African Admixture Research Articles

Population genetic structure of the people of Qatar

Abstract People of the Qatari peninsula represent a relatively recent founding by a small number of families from three tribes of the Saudi peninsula, Persia, and Oman, with some African admixture. To assess the combination of this founding effect and first-cousin marriages on Qatar's population genetic structure, in a collaborative program of Weill Cornell-Qatar and Weill Cornell-New York, Cornell University and Qatar University, we assessed DNA samples from self-reported Qatari nationals using Affymetrix SNP Array 5.0 to obtain genotype calls of nearly 500,000 single nucleotide polymorphisms (SNPs) in each individual. Principal component analysis was performed along with samples from the Human Genetic Diversity Project dataset, revealing three clusters of genotypes whose proximity to other human population samples is consistent with Arabian origin, a more eastern/Persian origin, and African admixture. The extent of linkage disequilibrium is greater than that of African populations, and runs of homozygosity reflect substantial consanguinity. Despite the fact that the SNPs have a bias toward SNPs common in Europeans, the data strongly support the notion that the Qatari population will provide a valuable resource for the mapping of genes associated with complex disorders. This approach is being tested in samples of the 3 Qatari genomic clusters of healthy vs individuals with type 2 diabetes, a disorder with a high incidence in the Qatari population. To provide a basis for these studies, we have initiated a detailed assessment of the 3 clusters of Qatari genotypes using exome capture and massive parallel sequencing. We expect that these data will provide an invaluable resource for the adaptation of “personalized medicine” for the assessment of risk and the rational use of therapies for the Qatari population.

Abstract PR-1: Genetic African ancestry and race differences in blood insulin-like growth factor 1 (IGF-1), IGF-2, and IGF binding protein 3 (IGFBP-3)

Abstract Purpose: We have previously reported that African American women have significantly higher IGF-1 levels, and lower IGF-2 and IGFBP-3, compared to white women. This investigation aims to determine if genetic African ancestry is associated with these racial differences in blood IGF levels. Methods: The Southern Community Cohort Study (SCCS) is a prospective cohort study of 86,000 men and women, with two-thirds African American recruitment, designed to investigate racial disparities in cancer. We randomly selected 1000 African American and 1000 non-Hispanic white female participants to support focused investigations of racial differences in biomarkers possibly related to breast cancer. Serum IGF-1, IGF-2, and IGFBP-3 levels were measured by ELISA. We estimated African and European admixture using a panel of 276 ancestry informative genetic markers. Final analyses included 821 African American women and 816 white women after excluding women taking hormone replacement therapy or insulin for diabetes. White women had a low African ancestry (median = 0.4%, range=0.1 % to 17.1 %) and thus were considered as a single ancestry category. For African Americans, cutpoints of <85% (n=149), 85%-95% (n=230), and ≥95% (n=442) defined “low,” “medium,” and “high” African ancestry. Using multivariable linear regression, we estimated differences in IGF levels across ancestry categories while adjusting for age, body mass index (BMI), height, menopausal status, and BMI at age 21 years. Results: African American women having 85% African ancestry. For example, IGF-2 levels among white women and African American women with <85%, 85%-95%, and ≥95% African ancestry were 1771.9 ng/ml, 1713.5 ng/ml, 1620.3 ng/ml, and 1620.6 ng/ml, respectively. African American women with < 85% African ancestry had IGF-2 levels that were about 5.8% higher than African American women with 85%-95% (p=0.03) or ≥95% (p=0.01) ancestry. IGF-1 levels among white women and African American women with <85%, 85%-95%, and ≥95% African ancestry were 134.7 ng/ml, 143.8 ng/ml, 147.8 ng/ml, and 147.4 ng/ml, respectively, while IGFBP-3 levels were 3871.8 ng/ml, 3816.9 ng/ml, 3629.0 ng/ml, and 3693.9 ng/ml, respectively. African American women with 85% African ancestry, but these differences in IGF-1 and IGFBP-3 levels between African American ancestry groups were not statistically significant. We also calculated the molar ratio of IGF-1 to IGFBP-3 as an index of biologically available or free IGF-1. Differences in free IGF-1 among white women and African American women with <85%, 85%-95%, and ≥95% African ancestry were 0.126,0.137,0.148, and 0.145, respectively. Free IGF-1 levels were significantly lower among African American women with <85% compared to women with 85%-95% (p=0.02) or ≥95% (p=0.05) ancestry. Conclusion: Estimates of African ancestry are significantly associated with IGF-2 and free IGF-1, and suggest inherited genetic traits associated with African ancestry contribute to racial differences in IGF levels. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):PR-1.

