The document discusses how ancestry influences autoimmune diseases. It finds that Amerindian ancestry in Latin America is associated with increased risk for certain autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, as well as increased risk for lupus nephritis. Meanwhile, European ancestry is protective against lupus nephritis and influences less frequent autoimmune phenotypes. The document also reports that Amerindian ancestry influences polyautoimmunity in Colombians, with higher Amerindian ancestry associated with polyautoimmunity. Admixed populations provide an important resource for understanding the genetic factors influencing autoimmune diseases.

1. The Effect of Ancestry
on Autoimmune Diseases
Center for Autoimmune Diseases Research
Universidad del Rosario
Bogota, Colombia

2. Ancestry
Ancestry (n.)
Early 14c., from Old French ancesserie "ancestry,
ancestors, from ancestre; spelling modified in
English by influence of ancestor.
Ancestor (n.)
c.1300, ancestre, antecessour, from Old French
ancestre, from Late Latin antecessor
"predecessor," literally "foregoer," agent noun
from past participle stem of Latin antecedere "to
precede," from ante- "before" (see ante) +
cedere "to go" (see cede). Current form from
early 15c. Feminine form ancestress recorded
from 1570s.
Online Etymology Dictionary

3. Ancestry
• Continental ancestry. The geographical origin of
populations (e.g. European-ancestry).
• Biogeographic ancestry. To describe
populations/individuals for whom the geographic
origin of their predecessors is different from their
current place of residence (e.g., African Americans, or
European Americans).
• Familial ancestry (history). To refer to the genetic
background of individuals, or to sections of DNA along
a chromosome, as inferred by the analysis of multi-
locus genotypes.
Ali-Khan SE, et al. Hugo J 2011;5:47-63.
Royal CD, Am J Hum Genet 2010;86:661-73.

4. Self-Reported Ancestry and Genetic Admixture
“Although the need for cautious interpretation of racial data is
indisputable, genetic analyses show that self-reported race is
informative for the classification of genetic clusters”
Sinha et al. NEJM, 2006
“In admixed populations such as Hispanic, self-reported race/
ethnicity may not accurately represent them genetically because
they are admixed with European, African and Native American
ancestry.”
Lee et al. J Genet. 2010
“Self-reported ethnicity and race have some limitations in
accurately capturing Hispanic and South Asian populations.”
Smith et al. Genome Biol. 2014

5. Ancestry Report

6. Ancestry Report

7. Ancestry Report

8. Ancestry Report

9. Markers of Genetic Ancestry
• Haploid markers [mitochondrial DNA (mtDNA) or Y
chromosome haplotypes)
• Multiple unlinked autosomal markers. Diploid and
‘‘ancestry informative.’’

10. Ancestry-Informative Markers (AIMs)
• Sets of polymorphisms for a particular DNA sequence
that appear in substantially different frequencies
between populations from different geographical
regions of the world.
• AIMs can be used to estimate the geographical origins of
the ancestors of an individual typically by continent of
origin (Africa, Asia, or Europe).
• A major application of AIMs is to reduce false positives
in association studies.

11. Population Stratification
The presence of a systematic
difference in allele frequencies
between subpopulations in a
population due to different
ancestry, especially in the context
of association studies.
Tian C, et al. Hum Mol Genet. 2008;17:R143-50.

12. Ancestry-informative Markers (AIMs)
Utilities
• Admixture and association mapping
• Forensics.
• Prediction of medical risks.
• Wildlife management.
• Studies of dispersal, gene flow, and
evolutionary history.

13. Software and Methods
for Estimating Genetic Ancestry
Name Algorithm Outcome Speed
STRUCTURE Probabilistic model Ancestral profile Slow
Admixture Probabilistic model Ancestral profile Moderate
Frappe Probabilistic model Ancestral profile Moderate
ipPCA/
EigenDev
PCA
Principal
components
Fast
GEMTools PCA + graph aproach clusters Fast
Liu et al. Hum Genomics 2013;7: 1.

14. How Does Ancestry Affect
Autoimmune Diseases?

15.  Latin America has millions of tri-racial people of
European, African and Amerindian ancestry.
 The Americas were first inhabited by people
crossing the Bering Land Bridge from northeast
Asia into Alaska well over 10,000 years ago.
 Europeans arrived after 1492 following
Christopher Columbus's voyages.
 African people were captured and taken to
America by the transatlantic slave trade from the
16th to the 19th centuries.

