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1.  Childhood Family Living Arrangements and Blood Pressure in African American Men: The Howard University Family Study 
Hypertension  2013;63(1):48-53.
African American men have higher blood pressure levels and consequentially higher prevalence of hypertension compared to men from other ethnic groups in the United States. Socio-familial factors in childhood have been found to play an important role in hypertension, but few studies have examined this relationship among African American men. We investigated whether childhood family living arrangements are independently associated with mean blood pressure and hypertension in a cross-sectional sample of 515 unrelated African American male participants aged 20 years and older enrolled in the Howard University Family Study between 2001 and 2008. African American men who lived with both parents compared to the reference group of men who never lived with both parents during their lifetime had lower systolic blood pressure [−4.4 mmHg (95% Confidence Interval: −7.84, −0.96)], pulse pressure [−3.9 mmHg (95% Confidence Interval: −6.28, −1.51)] and mean arterial blood pressure [−2.0 mmHg (95% Confidence Interval: −4.44, 0.51)]. This protective effect was more pronounced among men who lived with both parents for 1 to 12 years of their lives; they had decreased systolic blood pressure [−6.5 mmHg, (95% Confidence Interval: −10.99, −1.95)], pulse pressure [−5.4 mmHg, (95% Confidence Interval: −8.48, −2.28)], mean arterial pressure [−3.3 mmHg, (95% Confidence Interval: −6.56, 0.00)], and a 46% decreased odds of developing hypertension (OR = 0.54; 95% Confidence Interval: 0.30, 0.99). No statistically significant associations were found for diastolic blood pressure. These results provide preliminary evidence that childhood family structure exerts a long-term influence on blood pressure among African American men.
doi:10.1161/HYPERTENSIONAHA.113.01629
PMCID: PMC3891049  PMID: 24296284
Blood Pressure; Hypertension; African Americans; Family Characteristics; Social Environment
2.  Genetic epidemiology of type 2 diabetes and cardiovascular diseases in Africa 
Progress in cardiovascular diseases  2013;56(3):10.1016/j.pcad.2013.09.013.
The burdens of type 2 diabetes (T2D) and cardiovascular diseases (CVD) are increasingin Africa. T2D and CVD are the result of the complex interaction between inherited characteristics, lifestyle, and environmental factors. The epidemic of obesity is largely behind the exploding global incidence of T2D. However, not all obese individuals develop diabetes and positive family history is a powerful risk factor for diabetes and CVD. Recent implementations of high throughput genotyping and sequencing approaches have advanced our understanding of the genetic basis of diabetes and CVD by identifying several genomic loci that were not previously linked to the pathobiology of these diseases. However, African populations have not been adequately represented in these global genomic efforts. Here, we summarize the state of knowledge of the genetic epidemiology of T2D and CVD in Africa and highlight new genomic initiatives that promise to inform disease etiology, public health and clinical medicine in Africa.
doi:10.1016/j.pcad.2013.09.013
PMCID: PMC3840391  PMID: 24267432
Type 2 diabetes; cardiovascular diseases; genetics; epidemiology; Africa
3.  Rare Functional Variants in Genome–wide Association Identified Candidate Genes for Non-syndromic Clefts in the African Population 
Nonsyndromic clefts of the lip and palate [NSCLP] are complex genetic traits. Together, they are classified as one of the most common birth defects with a prevalence of 1/700 live births. Genome-wide association studies [GWAS] for non-syndromic cleft lip with or without cleft palate [NSCL[P]] revealed significant association for common single nucleotide polymorphisms near genes involved in craniofacial development i.e. MAFB, PAX7, VAX1, ARHGAP29 (ABCA4 locus), and IRF6. Sequencing of protein coding regions of the NSCL[P] GWAS candidate genes or adjacent genes suggest a role for rare functional variants. Replication studies in the African population did not observe any significant association with the GWAS candidate genes. On the other hand, the role of rare functional variants in GWAS candidate genes has not been evaluated in the African population. We obtained saliva samples from case triads in Nigeria and Ethiopia for Sanger sequencing of the GWAS candidate genes [MAFB, PAX7, VAX1, ARHGAP29, and IRF6] in order to identify rare functional variants. A total of 220 African samples [140 Nigerians and 80 Ethiopians] were sequenced and we found the following new rare variants— p.His165Asn in the MAFB gene, p.Asp428Asn in the PAX7, a splice-site variant that creates a new donor splice-site in PAX7. We also found three previously reported missense variants p.Gly466Ser in PAX7; p.Leu913Ser and Arg955His in ARHGAP29. No de novo mutations were found. Future genome-wide association and sequencing studies should be conducted using samples from Africa in order to identify new molecular genetic factors that contribute to the etiology of NSCLP.
doi:10.1002/ajmg.a.36691
PMCID: PMC4169286  PMID: 25081408
Africa; GWAS; rare variants
4.  Relationships Among Obesity, Inflammation, and Insulin Resistance in African Americans and West Africans 
Obesity (Silver Spring, Md.)  2009;18(3):598-603.
