to
the first quartile (Q
1,
25%) as anything below 22%, and the third quartile (Q
3,
75%) as anything greater
than 38% Asian proportion (Figure 2). Thus, samples falling below Q1 were deemed Asian low and
samples with proportions greater than Q3 were set as Asian high. The clinical characteristics are
described in Table 6.
To examine if the risk of development of severe disability differs by degree of Asian
background, we
restricted to those
with high and low
proportions of
Asian background
(n=80, Table 6).
Using logistic
regression longer
20

disease duration and
presence of LESCLs are
independently associated
with greater disability (Table
7). Asian ancestry while not
reaching significance could
be protective while
immigrant may not.
Our secondary outcome was to assess the risk of LESCLs in this restricted sample.
Individuals with high Asian
proportions are more than
twice the risk of having
LESCLs, without reaching
statistical significance
(Table 8). Interestingly,
higher African ancestry also appears to increase the risk of LESCLs but it also does not reach
statistical significance. As expected, spinal cord as a presenting symptom is also associated with 4x
the risk of LESCLs (unadjusted; p=0.02). When adjusting for age of first symptom and Asian
ancestry, only younger age of MS onset was found to be statistically associated with the risk of
developing LESCLs. Greater Asian proportion was also found to increase the risk without reaching
statistical significance.

21

Discussion:
This initial study estimated the ancestral proportions in a sample of self-identified Hispanics
with MS and analyzed the relationship between Asian genetic ancestry and MS clinical characteristics
of disease severity. The Hispanics used in the study were collected in the medical centers serving
Los Angeles County, CA, and close to 70% were of Mexican origin. Our results show that Hispanics
with MS have different genetic ancestral proportions by birthplace and that Asian proportion is
significantly greater in the immigrant compare to the US born. Our results also indicate that certain
clinical characteristics may be driven by Asian background, particularly LESCLs and disability as
measured by EDSS independent of birthplace.
In this sample significant differences were seen between US born and immigrant, particularly,
Asian ancestry proportions were significantly greater in the immigrant while the disease started at an
earlier age for the US born. The younger age of onset of MS in the US born is not surprising as we
and others have found this to be the case, even when compare to non-Hispanic whites.
11, 17, 18
This
observation suggests that ancestry is likely to be a summary measure of genetic and environmental
interactions. Disability however was not observed to differ by group as we have previously
observed.
11, 38
And interestingly, birthplace had no association with disability status. These findings
suggest that for now birthplace may play a much smaller role in the development of disability when
compared to Asian ancestry. Nevertheless, of all major racial/ethnic groups in the US, Hispanics are
reported to use fewer health care services than whites.
45
Thus birthplace is unlikely to be an accurate
estimate of socioeconomic and cultural competence and its relationship to utilization of MS services
and treatment will need to be further assessed.
While no significant association was found between Asian ancestry and disability in Hispanics
with MS, after adjusting for known risk factors of disease severity, LESCLs was found to be a
significant risk factor to disability. This is very similar to what we and others from Asia have previously
22

reported.
16, 46
This suggests that LESCLs is a sensitivie marker of disability and individuals with
LESCLs may be at higher risk of disability progression early on.
In the investigation of Asian ancestry and LESCLs, no significant association was found. The
small sample size could be to blame. Nevertheless, higher Asian ancestry increases the odds of
LESCLs independent of age of first symptom. In addition, this is also seen with presenting with spinal
cord syndrome, a well-known risk factor to long term disability.
44
This suggests that greater Asian
background could still potentially be a risk factor in the development of long term disability by
promoting early spinal cord involvement. While spinal cord abnormalities are seen on MRI in up to
90% of patients of MS
47
, the mechanisms behind the association between spinal cord pathology and
disability is unclear. Thus, LESCLs likely is the result of genetic and environmental factors that lead
to the phenomenon of high lesion burden and spinal cord atrophy. This includes the possibility that
higher Asian ancestry is associated with clinically severe disease at onset which could signal poorer
functional recovery. In addition, the influence of disease modifying therapies on disease in individuals
with LESCLs is unknown. Hence, we cannot make conclusions about therapeutic aspects related to
outcome.
Limitations
The small sample size presented a limitation as well as its cross-sectional design. Genetic
ancestral proportions were derived by only one statistical procedure and set to 3 global ancestries
(Asian, European, and African) without including Amerindian assessment. However, the errors are
likely to be random and unbiased with respect to the outcomes of interest. We also did not include
disease-modifying drug therapy in our analysis. In fact, considering the variability in the duration and
type of treatment in our population, it may be very hard to include this component in a cross-sectional
evaluation. Nevertheless, the cohort was well–characterized. While this study provides important
information that Asian background may be influential in the characteristic and/or behavior of the
23

disease in Hispanics, it cannot address if differential ancestral proportions, such as Asian ancestry is
a predictor of poor treatment response and disease progression.
Conclusion
In summary, we have capitalized on the genetic heterogeneity within Hispanics to more
effectively dissect the relationship between ethnicity and disease severity. Using this approach, we
have demonstrated that genetic ancestry has a place in the assessment of MS in Hispanics. Further
validation studies with a large sample size are needed to better understand if individuals with higher
Asian background need to be treated differently.