16. Admixture in Latin America
Sans M. Hum Biol 2000;72:155.
503711Cuba
80<10<10Peru
80<10<10Ecuador
>80<10>10Bolivia
<4010>50Venezuela
266.567.5Argentina
43~057Chile
201565Brasil
1-207-15>80Uruguay
56341Mexico
>15>15<60Colombia
Amerindian
(%)
African
(%)
European
(%)
Country

17. Structure of Colombian Populations
Rojas W, et al. Am J Phys Anthropol 2010;143:13-20.

18. Amerindian Ancestry Influences Rheumatoid Arthritis
• The prevalence of RA is higher than expected among some
Amerindian groups (Tlingit, Yakima, Pima, and Chippewa
Indians).
Del Puente A, et al. Am J Epidemiol. 1989;129:1170-8.
Ferucci ED, et al. Semin Arthritis Rheum. 2005;34:662-7.
• Loci associated with Amerindian ancestry in Latin American
patients with RA were found in the “Genómica de artritis
reumatoide” (GENAR) project (1,475 patients and 1,213
controls).
López Herráez D, et al. Arthritis Rheum 2013;65:1457-67.

19. Amerindian Ancestry and Type 1 Diabetes
• Both, the prevalence and the incidence of type 1 diabetes, are
lower in Latin American countries compared to that reported in
Europe, North America, southern Asia and northern Africa.
Borchers AT, et al. Autoimmun Rev 2010;9:A355-65.
Gómez-Díaz RA et al. Curr Diabetes Rev 2014 Feb 23.
• T1D in the Mexican-American population may be due in
significant part to an original genetic contribution from the
Spanish-European population.
Shaw SJ, et al. Int J Epidemiol 1992;21:725-9.

20. Amerindian Ancestry and Type 1 Diabetes
• The presence of the Amerindian component of the population
in Latin America provides protection against T1D.
Collado-Mesa F, et al. Rev Panam Salud Publica 2004;15:388-94.
• Susceptibility alleles in Latin American Mestizos are of
Mediterranean ancestry (DRB1*0301-DQA1*0501-DQB1*0201)
whereas protective alleles are of Amerindian origin
(DRB1*0403/*0407/*0411).
Gorodezky C, et al. Autoimmun Rev 2006;5:187-94.

21. Amerindian Ancestry and Multiple Sclerosis
A relatively high prevalence of Multiple
Sclerosis (MS) is found in Western Europe
and North America. On the contrary, the
lowest prevalence of MS has been
reported in the “Mestizo” (mixed white
and Amerindian) populations living in the
Tropics.
Ojeda E, et al. Clin Neurol Neurosurg
2013;115:381-7.

22. Amerindian Ancestry and Multiple Sclerosis
European Ancestry
Predominates in
Neuromyelitis Optica (NMO)
and Multiple Sclerosis (MS)
Patients from Brazil
Brum DG, et al. PLoS One
2013;8:e58925.
PCA for NMO and MS patients and controls
They clustered closer to Europeans than to Africans
and Amerindians.

23. Ancestry influences Systemic Lupus Erythematosus
Siegel M, et al. Am J Public Health Nations Health. 1964; 54: 33–43.
Alarcón GS, et al. Lupus 1999;8:197-209.
Cervera R, et al. Medicine (Baltimore) 1993;72:113-24.
Pons-Estel BA, et al. Medicine (Baltimore) 2004;83:1-17.

24. Higher Lupus Nephritis Prevalence
in Hispanics, Latin Americans, African Americans and Asians
0
10
20
30
40
50
60
70
80
González LA, et al. Lupus 2013;22:1214-24.

25. Amerindian Ancestry and Systemic Lupus Erythematosus
Amerindian contribution to cases and controls
in 10% intervals
Odds ratio P-value 95% CI
Amerindian (AMI) 7.55 6.30E- 05 2.8–20.6
Gender 7.72 5.50E- 05 2.9–21.2
Gender, age 7.81 5.20E- 05 2.9–21.4
Gender, age and site 7.94 6.10E- 05 2.9–22.2
Amerindian ancestry and SLE
Amerindian ancestry in Argentina is associated with increased
risk for systemic lupus erythematosus.
Seldin MF, et al. Genes Immun 2008;9:389-93.