Abstract B75: Racial differences in Helicobacterpylori infection in the southeastern United States

Abstract Context: Gastric cancer incidence in African Americans is twice that in whites, and differing prevalence of strain-specific Helicobacter pylori infection may explain the disparity. Objective: To investigate if there are racial differences in Helicobacter pylori infection. Design, Setting, and Participants: The Southern Community Cohort Study recruited 86,000 participants, two-thirds African American, from 12 southeastern states from 2002-2009. Serum levels of antibodies to Helicobacter pylori proteins were assessed for a sample of 712 African American and non-Hispanic white participants using multiplex serology. Sero-positivity to each Helicobacter pylori protein was defined by predetermined cut-points based on median reporter fluorescence intensity. African and European admixture was estimated using a panel of 276 ancestry genetic markers, with “low,” “medium,” and “high” categories of African ancestry defined as <85%, 85-95%, and ≥95%. Main Outcome Measures: Odds ratios (ORs) for sero-positivity to antibodies to Helicobacter pyloriproteins, by race and African ancestry. Results: In this sample of low-income African Americans and whites, 88% of African Americans and 69% of whites were sero-positive for Helicobacter pylori. Being African American, compared to being white, was associated with a 2- to 6-fold increased risk for sero-positivity to 8 of 15 Helicobacter pylori proteins examined, including CagA (OR, 5.88; 95% CI, 4.21 −8.22), and VacA (OR, 2.70; 1.96-3.72), previously established as virulence factors for gastric cancer risk. Compared to whites, African Americans of low, medium, and high African ancestry had 1.5-, 4.1 -, and 5.0-fold increased risks of sero-positivity to Helicobacter pylori, respectively, primarily related to CagA+ strains, for which increasing African ancestry led to 2.7-, 8.7-, and 12.3-fold increased risks, respectively (all Pfor trend <0.0001). Conclusions: African American race and increasing percentage of genetic estimation of African ancestry are strongly associated with prevalence of infection with Helicobacter pylori, particularly its virulent strains. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B75.

African genetic admixture is associated with body composition and fat distribution in a cross-sectional study of children

Although differences in body composition parameters among African American (AA), Hispanic American (HA) and European American (EA) children are well documented, the factors underlying these differences are not completely understood. Environmental and genetic contributors have been evaluated as contributors to observed differences. This study evaluated the extent to which African or European ancestral genetic background influenced body composition and fat distribution in 301 peripubertal AA (n = 107), HA (n = 79) and EA (n = 115) children aged 7-12. Estimates of African admixture (AFADM) and European admixture (EUADM) were obtained for every subject using 142 ancestry informative DNA markers. Dual energy X-ray absorptiometry and computed tomography scanning were used to determine body composition and abdominal fat distribution, respectively. Multiple regression models were conducted to evaluate the contribution of admixture estimates to body composition and fat distribution. Greater AFADM was associated with lower fat mass (P = 0.0163), lower total abdominal adipose tissue (P = 0.0006), lower intra-abdominal adipose tissue (P = 0.0035), lower subcutaneous abdominal adipose tissue (P = 0.0115) and higher bone mineral content (BMC) (P = 0.0253), after adjusting for socio-economic status, sex, age, height, race/ethnicity and pubertal status. Greater EUADM was associated with lower lean mass (LM) (P = 0.0056). These results demonstrate that ancestral genetic background contributes to racial/ethnic differences in body composition above and beyond the effects of racial/ethnic classification and suggest a genetic contribution to total body fat accumulation, abdominal adiposity, LM and BMC.

