Race, Genetic Ancestry, and Health: A Direction for Anthropological Genetics in the 2010′s?

Batai, K. and R. A. Kittles (2013). “Race, Genetic Ancestry, and Health.” Race and Social Problems 5(2): 81-87.

In June 2013 edition of Race and Social Problems journal, we published this review article.  I think, for anthropologists who have a training in genetics, it is an interesting direction that we should explore more.  When I was almost done with my dissertation work, I began to think what I could do after I got my degree.  I was dissatisfied with anthropological genetics.  Although I was excited to investigate human genetic variation and evolution and had fun learning and teaching (I am still interesting in these topic and continue to explore), I felt “so what?”  I understand the importance of understanding migration history and genetic variation in the world, but I felt that anthropologists and many people, mostly wealthy people, are interested in human past and variation mostly only for their intellectual interests.  Who really care about our findings?  Are they really useful knowledge?

Then, I began thinking about using anthropological perspectives and methods to help other people.  I contacted my current mentor, Dr. Rick Kittles, to see if I could do genetic research on health disparities.  I learnt genetic epidemiology, a study of roles of genetics in determining or influencing disease risk in families or populations.  In the genetic epidemiology, a lot of population genetics knowledge and methods are applied to the basic epidemiological research design.  More recently, genetic epidemiologists are showing interests in gene and environment interactions.  Here, environment refers to lifestyle and socio-cultural factors.  Gene and environmental interactions is basically what anthropologists call “bio-cultural perspective,” but genetic epidemiologists think more statistically.

In the U.S., we see a great racial health disparities.  Differences in access to health care and health screen can explain a part of health disparities, but there are more complex, genetic, biological, and socio-cultural factors that are intertwined with ‘race.’  Anthropologists are trained to understand this complex relationship.  We can bring different insights in the genetic research of health disparities from scientists who were trained in other fields, and we can contribute to biomedical science in unique ways.

Vitamin D level in traditional societies in Africa

Luxwolda, M. F., et al. (2012). “Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l.” British Journal of Nutrition 108(09): 1557-1561.

I was very excited to find this article.  Anthropologists say that people with dark pigmentation in the equatorial areas can have optimal serum vitamin D levels, but I have not been able to find any good paper showing the serum vitamin D levels in African people who still live in traditional societies.  I was always wondering what is the natural variation in serum vitamin D levels in Africa.

In this paper, Luxwolda et al. (2012) report that the Massai pastoralists and Hadzabe hunter-gathers have high serum vitamin D concentrations.  They measured serum 25(OH)D, a major circulating form of vitamin D in the blood, in 35 Massai and 25 Hadzabe and found that mean serum 25(OH)D levels was 47.7 ng/mL for the Massai and 43.7 ng/mL for the Hadzabe.  Although sample size was very small, nobody was vitamin D deficient (<20 ng/mL).  The Massai and Hadzabe people spend most of their days in the sun and do not have excess clothes covering their body.

As an anthropologist, I am interested in vitamin D level, first because of vitamin D hypothesis of skin color (see here) and second because of link between low vitamin D and health disparities.  The authors says that serum vitamin D levels observed should be similar to vitamin D levels in African populations before the Out-of-Africa event.  If so, traits, such as skin color, vitamin D binding proteins, and enzymes in vitamin D metabolic pathway, that help maintain optimal levels of serum vitamin D (more than 40 ng/mL?) should have been positively selected outside of Africa.  They also note that it is not clear, if observed vitamin D levels should be a target optimal level in the westernized societies.

Bantu expansion in East Africa: mtDNA variation in two Bantu-speaking ethnic groups (Taita and Mijikenda)

Batai K, Babrowski KB, Arroyo JP, Kusimba CM, Williams SR. 2013. Mitochondrial DNA diversity in two ethnic groups in Southeastern Kenya: Perspectives from the northeastern periphery of the Bantu expansion. American Journal of Physical Anthropology 150 (3):482–49. 