Addendum
Projects and future collaborations:
As a pilot investigation, we would like to identify if there are genomic regions that have been
previously described in whites with MS using a genome wide scan comparing Hispanics MS cases to
non-MS controls of also Hispanic origin. More specifically we are also interested in identifying if
cases compared to controls also have increasing proportions of European and Asian background
compared to recent published data.
23
For this study we plan to conduct a case-control GWAS study
using genetic data from LALES (Los Angeles Latino Eye Study) as controls to identify gene regions
previously identified as candidate genes in the risk of developing MS. LALES is an ongoing cohort
study supported by the National Eye Institute and Health disparities investigating environmental and
genetic risk factors in eye conditions such as glaucoma and diabetic retinopathy in Hispanic
Americans.
48-50
Any case with a history of optic neuritis will be excluded as optic neuritis can be the
presenting sign for MS. Estimation of global ancestry using both STRUCTURE and EIGENSTRAT
will be used. For estimation of local ancestry we will use HAPMIX. An association study using either
linear or logistic regression as implemented in PLINK program can then be used and statistical
24

significance can be determined by the likelihood ratio test. Adjustment variables will likely include
age, sex and, most importantly, the top two principle components from EIGENSTRAT result to control
for confounding by population substructure.
We have recently formed the Alliance for Hispanic MS research (ARHMS) which brings
together the additional expertise and aggregation of samples from the labs of Dr. Jorge Oksenberg
(UCSF) and Dr. Jacob McCauley (University of Miami). Preliminary findings from the combined
samples (n=961) are currently being examined.