Blood Vitamin D Levels in Relation to Genetic Estimation of African Ancestry

African-Americans generally have lower circulating levels of 25 hydroxyvitamin D [25(OH)D] than Whites, attributed to skin pigmentation and dietary habits. Little is known about the genetic determinants of 25(OH)D levels nor whether the degree of African ancestry associates with circulating 25(OH)D. With the use of a panel of 276 ancestry informative genetic markers, we estimated African and European admixture for a sample of 758 African-American and non-Hispanic White Southern Community Cohort Study participants. For African-Americans, cut points of <85%, 85% to 95%, and >or=95% defined low, medium, and high African ancestry, respectively. We estimated the association between African ancestry and 25(OH)D and also explored whether vitamin D exposure (sunlight, diet) had varying effects on 25(OH)D levels dependent on ancestry level. The mean serum 25(OH)D levels among Whites and among African-Americans of low, medium, and high African ancestry were 27.2, 19.5, 18.3, and 16.5 ng/mL, respectively. Serum 25(OH)D was estimated to decrease by 1.0 to 1.1 ng/mL per 10% increase in African ancestry. The effect of high vitamin D exposure from sunlight and diet was 46% lower among African-Americans with high African ancestry than among those with low/medium ancestry. We found novel evidence that the level of African ancestry may play a role in clinical vitamin D status. This is the first study to describe how 25(OH)D levels vary in relation to genetic estimation of African ancestry. Further study is warranted to replicate these findings and uncover the potential pathways involved.

African and non-African admixture components in African Americans and an African Caribbean population.

Admixture is a potential source of confounding in genetic association studies, so it becomes important to detect and estimate admixture in a sample of unrelated individuals. Populations of African descent in the US and the Caribbean share similar historical backgrounds but the distributions of African admixture may differ. We selected 416 ancestry informative markers (AIMs) to estimate and compare admixture proportions using STRUCTURE in 906 unrelated African Americans (AAs) and 294 Barbadians (ACs) from a study of asthma. This analysis showed AAs on average were 72.5% African, 19.6% European and 8% Asian, while ACs were 77.4% African, 15.9% European, and 6.7% Asian which were significantly different. A principal components analysis based on these AIMs yielded one primary eigenvector that explained 54.04% of the variation and captured a gradient from West African to European admixture. This principal component was highly correlated with African vs. European ancestry as estimated by STRUCTURE (r(2)=0.992, r(2)=0.912, respectively). To investigate other African contributions to African American and Barbadian admixture, we performed PCA on approximately 14,000 (14k) genome-wide SNPs in AAs, ACs, Yorubans, Luhya and Maasai African groups, and estimated genetic distances (F(ST)). We found AAs and ACs were closest genetically (F(ST)=0.008), and both were closer to the Yorubans than the other East African populations. In our sample of individuals of African descent, approximately 400 well-defined AIMs were just as good for detecting substructure as approximately 14,000 random SNPs drawn from a genome-wide panel of markers.

Population Genetic Structure of the People of Qatar

People of the Qatar peninsula represent a relatively recent founding by a small number of families from three tribes of the Arabian Peninsula, Persia, and Oman, with indications of African admixture. To assess the roles of both this founding effect and the customary first-cousin marriages among the ancestral Islamic populations in Qatar's population genetic structure, we obtained and genotyped with Affymetrix 500k SNP arrays DNA samples from 168 self-reported Qatari nationals sampled from Doha, Qatar. Principal components analysis was performed along with samples from the Human Genetic Diversity Project data set, revealing three clear clusters of genotypes whose proximity to other human population samples is consistent with Arabian origin, a more eastern or Persian origin, and individuals with African admixture. The extent of linkage disequilibrium (LD) is greater than that of African populations, and runs of homozygosity in some individuals reflect substantial consanguinity. However, the variance in runs of homozygosity is exceptionally high, and the degree of identity-by-descent sharing generally appears to be lower than expected for a population in which nearly half of marriages are between first cousins. Despite the fact that the SNPs of the Affymetrix 500k chip were ascertained with a bias toward SNPs common in Europeans, the data strongly support the notion that the Qatari population could provide a valuable resource for the mapping of genes associated with complex disorders and that tests of pairwise interactions are particularly empowered by populations with elevated LD like the Qatari.