My article from my dissertation project was published on the March issue of American Journal of Physical Anthropology.  We found a great genetic diversity in small Bantu-speaking ethnic groups in southeastern Kenya, the Taita and Mijikenda.  The Taita was genetically similar to the Turkana, Nilo-Saharan-speaking ethnic group in Kenya.  The Mijikenda showed mtDNA variation between the Central African Bantu populations and Northeastern East African populations.  The migration rates between different ethnic groups estimated using MIGRATE were high, and gene flow between different ethnic groups from different language families were common in East Africa.  The results suggest that the Bantu-speaking groups chose many different strategies as they arrived or after they arrived in East Africa.  Probably, the Taita incorporated local females into their group through inter-ethnic marriage and ethnohistorical studies support this data.  On the other hand, the Mijikenda maintained close ties with other Bantu-speaking groups.

In this paper, I wanted to show that although Bantu languages are very homogeneous, the Bantu speaking populations are genetically very heterogeneous and show great differentiation, especially in East Africa.  Although language differences can reduce rates of gene flow, I believe that language difference is not that important, and language and gene have different evolutionary processes.

IL16 variants associated with prostate cancer risk in African Americans

Batai, K., et al. (2012). “Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans.” Cancer Epidemiology Biomarkers & Prevention 21(11): 2059-2068.

My first paper, “Fine-mapping of IL16 gene and prostate cancer risk in African Americans,” was published on the November  issue of Cancer Epidemiology, Biomarkers, and Prevention last year (here).

You may think why my paper is related to anthropological genetics, but there are at least three reasons that I can think of why anthropologists should conduct more research projects related to genetic epidemiology and cancer genetics.

1) Cancer health disparities – many types of cancer are more common among African Americans, due to their gene, biology, or socio-cultural factors.  Anthropologists are uniquely trained to understand the relationship of these factors.

2) I used IMPUTE to estimate untyped genotype using 1000 Genomes data as references.  Imputation method used is based on population genetics and require understanding population history.  I also used STRUCTURE to estimate individual’s genetic ancestry, which was used to correct for effect of population stratification.

3) Evolutionary geneticists may think that cancer risk is not affected by evolutionary process, because people get cancer after reproductive age, but we have to look at the processes or mechanisms of cancer development.  Inflammatory response is important in cancer development and inflammation is common or more severe among African populations.

I believe there are a lot more that anthropologists can learn from other disciplines.

 

 

Genetic epidemiological studies in European and Asian populations support findings from genome wide association studies showing vitamin D related gene variants associated with serum vitamin D levels.

Previously, I reviewed if the variants identified in the genome-wide association studies (GWAS) of serum vitamin D levels in people of European descent are replicated in African Americans (here).  In this post, I will review replication and candidate gene studies conducted in other populations.

Two GWAS among people of European descent have found vitamin D metabolic pathway gene variants associated with serum 25(OH)D levels (Ahn et al. 2010; Wang et al. 2010; see here).  In the GWAS, the strongest signal of association was observed in vitamin D binding protein (GC), and Single Nucleotide Polymorphism (SNP) rs2282679 had lowest P value.  Smaller scale replication and candidate gene studies in European, Asian, and Hispanic populations also demonstrated the association of GC variants with serum 25(OH)D levels.  Although rs2282679 consistently show strong association in many studies, in these smaller studies, other SNPs in the GC show stronger association than rs2282679 (Bu et al. 2010; Lu et al. 2011; Zhang et al. 2012).

The region around DHCR7 and NADSYN1 showed the second strongest association the GWAS.  Again these GWAS identified SNPs are replicated well, but other SNPs also show strong signal of association (Zhang et al. 2012).  CYP2R1 variants also showed strong signal of association in GWAS.  Of all CYP2R1 SNPs, rs170741657 had lowest P value in one of the GWAS (Wang et al. 2010) and association of this SNP with serum vitamin D level is replicated in European and Chinese population with the lowest P value in the gene (Cooper et al. 2011; Zhang et al. 2012).  In one study in European Americans, another SNP, rs12794714, had lower P value than rs170741657 (Bu et al. 2010).  Another GWAS showed that two other SNPs, rs2060793 and rs1993116, were associated with plasma vitamin D levels (Ahn et al. 2010), but an attempt to replicate in Chinese population was not successful (Lu et al. 2011).