25

References
1. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, et al. Risk alleles for multiple sclerosis
identified by a genomewide study. The New England journal of medicine. 2007; 357(9): 851-62.
2. Isobe N, Madireddy L, Khankhanian P, Matsushita T, Caillier SJ, More JM, et al. An ImmunoChip study of multiple
sclerosis risk in African Americans. Brain : a journal of neurology. 2015; 138(Pt 6): 1518-30.
3. Langer-Gould A, Brara SM, Beaber BE, Zhang JL. Incidence of multiple sclerosis in multiple racial and ethnic
groups. Neurology. 2013; 80(19): 1734-9.
4. Ojeda E, Diaz-Cortes D, Rosales D, Duarte-Rey C, Anaya JM, Rojas-Villarraga A. Prevalence and clinical features of
multiple sclerosis in Latin America. Clinical neurology and neurosurgery. 2013; 115(4): 381-7.
5. Rivera VM. Multiple sclerosis in Latin America: reality and challenge. Neuroepidemiology. 2009; 32(4): 294-5.
6. Fleming J, Fabry Z. The hygiene hypothesis and multiple sclerosis. Annals of neurology. 2007; 61(2): 85-9.
7. Flores J, Gonzalez S, Morales X, Yescas P, Ochoa A, Corona T. Absence of Multiple Sclerosis and Demyelinating
Diseases among Lacandonians, a Pure Amerindian Ethnic Group in Mexico. Multiple sclerosis international. 2012; 2012:
292631.
8. Langer-Gould A, Brara SM, Beaber BE, Zhang JL. The incidence of clinically isolated syndrome in a multi-ethnic
cohort. Journal of neurology. 2014; 261(7): 1349-55.
9. Wallin MT, Kurtzke JF, Culpepper WJ, Coffman P, Maloni H, Haselkorn JK, et al. Multiple sclerosis in gulf war era
veterans. 2. Military deployment and risk of multiple sclerosis in the first gulf war. Neuroepidemiology. 2014; 42(4): 226-
34.
10. Cordova J, Vargas S, Sotelo J. Western and Asian features of multiple sclerosis in Mexican Mestizos. Clinical
neurology and neurosurgery. 2007; 109(2): 146-51.
11. Amezcua L, Lund BT, Weiner LP, Islam T. Multiple sclerosis in Hispanics: a study of clinical disease expression.
Mult Scler. 2011; 17(8): 1010-6.
12. Buchanan RJ, Zuniga MA, Carrillo-Zuniga G, Chakravorty BJ, Tyry T, Moreau RL, et al. Comparisons of Latinos,
African Americans, and Caucasians with multiple sclerosis. Ethnicity & disease. 2010; 20(4): 451-7.
13. Cree BA, Khan O, Bourdette D, Goodin DS, Cohen JA, Marrie RA, et al. Clinical characteristics of African
Americans vs Caucasian Americans with multiple sclerosis. Neurology. 2004; 63(11): 2039-45.
14. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple
sclerosis: a geographically based study. I. Clinical course and disability. Brain : a journal of neurology. 1989; 112 ( Pt 1):
133-46.
15. Balcer LJ. Clinical practice. Optic neuritis. The New England journal of medicine. 2006; 354(12): 1273-80.
16. Amezcua L, Lerner A, Ledezma K, Conti D, Law M, Weiner L, et al. Spinal cord lesions and disability in Hispanics
with multiple sclerosis. Journal of neurology. 2013; 260(11): 2770-6.
17. Minohara M, Matsuoka T, Li W, Osoegawa M, Ishizu T, Ohyagi Y, et al. Upregulation of myeloperoxidase in
patients with opticospinal multiple sclerosis: positive correlation with disease severity. Journal of neuroimmunology.
2006; 178(1-2): 156-60.
18. Su JJ, Osoegawa M, Matsuoka T, Minohara M, Tanaka M, Ishizu T, et al. Upregulation of vascular growth factors
in multiple sclerosis: correlation with MRI findings. Journal of the neurological sciences. 2006; 243(1-2): 21-30.
19. Tartaglino LM, Friedman DP, Flanders AE, Lublin FD, Knobler RL, Liem M. Multiple sclerosis in the spinal cord: MR
appearance and correlation with clinical parameters. Radiology. 1995; 195(3): 725-32.
20. Qiu W, Wu JS, Zhang MN, Matsushita T, Kira JI, Carroll WM, et al. Longitudinally extensive myelopathy in
Caucasians: a West Australian study of 26 cases from the Perth Demyelinating Diseases Database. Journal of neurology,
neurosurgery, and psychiatry. 2010; 81(2): 209-12.
21. Millstein J, Conti DV, Gilliland FD, Gauderman WJ. A testing framework for identifying susceptibility genes in the
presence of epistasis. American journal of human genetics. 2006; 78(1): 15-27.
22. Johnson NA, Coram MA, Shriver MD, Romieu I, Barsh GS, London SJ, et al. Ancestral components of admixed
genomes in a Mexican cohort. PLoS genetics. 2011; 7(12): e1002410.
23. Ordonez G, Romero S, Orozco L, Pineda B, Jimenez-Morales S, Nieto A, et al. Genomewide admixture study in
Mexican Mestizos with multiple sclerosis. Clinical neurology and neurosurgery. 2015; 130: 55-60.
26