Several research studies in different populations indicate that inflammation may be the link between obesity and insulin resistance (IR). However, this relationship has not been adequately explored among African Americans, an ethnic group with disproportionately high rates of obesity and IR. In this study, we conducted a comparative study of the relationship among adiposity, inflammation, and IR in African Americans and West Africans, the ancestral source population for African Americans. The associations between obesity markers (BMI and waist-to-hip ratio (WHR)), inflammatory markers (high-sensitivity C-reactive protein (hsCRP), haptoglobin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α), and IR (homeostasis model assessment of insulin resistance (HOMAIR)) were evaluated in 247 West Africans and 315 African Americans. In average, African Americans were heavier than the West Africans (by an average of 1.6 BMI units for women and 3 BMI units for men). Plasma hsCRP, haptoglobin, and IL-6 (but not TNF-α level) were higher in African Americans than in West Africans. In both populations, BMI was associated with markers of inflammation and with HOMAIR, and these associations remained significant after adjusting for sex and age. However, the pattern of associations between measured inflammatory markers and IR was different between the two groups. In West Africans, hsCRP was the only inflammatory marker associated with IR. In contrast, hsCRP, haptoglobin, and IL-6 were all associated with IR in African Americans. Interestingly, none of the associations between markers of inflammation and IR remained significant after adjusting for BMI. This finding suggests that in African Americans, the relationship between inflammatory markers and IR is mediated by adiposity.
doi:10.1038/oby.2009.322
PMCID: PMC4151268  PMID: 19798069
5.  Genome-wide genotype and sequence-based reconstruction of the 140,000 year history of modern human ancestry 
Scientific Reports  2014;4:6055.
We investigated ancestry of 3,528 modern humans from 163 samples. We identified 19 ancestral components, with 94.4% of individuals showing mixed ancestry. After using whole genome sequences to correct for ascertainment biases in genome-wide genotype data, we dated the oldest divergence event to 140,000 years ago. We detected an Out-of-Africa migration 100,000–87,000 years ago, leading to peoples of the Americas, east and north Asia, and Oceania, followed by another migration 61,000–44,000 years ago, leading to peoples of the Caucasus, Europe, the Middle East, and south Asia. We dated eight divergence events to 33,000–20,000 years ago, coincident with the Last Glacial Maximum. We refined understanding of the ancestry of several ethno-linguistic groups, including African Americans, Ethiopians, the Kalash, Latin Americans, Mozabites, Pygmies, and Uygurs, as well as the CEU sample. Ubiquity of mixed ancestry emphasizes the importance of accounting for ancestry in history, forensics, and health.
doi:10.1038/srep06055
PMCID: PMC4131216  PMID: 25116736
6.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
doi:10.1371/journal.pgen.1004517
PMCID: PMC4125087  PMID: 25102180
BMC Medical Ethics  2014;15:38.
Background
Studies on informed consent to medical research conducted in low or middle-income settings have increased, including empirical investigations of consent to genetic research. We investigated voluntary participation and comprehension of informed consent among women involved in a genetic epidemiological study on breast cancer in an urban setting of Nigeria comparing women in the case and control groups.
Methods
Surveys were administered in face-to-face interviews with 215 participants following their enrollment in the genetic study (106 patients, 109 controls). Audio-taped in-depth interviews were conducted with a sub-sample of 17 (8%) women who completed the survey.
Results
The majority of all participants reported being told that participation in the genetic study was voluntary (97%), that they did not feel pressured to participate in the study (99%), and that they could withdraw from the study (81%). The majority of the breast cancer patients (83%) compared to 58% of women in the control group reported that the study purpose was to learn about the genetic inheritance of breast cancer (OR 3.44; 95% CI =1.66, 7.14, p value = 0.001). Most participants reported being told about study procedures (95%) and study benefits (98%). Sixty-eight percent of the patients, compared to 47% of the control group reported being told about study risks (p-value <0.001). Of the 165 married women, 19% reported asking permission from their husbands to enroll in the breast cancer study; no one sought permission from local elders. In-depth interviews highlight the use of persuasion and negotiation between a wife and her husband regarding study participation.