26. Amerindian ancestry correlates with
increased frequency of risk alleles for SLE.
Sanchez E, et al. Arthritis Rheum 2010;62:3722-9.
Amerindian Ancestry and Systemic Lupus Erythematosus
Characteristic AOR (95% CI) p-value
Malar rash 0.73 (0.56–0.96) 0.03
Discoid rash 0.51 (0.34–0.76) 0.001
Photosensitivity 0.58 (0.44–0.76) <0.0001
Oral ulcers 0.55 (0.42–0.72) <0.0001
Arthritis 0.59 (0.43–0.80) 0.001
Serositis 0.56 (0.41–0.75) <0.0001
Lupus nephritis 3.50 (2.63–4.63) <0.0001
Amerindian ancestry increases both the
risk of developing SLE at an earlier age and
the risk of developing renal disease.
Sánchez E, et al. Arthritis Rheum 2012;64:3687-94.

27. European ancestry is associated
with a decreased risk of lupus nephritis
Renal disease status
by percentage of European ancestry.
European ancestry is protective against the
development of renal disease in SLE, an
effect that is independent of other genetic
ancestries, candidate risk alleles, and
socioeconomic factors.
Richman IB, et al. Arthritis Rheum 2012;64:3374-82.

28. PolyautoimmunityFamilial Autoimmunity
Familial Autoimmunity and Polyautoimmunity
are frequent in Latin Americans
Clustering of autoimmune diseases is not random
Anaya JM. Autoimmun Rev 2014;13:423-6.
Cárdenas-Roldán J, et al. BMC Med 2013;11:73.
Anaya JM. Arthritis Res Ther 2010;12:147.
Anaya JM, et al. Expert Rev Clin Immunol 2007;3:623-35

29. Disease in first-degree relatives Parents Offspring Siblings
Systemic lupus erythematosus 25 (2,1%) 7 (0,6%) 39 (3,3%)
Rheumatoid arthritis 19 (1,6%) 0 13 (1,1%)
Autoimmune thyroid disease 12 (1%) 0 4 (0,3%)
Systemic sclerosis 0 0 1 (0,08%)
Polymyositis 1 (0,08%) 0 0
Familial Autoimmunity is frequent in Latin American patients with SLE
GLADEL cohort (N =1,177)
Alarcón-Segovia D, et al. Arthritis Rheum 2005;52:1138-47.
 High familial aggregation of RA in Latin American families with
SLE (ls: 3.3, lp: 5.3).
 A higher percentage of Mestizo SLE patients had relatives with
autoimmune disease (54.9%) compared with non-Mestizo
patients (41.1%) (p=0.001).

30. Factors Influencing Polyautoimmunity
in Systemic Lupus Erythematosus
Variable AOR 95% CI p
Gender (female) 2.30 1.03 5.15 0.043
Articular involvement 2.02 1.26 3.23 0.003
Familial autoimmunity 1.61 1.14 2.28 0.007
Anti-Ro Ab 1.54 1.10 2.16 0.013
Origin
(Colombia vs Spain)
1.78 1.40 2.27 < 0.0001
Rojas-Villarraga A, et al. Autoimmun Rev. 2010;9:229-32.

31. Does ancestry influence
polyautoimmunity in Colombians?

32. • Population: 508 individuals: 240 single autoimmune
disease, 51 with polyautoimmunity, 36 with MAS, and 181
matched-controls.
• Marshfield Screening Set 16. 353 STRs, 32 AIMs.
• The individual Admixture map was built using STRUCTURE
2.3.4
• Independence was assumed in allele frequencies between
populations.
• The number of cluster was set in 3, the number of burn-in
simulations was set in 5000 and 100000 simulations for
inference.
• A MANOVA model on arl transformed ancestral profiles
was adjusted to evaluate differences in ancestral profiles
among different cases (AD, POLY and MAS) and controls.
Influence of Ancestry on Polyautoimmunity
in Colombians
Molano-González N et al. Submitted

33. Reference populations and
Colombian population.
Ameridian Ancestry Influences Polyautoimmunity
in Colombians
Molano-González N et al. Submitted
Colombian population
by autoimmune disease status.

34. Ameridian Ancestry Influences Polyautoimmunity
in Colombians
Amerindian ancestry European ancestry
p: 0.001 p: 0.003
Molano-González N et al. Submitted

35. Ancestry and Autoimmune Diseases
Conclusions
 Ancestry is an important genetic factor influencing autoimmune
diseases.
 In Latin Americans, Amerindian ancestry is associated with some
prevalent and severe autoimmune phenotypes, whereas European
ancestry influences less frequent phenotypes.
 Admixed populations are important resources to approach low effect
and heterogenic causal genetic variants associated with specific
geographical origin.
 The need for more and specific genome-wide approaches as well as
admixture mapping is necessary to decipher new autoimmune
associated variables.

36. Acknowledgments