Abraham's Children in the Genome Era: Major Jewish Diaspora Populations Comprise Distinct Genetic Clusters with Shared Middle Eastern Ancestry

For more than a century, Jews and non-Jews alike have tried to define the relatedness of contemporary Jewish people. Previous genetic studies of blood group and serum markers suggested that Jewish groups had Middle Eastern origin with greater genetic similarity between paired Jewish populations. However, these and successor studies of monoallelic Y chromosomal and mitochondrial genetic markers did not resolve the issues of within and between-group Jewish genetic identity. Here, genome-wide analysis of seven Jewish groups (Iranian, Iraqi, Syrian, Italian, Turkish, Greek, and Ashkenazi) and comparison with non-Jewish groups demonstrated distinctive Jewish population clusters, each with shared Middle Eastern ancestry, proximity to contemporary Middle Eastern populations, and variable degrees of European and North African admixture. Two major groups were identified by principal component, phylogenetic, and identity by descent (IBD) analysis: Middle Eastern Jews and European/Syrian Jews. The IBD segment sharing and the proximity of European Jews to each other and to southern European populations suggested similar origins for European Jewry and refuted large-scale genetic contributions of Central and Eastern European and Slavic populations to the formation of Ashkenazi Jewry. Rapid decay of IBD in Ashkenazi Jewish genomes was consistent with a severe bottleneck followed by large expansion, such as occurred with the so-called demographic miracle of population expansion from 50,000 people at the beginning of the 15th century to 5,000,000 people at the beginning of the 19th century. Thus, this study demonstrates that European/Syrian and Middle Eastern Jews represent a series of geographical isolates or clusters woven together by shared IBD genetic threads.

GJB2 mutation spectrum in 209 hearing impaired individuals of predominantly Caribbean Hispanic and African descent

Objective The purpose of the study is to determine whether Caribbean Hispanic and African admixture populations have a paucity of mutations in GJB2, encoding connexin 26. Methods We reported the paucity of mutations in GJB2 and deletions in GJB6 in Caribbean Hispanic and African admixture populations in the Bronx, NY, in 2007 [1]. We have now collected 102 additional probands with non-syndromic sensorineural hearing impairment (NSHI), for a total of 209. We describe here a presentation of the combined data. Results Of the 209 probands, 36% have affected family members with NSHI and the rest have sporadic occurrence. Of the familial cases, 43% had a first-degree relative affected, and the remainder a more distant relative. The hearing impairment ranged from unilateral mild to bilateral profound, with 76% exhibiting bilateral NSHI (BLNSHI). The single coding exon of the GJB2 gene was sequenced in 209 probands, PCR screening for del(GJB6-D13S1830) and sequencing of the non-coding exon of GJB2 to look for the known splice site mutation was performed in 32 NSHI patients with a heterozygous variation in GJB2, and multiplex ligation-dependent probe amplification (MLPA) testing of GJB2 and GJB6 exon deletions or amplifications (P163 GJB-WFS1 kit) was done in 70 probands. Eight unrelated individuals had biallelic GJB2 mutations, representing 4% of our entire cohort, or 5% of our probands with BLNSHI. Of 127 probands of Hispanic or African descent with BLNSHI, six (4.7%) had biallelic pathogenic mutations, three (2.3%) had monoallelic mutations and 118 (93%) had no disease-causing mutations in GJB2. At the same time, no major deletions were identified either by PCR screening (del(GJB6-D13S1830)) or by MLPA analysis ( GJB2 or GJB6), and no subjects had the known splice site mutation in GJB2. Conclusion These results demonstrate that GJB2 is not the major contributor to the genetic basis of NSHI for the Bronx minority admixture populations.