The results of replication and candidate gene studies suggest that 1) these GWAS identified SNPs are highly linked and high LD patterns in European and Asian population make it difficult to pinpoint the causal SNPs.  the causal variants that affect serum vitamin D levels have not been found.  2) In addition to genetic variants, biological (age, BMI, skin color, etc.), socio-cultural (smoking, dietary intake, supplement use, occupation, outdoor activities, sunscreen use, etc.) and environmental (latitude, climate, etc.) factors affect serum vitamin D.  We need to properly adjust these factors in the analysis and examine the interaction of these factors with genetic variants.3) Additional studies are necessary to examine which mutations alter the function of these genes and affect serum vitamin D level.

References;

Ahn, J., K. Yu, et al. (2010). “Genome-wide association study of circulating vitamin D levels.” Human Molecular Genetics 19(13): 2739-2745.

Bu, F.-X., L. Armas, et al. (2010). “Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects.” Human Genetics 128(5): 549-556.

Cooper, J. D., D. J. Smyth, et al. (2011). “Inherited Variation in Vitamin D Genes Is Associated With Predisposition to Autoimmune Disease Type 1 Diabetes.” Diabetes 60(5): 1624-1631.

Lu, L., H. Sheng, et al. (2012). “Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans.” Human Genetics 131(3): 505-512.

Wang, T. J., F. Zhang, et al. (2010). “Common genetic determinants of vitamin D insufficiency: a genome-wide association study.” The Lancet 376(9736): 180-188.

Zhang, Y., X. Wang, et al. (2012). “The GC, CYP2R1 and DHCR7 genes are associated with vitamin D levels in northern Han Chinese children” Swiss Med Wkly 142: w13636.

A study show three variants in vitamin D pathway genes are associated with serum vitamin D levels in African Americans

Signorello, L. B., J. Shi, et al. (2011). “Common Variation in Vitamin D Pathway Genes Predicts Circulating 25-Hydroxyvitamin D Levels among African Americans.” PLoS ONE 6(12): e28623.

In scientific communities, there are increased interests in vitamin D, variants in vitamin D metabolic and signaling pathway, and their association with common diseases.  It is interesting to see more research findings published recently showing that vitamin D level and variants in vitamin D metabolic pathway genes are contributing factors for race/ethnic health disparities.  These findings from clinical and medical genetic research should provide insights on evolutionary mechanism that contributed to evolution of skin color and other pigmentation traits (here).

Signerello et al. genotyped 94 SNPs (Single Nucleotide Polymorphisms) in five vitamin D metabolic pathway genes (GC, VDR, CYP2R1, CYP24R1, and CYP27B1) among 379 African Americans and 379 European Americans and tested associated with serum vitamin D levels.  To test the association, they used linear regression models adjusting for sex and percent west African genetic ancestry (just for African Americans), and they found that three SNPs, two in GC (vitamin D binding protein) and one in CYP27B1, were associated with serum vitamin D levels in only African Americans.  One of the SNPs in GC, rs2282679, showed the strongest signal of association in two previous GWAS (here), while CYP27B1 variants were not significantly associated with serum vitamin D in the GWAS.  For African American dataset, they also conducted linear regression analyses to compare two regression model (Model 1: west African ancestry, dietary vitamin D intake, UVR exposure, age, BMI, smoking, and sex; Model 2: three SNPs were added to the Model 1).  Adding three SNPs in the linear regression model increased R² from 0.259 to 0.285, so these three SNPs explain only 2.6% serum vitamin D variation in African Americans.

There are several explanations for their inconsistent findings between African Americans.  First, Signerello et al. genotyped only 6 SNPs (3 in GC and 3 in CYP2R1) that show very strong association with serum vitamin D in two previous GWAS (here), though other genotyped SNPs could be linked to the GWAS identified SNPs.  It is possible that these GWAS identified variants that were not included in this study have a greater effect on serum vitamin D levels than some of the genotyped SNPs.  Second, lifestyle (diet and physical activities) and biological (skin color) differences that might affect serum vitamin D levels are not accounted for in their study.  Further adjusting for a various environmental factors in their initial association analyses may give different results.  Third, the sample size for both African Americans and European Americans is small and insufficient statistical power could be one of the reason why they found only three SNPs associated with vitamin D level in African Americans.

