The Effect of Ancestry on Autoimmune Diseases

Center for Autoimmune Diseases ResearchUniversidad del Rosario

Bogota, Colombia

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

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.

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

Ancestry Report

Ancestry Report

Ancestry Report

Ancestry Report

Markers of Genetic Ancestry

• Haploid markers [mitochondrial DNA (mtDNA) or Y chromosome haplotypes)

• Multiple unlinked autosomal markers. Diploid and

‘‘ancestry informative.’’

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.

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.

Ancestry-informative Markers (AIMs)Utilities

• Admixture and association mapping• Forensics. • Prediction of medical risks. • Wildlife management.• Studies of dispersal, gene flow, and

evolutionary history.

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.

How Does Ancestry Affect Autoimmune Diseases?

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.

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

Structure of Colombian Populations

Rojas W, et al. Am J Phys Anthropol 2010;143:13-20.

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.

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.

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.

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.

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.

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.

Higher Lupus Nephritis Prevalence in Hispanics, Latin Americans, African Americans and Asians

Euro-Lu

pus

LUM

INA Hisp

anic TX

LUM

INA Hisp

anic PR

LUM

INA AA

LUM

INA Cauca

sian

GLADEL M

estizo

GLADEL A

LA

GLADEL C

aucasia

n

Chinese

Chinese Hong K

ongIndian

01020304050607080

González LA, et al. Lupus 2013;22:1214-24.

Amerindian Ancestry and Systemic Lupus Erythematosus

Amerindian contribution to cases and controls in 10% intervals

Odds ratio P-value 95% CIAmerindian (AMI) 7.55 6.30E- 05 2.8–20.6Gender 7.72 5.50E- 05 2.9–21.2Gender, age 7.81 5.20E- 05 2.9–21.4Gender, 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.

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.

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.

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

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).

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.

Does ancestry influence polyautoimmunity in Colombians?

• 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

Reference populations and Colombian population.

Ameridian Ancestry Influences Polyautoimmunity in Colombians

Molano-González N et al. Submitted

Colombian population by autoimmune disease status.

Ameridian Ancestry Influences Polyautoimmunity in Colombians

Amerindian ancestry European ancestry

p: 0.001 p: 0.003

Molano-González N et al. Submitted

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.

Acknowledgments