Development of aptitude at altitude

Millions of people currently live at altitudes in excess of 2500 metres, where oxygen supply is limited, but very little is known about the development of brain and behavioural function under such hypoxic conditions. We describe the physiological, cognitive and behavioural profile of a large cohort of infants (6-12 months), children (6-10 years) and adolescents (13-16 years) who were born and are living at three altitude locations in Bolivia ( approximately 500 m, approximately 2500 m and approximately 3700 m). Level of haemoglobin oxygen saturation and end-tidal carbon dioxide were significantly lower in all age groups living above 2500 metres, confirming the presence of hypoxia and hypocapnia, but without any detectable detriment to health. Infant measures of neurodevelopment and behaviour yielded comparable results across altitude groups. Neuropsychological assessment in children and adolescent groups indicated a minor reduction in psychomotor speed with increasing altitude, with no effect of age. This may result from slowing of underlying brain activity in parallel with reduced cerebral metabolism and blood flow, evidenced here by reduced cerebral blood flow velocity, particularly in the basilar artery, in children and adolescents. The proportion of European, Native American and African genetic admixture was comparable across altitude groups, suggesting that adaptation to high altitude in these children occurred in response to chronic hypoxic exposure irrespective of ethnic origin. Thus, psychomotor slowing is proposed to be an adaptive rather than a deficient trait, perhaps enabling accuracy of mental activity in hypoxic conditions.

African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans

Recent studies identified MYH9 as a major susceptibility gene for common forms of non-diabetic end-stage kidney disease (ESKD). A set of African ancestry DNA sequence variants comprising the E-1 haplotype, was significantly associated with ESKD. In order to determine whether African ancestry variants are also associated with disease susceptibility in admixed populations with differing genomic backgrounds, we genotyped a total of 1425 African and Hispanic American subjects comprising dialysis patients with diabetic and non-diabetic ESKD and controls, using 42 single nucleotide polymorphisms (SNPs) within the MYH9 gene and 40 genome-wide and 38 chromosome 22 ancestry informative markers. Following ancestry correction, logistic regression demonstrated that three of the E-1 SNPs are also associated with non-diabetic ESKD in the new sample sets of both African and Hispanic Americans, with a stronger association in Hispanic Americans. We also identified MYH9 SNPs that are even more powerfully associated with the disease phenotype than the E-1 SNPs. These newly associated SNPs, could be divided into those comprising a haplotype termed S-1 whose association was significant under a recessive or additive inheritance mode (rs5750248, OR 4.21, P < 0.01, Hispanic Americans, recessive), and those comprising a haplotype termed F-1 whose association was significant under a dominant or additive inheritance mode (rs11912763, OR 4.59, P < 0.01, Hispanic Americans, dominant). These findings strengthen the contention that a sequence variant of MYH9, common in populations with varying degrees of African ancestry admixture, and in strong linkage disequilibrium with the associated SNPs and haplotypes reported herein, strongly predisposes to non-diabetic ESKD.

Fat Distribution, Aerobic Fitness, Blood Lipids, and Insulin Sensitivity in African‐American and European‐American Women