Social and cultural factors are better predictors of blood pressure in African Americans more than genetic ancestry

The association between genetic ancestry and skin color has been well demonstrated (see here).  The heritability of skin color is quite high suggesting that contribution of genetic components to skin color is high as well.  Many genetic research projects support this showing that variants in pigmentation candidate genes are associated with skin color or other pigmentation traits (reviewed here).  However, it is often difficult to demonstrate the association between genetic ancestry and common diseases because social-cultural factors (socio-economic status, education, income, employment status, access to health care, etc.) confound the relationship.

The association between skin color and blood pressure among African Americans has been investigated by many researchers (see here), but more recently researchers started using genetic ancestry estimates to test the association between African ancestry and blood pressure.  In genetic studies, information on only clinically relevant variables are collected, so association between genetic ancestry and disease phenotype (here blood pressure) is often tested without adjusting for socio-cultural and environmental factors.  Only a few studies conducted so far examined 1) effects of genetic ancestry and socio-cultural factors simultaneously and 2) interactions of these factors.

Non et al. (2012) explored the association between genetic ancestry and blood pressure and between education and blood pressure using publically available Family Blood Pressure Program (FBPP) study data.  They found that education, not genetic ancestry, was significantly associated with blood pressure in African Americans and interaction between education and race also plays a role in the racial difference in blood pressure.

First, they examined if African ancestry estimated using 294 autosomal STR was a predictor of blood pressure in African Americans.  They did not observe significant difference in African ancestry between hypertensive and non-hypertensive African Americans.  In the linear regression model, education was significantly associated with blood pressure but African ancestry was not.  They did not observe interaction between African ancestry and education either.

Second, they examined if education explains difference in blood pressure between African Americans and European Americans.  African Americans with high-school degree or who did not complete high-school degree have significantly higher blood pressure than people with higher educations.  They did not observe the same pattern in European American, however.  In the regression analysis, they observed the interaction between education and race.  In addition, they showed that decline in SBP is sharper with increasing educational levels in African Americans than in European Americans.

This is an interesting study to show that education (and probably poverty), not genetic ancestry, is a very important factor affecting blood pressure in African American, suggesting that obtaining higher education will benefit African Americans more than European Americans.  As noted by the authors, one of the limitations of this study is that education was only social-environmental factor available in the dataset and they used it as a proxy for socio-economic status and other social environmental factors.  While I agree that education can be very useful for capturing the many social-environmental factors and their analyses clearly show that socio-environmental factors measured with education are very important predictors or risk factors of blood pressure in African Americans, African American societies are too diverse and heterogeneous, and there should be many socio-environmental factors that affect blood pressure but not captured with education.  They also could explore more what socio-economic factors were captured with education.

It is interesting to note that anthropologically trained scientists are showing that socio-cultural factors are as important as genetic factors assessed with genetic ancestry estimates and skin color.  In other papers, Gravlee at al. (2005 and 2009) have shown that skin color or genetic ancestry is associated with blood pressure in Puerto Ricans, but social classification based on skin color is associated with blood pressure in Puerto Ricans.  They also observed statistically significant interaction between skin color and socio-economic status.

References:

Gravlee, C. C., W. W. Dressler, et al. (2005). “Skin Color, social classification, and blood pressure in Southeastern Puerto Rico.” Am J Public Health 95(12): 2191-2197.

Gravlee, C. C., A. L. Non, et al. (2009). “Genetic ancestry, social classification, and racial inequalities in blood pressure in Southeastern Puerto Rico.” PLoS ONE 4(9): e6821.

Non, A. L., C. C. Gravlee, et al. (2012). “Education, genetic ancestry, and blood pressure in African Americans and Whites.” Am J Public Health 102(8): 1559-1565.