24. Dean G, Kurtzke JF. On the risk of multiple sclerosis according to age at immigration to South Africa. British
medical journal. 1971; 3(5777): 725-9.
25. McLeod JG, Hammond SR, Kurtzke JF. Migration and multiple sclerosis in United Kingdom and Ireland
immigrants to Australia: a reassessment. II. Characteristics of early (pre-1947) compared to later migrants. Journal of
neurology. 2012; 259(4): 684-93.
26. McLeod JG, Hammond SR, Kurtzke JF. Migration and multiple sclerosis in immigrants to Australia from United
Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration. Journal of neurology. 2011; 258(6): 1140-9.
27. Elian M, Nightingale S, Dean G. Multiple sclerosis among United Kingdom-born children of immigrants from the
Indian subcontinent, Africa and the West Indies. Journal of neurology, neurosurgery, and psychiatry. 1990; 53(10): 906-
11.
28. Berg-Hansen P, Smestad C, Sandvik L, Harbo HF, Celius EG. Increased disease severity in non-Western
immigrants with multiple sclerosis in Oslo, Norway. European journal of neurology : the official journal of the European
Federation of Neurological Societies. 2013.
29. Debouverie M, Lebrun C, Jeannin S, Pittion-Vouyovitch S, Roederer T, Vespignani H. More severe disability of
North Africans vs Europeans with multiple sclerosis in France. Neurology. 2007; 68(1): 29-32.
30. Torres JM, Wallace SP. Migration circumstances, psychological distress, and self-rated physical health for Latino
immigrants in the United States. American journal of public health. 2013; 103(9): 1619-27.
31. Lara M, Gamboa C, Kahramanian MI, Morales LS, Bautista DE. Acculturation and Latino health in the United
States: a review of the literature and its sociopolitical context. Annual review of public health. 2005; 26: 367-97.
32. Delavari M, Sonderlund AL, Swinburn B, Mellor D, Renzaho A. Acculturation and obesity among migrant
populations in high income countries--a systematic review. BMC public health. 2013; 13: 458.
33. Nokes B, Sim Y, Gibson B, Byreddy S, Labiner DM, Coull B, et al. Assessment of Stroke Risk in Southern Arizona,
the Pairing of Acculturation and Stroke Risk Factor Development. Journal of immigrant and minority health / Center for
Minority Public Health. 2013.
34. Fu SS, Burgess D, van Ryn M, Hatsukami DK, Solomon J, Joseph AM. Views on smoking cessation methods in
ethnic minority communities: a qualitative investigation. Preventive medicine. 2007; 44(3): 235-40.
35. Bates LM, Acevedo-Garcia D, Alegria M, Krieger N. Immigration and generational trends in body mass index and
obesity in the United States: results of the National Latino and Asian American Survey, 2002-2003. American journal of
public health. 2008; 98(1): 70-7.
36. Argeseanu Cunningham S, Ruben JD, Narayan KM. Health of foreign-born people in the United States: a review.
Health & place. 2008; 14(4): 623-35.
37. Neuhouser ML, Thompson B, Coronado GD, Solomon CC. Higher fat intake and lower fruit and vegetables
intakes are associated with greater acculturation among Mexicans living in Washington State. Journal of the American
Dietetic Association. 2004; 104(1): 51-7.
38. Amezcua L, Conti DV, Liu L, Ledezma K, Langer-Goulda AM. Place of birth,age of immigration,and disability in
Hispanics with multiple sclerosis. Multiple sclerosis and related disorders. 2015; 4(1): 25-30.
39. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
Neurology. 1983; 33(11): 1444-52.
40. Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, et al. Intensive immunosuppression in
progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma
exchange, and ACTH. The New England journal of medicine. 1983; 308(4): 173-80.
41. Cozen W, Li D, Best T, Van Den Berg DJ, Gourraud PA, Cortessis VK, et al. A genome-wide meta-analysis of
nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood. 2012; 119(2): 469-75.
42. Liu J, Lewinger JP, Gilliland FD, Gauderman WJ, Conti DV. Confounding and heterogeneity in genetic association
studies with admixed populations. Am J Epidemiol. 2013; 177(4): 351-60.
43. Falush D, Stephens M, Pritchard JK. Inference of population structure using multilocus genotype data: linked loci
and correlated allele frequencies. Genetics. 2003; 164(4): 1567-87.
44. Langer-Gould A, Popat RA, Huang SM, Cobb K, Fontoura P, Gould MK, et al. Clinical and demographic predictors
of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review. Archives of neurology.
2006; 63(12): 1686-91.
27

45. Guendelman S, Wagner TH. Health services utilization among Latinos and white non-Latinos: results from a
national survey. Journal of health care for the poor and underserved. 2000; 11(2): 179-94.
46. Matsuoka T, Matsushita T, Osoegawa M, Ochi H, Kawano Y, Mihara F, et al. Heterogeneity and continuum of
multiple sclerosis in Japanese according to magnetic resonance imaging findings. Journal of the neurological sciences.
2008; 266(1-2): 115-25.
47. Bot JC, Barkhof F, Polman CH, Lycklama a Nijeholt GJ, de Groot V, Bergers E, et al. Spinal cord abnormalities in
recently diagnosed MS patients: added value of spinal MRI examination. Neurology. 2004; 62(2): 226-33.
48. Gauderman WJ, Avol E, Gilliland F, Vora H, Thomas D, Berhane K, et al. The effect of air pollution on lung
development from 10 to 18 years of age. N Engl J Med. 2004; 351(11): 1057-67.
49. McConnell R, Berhane K, Gilliland F, London SJ, Vora H, Avol E, et al. Air pollution and bronchitic symptoms in
Southern California children with asthma. Environ Health Perspect. 1999; 107(9): 757-60.
50. Navidi W, Thomas D, Stram D, Peters J. Design and analysis of multilevel analytic studies with applications to a
study of air pollution. Environ Health Perspect. 1994; 8: 25-32.

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Asset Metadata

Creator Amezcua, Lilyana (author)

Core Title Hispanic ethnicity in multiple sclerosis

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 08/06/2015

Defense Date 08/06/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag ancestry,Disability,genetic ancestry,Hispanic,multiple sclerosis,OAI-PMH Harvest

Format application/pdf (imt)

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Contributor Electronically uploaded by the author (provenance)

Advisor Conti, David V. (committee chair)

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