The purpose of this study was to determine independent relationships of intra-abdominal adipose tissue (IAAT), leg fat, and aerobic fitness with blood lipids and insulin sensitivity (S(i)) in European-American (EA) and African-American (AA) premenopausal women. Ninety-three EA and ninety-four AA with BMI between 27 and 30 kg/m(2) had IAAT by computed tomography, total fat and leg fat by dual-energy X-ray absorptiometry, aerobic fitness by a graded exercise test, African admixture (AFADM) by ancestry informative markers, blood lipids by the Ektachem DT system, and S(i) by glucose tolerance test. Independent of age, aerobic fitness, AFADM, and leg fat, IAAT was positively related to low-density lipoprotein-cholesterol (LDL-C), cholesterol-high-density lipoprotein (HDL) ratio, triglycerides (TGs), and fasting insulin (standardized beta varying 0.16-0.34) and negatively related to HDL-cholesterol (HDL-C) and S(i) (standardized beta -0.15 and -0.25, respectively). In contrast, independent of age, aerobic fitness, AFADM, and IAAT, leg fat was negatively related to total cholesterol, LDL-C, cholesterol-HDL ratio, TGs, and fasting insulin (standardized beta varying -0.15 to -0.21) and positively related to HDL-C and S(i) (standardized beta 0.16 and 0.23). Age was not independently related to worsening of any blood lipid but was related to increased S(i) (standardized beta for S(i) 0.25, insulin -0.31). With the exception of total cholesterol and LDL-C, aerobic fitness was independently related to worsened blood lipid profile and increased S(i) (standardized beta varying 0.17 to -0.21). Maintenance of favorable fat distribution and aerobic fitness may be important strategies for healthy aging, at least in premenopausal EA and AA women.

Adiposity and genetic admixture, but not race/ethnicity, influence bone mineral content in peripubertal children

The effect of fat mass on bone mineral content (BMC) in children is not clear, particularly when considering a diverse population. Ancestral genetic admixture may be an approach to accurately identify population differences in BMC. Our objective was to evaluate the relationships between self-reported race/ethnicity, genetic admixture, and fat mass on BMC in a multiethnic sample of children (n = 270), taking into account dietary and physical activity variables. Ancestral genetic admixture was estimated using 140 ancestry informative markers, body composition by dual-energy X-ray absorptiometry, diet by 24-h recall, and physical activity by accelerometry. Multiple linear regression examined the relationships between race/ethnicity or genetic admixture and percent fat on BMC. Additional analyses were conducted to examine the relationship between race/ethnicity or genetic admixture and BMC stratified by body fat percentage cutpoints. In regression models, there was no association between race/ethnicity and BMC. In contrast, African admixture (AFADM) was positively associated with BMC, American Indian admixture (AMINADM) was inversely associated with BMC, and there was no association between European admixture (EUADM) and BMC. When stratified by percent fat group, high body fat percentage was inversely associated with BMC with EUADM and AMINADM (P = 0.03 and P = 0.02, respectively) and positively associated with AFADM (P < 0.001). Diet and physical activity were not related to BMC in this sample. Our findings suggest that genetic admixture and percent body fat, but not race/ethnicity, diet, or physical activity, influence BMC in our sample of peripubertal children. Further, there is a differential impact of percent fat on BMC that may be mediated by genetic admixture.

Development of two multiplex mini-sequencing panels of ancestry informative SNPs for studies in Latin Americans: an application to populations of the State of Minas Gerais (Brazil)

Admixture occurs when individuals from parental populations that have been isolated for hundreds of generations form a new hybrid population. Currently, interest in measuring biogeographic ancestry has spread from anthropology to forensic sciences, direct-to-consumers personal genomics, and civil rights issues of minorities, and it is critical for genetic epidemiology studies of admixed populations. Markers with highly differentiated frequencies among human populations are informative of ancestry and are called ancestry informative markers (AIMs). For tri-hybrid Latin American populations, ancestry information is required for Africans, Europeans and Native Americans. We developed two multiplex panels of AIMs (for 14 SNPs) to be genotyped by two mini-sequencing reactions, suitable for investigators of medium-small laboratories to estimate admixture of Latin American populations. We tested the performance of these AIMs by comparing results obtained with our 14 AIMs with those obtained using 108 AIMs genotyped in the same individuals, for which DNA samples is available for other investigators. We emphasize that this type of comparison should be made when new admixture/population structure panels are developed. At the population level, our 14 AIMs were useful to estimate European admixture, though they overestimated African admixture and underestimated Native American admixture. Combined with more AIMs, our panel could be used to infer individual admixture. We used our panel to infer the pattern of admixture in two urban populations (Montes Claros and Manhuaçu) of the State of Minas Gerais (southeastern Brazil), obtaining a snapshot of their genetic structure in the context of their demographic history.

Traces of sub-Saharan and Middle Eastern lineages in Indian Muslim populations

Islam is the second most practiced religion in India, next to Hinduism. It is still unclear whether the spread of Islam in India has been only a cultural transformation or is associated with detectable levels of gene flow. To estimate the contribution of West Asian and Arabian admixture to Indian Muslims, we assessed genetic variation in mtDNA, Y-chromosomal and LCT/MCM6 markers in 472, 431 and 476 samples, respectively, representing six Muslim communities from different geographical regions of India. We found that most of the Indian Muslim populations received their major genetic input from geographically close non-Muslim populations. However, low levels of likely sub-Saharan African, Arabian and West Asian admixture were also observed among Indian Muslims in the form of L0a2a2 mtDNA and E1b1b1a and J(*)(xJ2) Y-chromosomal lineages. The distinction between Iranian and Arabian sources was difficult to make with mtDNA and the Y chromosome, as the estimates were highly correlated because of similar gene pool compositions in the sources. In contrast, the LCT/MCM6 locus, which shows a clear distinction between the two sources, enabled us to rule out significant gene flow from Arabia. Overall, our results support a model according to which the spread of Islam in India was predominantly cultural conversion associated with minor but still detectable levels of gene flow from outside, primarily from Iran and Central Asia, rather than directly from the Arabian Peninsula.

CFTR structural rearrangements are not a major mutational mechanism in black and coloured southern African patients with cystic fibrosis.

1Most of these mutations have been identified in CF patients of European origin; however, a deletion of the promoter and exons 1 and 2 of the CFTR gene was detected in two African American families. 2 To increase the CFTR mutation detection rate in black and coloured South African CF patients for molecular diagnosis, we tested patients with a clinical phenotype of CF, and at least one unidentified CFTR mutation, for exon CNVs in the CFTR gene: 24 coloured patients (of Khoisan, Malay, European and African admixture), most of whom originate from the Western Cape, and 18 black patients (sub-Saharan African origin) were tested. Multiplex ligation-dependent probe amplification (MLPA) that detects deletions and duplications based on the principles of complementary probe binding, ligation and amplification with a comparison of patient data to control data, was used (CFTR P091 kit). 3 Controls were matched for ethnicity and geographical region of origin.

Obesity Attenuates the Contribution of African Admixture to the Insulin Secretory Profile in Peripubertal Children: A Longitudinal Analysis

The pubertal transition has been identified as a time of risk for development of type 2 diabetes, particularly among vulnerable groups, such as African Americans (AAs). Documented ethnic differences in insulin secretory dynamics may predispose overweight AA adolescents to risk for type 2 diabetes. The objectives of this longitudinal study were to quantify insulin secretion and clearance in a cohort of 90 AA and European American (EA) children over the pubertal transition and to explore the association of genetic factors and adiposity with repeated measures of insulin secretion and clearance during this critical period. Insulin sensitivity was determined by intravenous glucose tolerance test (IVGTT) and minimal modeling; insulin secretion and clearance by C-peptide modeling; genetic ancestry by admixture analysis. Mixed-model longitudinal analysis indicated that African genetic admixture (AfADM) was independently and positively associated with first-phase insulin secretion within the entire group (P < 0.001), and among lean children (P < 0.01). When examined within pubertal stage, this relationship became significant at Tanner stage 3. Total body fat was a significant determinant of first-phase insulin secretion overall and among obese children (P < 0.001). Total body fat, but not AfADM, was associated with insulin clearance (P < 0.001). In conclusion, genetic factors, as reflected in AfADM, may explain greater first-phase insulin secretion among peripubertal AA vs. EA; however, the influence of genetic factors is superseded by adiposity. The pubertal transition may affect the development of the beta-cell response to glucose in a manner that differs with ethnic/genetic background.

Uncoupling protein 2 Ala55Val polymorphism is associated with a higher acute insulin response to glucose

Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) in pancreatic β-cells plays a crucial role in insulin production and secretion. We hypothesized that 2 UCP2 polymorphisms, a −55C/T (Ala55Val) substitution in exon 4 and an exon 8 insertion, would alter the acute insulin response to glucose (AIRg). Subjects were 155 African American (AA) and European American (EA) women. Body composition was determined by dual-energy x-ray absorptiometry. Insulin sensitivity and AIRg were measured with an intravenous glucose tolerance test and minimal modeling. To account for the confounding effects of population stratification, estimates of African admixture were obtained from approximately 35 ancestry-informative markers. Uncoupling protein 2 genotyping was conducted with gel electrophoresis. Information was analyzed using mixed linear models. A positive association between the −55C/T homozygous mutation and AIRg was identified in the total sample ( P < .01) and independently in EA women ( P = .02) but not AA women. The exon 8 insertion did not significantly affect AIRg. No interaction effects of the 2 polymorphisms on AIRg were noted. These results indicate that AIRg is associated with the −55C/T UCP2 homozygous mutation and that the presence of this mutation could alter postchallenge insulin concentration.

Measurement of admixture proportions and description of admixture structure in different U.S. populations.

Variation in individual admixture proportions leads to heterogeneity within populations. Though novel methods and marker panels have been developed to quantify individual admixture, empirical data describing individual admixture distributions are limited. We investigated variation in individual admixture in four U.S. populations (European American [EA], African American [AA], Hispanics from Connecticut [East Coast, or EC], and Hispanics from California [West Coast, or WC]) assuming three-way intermixture among Europeans, Africans, and Indigenous Americans. Admixture estimates were inferred using a panel of 36 microsatellites and one SNP, which have significant allele frequency differences between ancestral populations, and by using both a maximum likelihood (ML)-based method and a Bayesian method implemented in the program STRUCTURE. Simulation studies showed that estimates obtained with this marker panel are within 96% of expected values. EAs had the lowest non-European admixture with both methods, but showed greater homogeneity with STRUCTURE than with ML. All other samples showed a high degree of variation in admixture estimates with both methods, were highly concordant, and showed evidence of admixture stratification. With both methods, AA subjects had on average, 16% European and <10% Indigenous American admixture. EC Hispanics had higher mean African admixture and the WC Hispanics had higher mean Indigenous American admixture, possibly reflecting their different continental origins.

Triglyceride Concentration is Independently Associated with Variation in the LPL Gene in African American and European American Women

Objective: The regulation of triglyceride (TG) metabolism may be affected by many factors including: race/ethnicity, body composition, body fat distribution, insulin action, and the activity of the lipoprotein lipase (LPL) enzyme. This study was designed to identify the independent effects of body composition, body fat distribution, insulin action, and LPL genetic variation on TG and HDL-C concentration. Subjects: The study consisted of premenopausal European American (EA) (n=114) and African American (AA) (n=140) women. Measurements: Body composition was measured by dual-energy X-ray absorptiometry (DXA), intra-abdominal adipose tissue (IAAT) by computed tomography (CT), insulin sensitivity (SI) and the acute insulin response to glucose (AIRg) by intravenous glucose tolerance test, median household income by zip-code. An estimate of individual genetic admixture was obtained from the genotyping of 85 ancestry informative markers and used to control for population stratification. Multiple linear regression analyses were used to identify contributions of body composition, IAAT, SI, AIRg, African genetic admixture, and LPL polymorphisms to TG and HDL-C. Results: AA had lower TG and higher HDL-C than EA. African genetic admixture, IAAT, AIRg, SI, and RS285 were significantly and independently related to TG concentration. SI was the only independent contributor to HDL-C. RS1800590 was not associated with variation in TG or HDL. Conclusion: Triglyceride concentration appears to be multifactorial in origin and emanates in part from variance in LPL RS285. Future investigations are necessary to understand the mechanisms through which gene polymorphisms, body fat distribution, and insulin action influence the lipid profile.