Conclusions
The global expansion of genetic and genomic research highlights our need to understand informed consent practices for studies in ethnically diverse cultural environments such as Africa. Quantitative and qualitative empirical investigations of the informed consent process for genetic and genomic research will further our knowledge of complex issues associated with communication of information, comprehension, decisional authority and voluntary participation. In the future, the development and testing of innovative strategies to promote voluntary participation and comprehension of the goals of genomic research will contribute to our understanding of strategies that enhance the consent process.
doi:10.1186/1472-6939-15-38
PMCID: PMC4032563  PMID: 24885380
Informed consent; Genetic epidemiological research; Breast cancer; Nigeria
Orofacial clefts (OFC) are complex genetic traits that are often classified as syndromic or nonsyndromic clefts. Currently, there are over 500 types of syndromic clefts in the Online Mendelian Inheritance in Man (OMIM) database, of which Van der Woude syndrome (VWS) is one of the most common (accounting for 2% of all OFC). Popliteal pterygium syndrome (PPS) is considered to be a more severe form of VWS. Mutations in the IRF6 gene have been reported worldwide to cause VWS and PPS. Here, we report studies of families with VWS and PPS in sub-Saharan Africa. We screened the DNA of eight families with VWS and one family with PPS from Nigeria and Ethiopia by Sanger sequencing of the most commonly affected exons in IRF6 (exons 3, 4, 7, and 9). For the VWS families, we found a novel nonsense variant in exon 4 (p.Lys66X), a novel splice-site variant in exon 4 (p.Pro126Pro), a novel missense variant in exon 4 (p.Phe230Leu), a previously reported splice-site variant in exon 7 that changes the acceptor splice site, and a known missense variant in exon 7 (p.Leu251Pro). A previously known missense variant was found in exon 4 (p.Arg84His) in the PPS family. All the mutations segregate in the families. Our data confirm the presence of IRF6-related VWS and PPS in sub-Saharan Africa and highlights the importance of screening for novel mutations in known genes when studying diverse global populations. This is important for counseling and prenatal diagnosis for high-risk families.
doi:10.1002/mgg3.66
PMCID: PMC4049366  PMID: 24936515
IRF6; popliteal pterygium syndrome; sub-Saharan Africa; Van der Woude syndrome
PLoS Genetics  2014;10(3):e1004190.
Although a considerable proportion of serum lipids loci identified in European ancestry individuals (EA) replicate in African Americans (AA), interethnic differences in the distribution of serum lipids suggest that some genetic determinants differ by ethnicity. We conducted a comprehensive evaluation of five lipid candidate genes to identify variants with ethnicity-specific effects. We sequenced ABCA1, LCAT, LPL, PON1, and SERPINE1 in 48 AA individuals with extreme serum lipid concentrations (high HDLC/low TG or low HDLC/high TG). Identified variants were genotyped in the full population-based sample of AA (n = 1694) and tested for an association with serum lipids. rs328 (LPL) and correlated variants were associated with higher HDLC and lower TG. Interestingly, a stronger effect was observed on a “European” vs. “African” genetic background at this locus. To investigate this effect, we evaluated the region among West Africans (WA). For TG, the effect size among WA was the same in AA with only African local ancestry (2–3% lower TG), while the larger association among AA with local European ancestry matched previous reports in EA (10%). For HDLC, there was no association with rs328 in AA with only African local ancestry or in WA, while the association among AA with European local ancestry was much greater than what has been observed for EA (15 vs. ∼5 mg/dl), suggesting an interaction with an environmental or genetic factor that differs by ethnicity. Beyond this ancestry effect, the importance of African ancestry-focused, sequence-based work was also highlighted by serum lipid associations of variants that were in higher frequency (or present only) among those of African ancestry. By beginning our study with the sequence variation present in AA individuals, investigating local ancestry effects, and seeking replication in WA, we were able to comprehensively evaluate the role of a set of candidate genes in serum lipids in AA.
Author Summary
Most of the work on the genetic epidemiology of serum lipids in African Americans (AA) has focused on replicating findings that were identified in European ancestry individuals. While this can be very informative about the generalizability of lipids loci across populations, African ancestry-specific variation will be missed using this approach. Our aim was to comprehensively evaluate five lipid candidate genes in an AA population, from the identification of variants of interest to population-level analysis of high-density lipoprotein cholesterol (HDLC) and triglycerides (TG). We sequenced five genes in individuals with extreme lipids (n = 48) drawn from a population-based study of AA. The variants identified were genotyped in 1,694 AA and analyzed. Notable among the findings were the observation of ancestry specific effect for several variants in the LPL gene among these admixed individuals, with a greater effect observed among those with European ancestry in this region. These associations were further elucidated by replication in West Africans. By beginning with the sequence variation present among AA, investigating ancestry effects, and seeking replication in West Africans, we were able to comprehensively evaluate these candidate genes with a focus on African ancestry individuals.
doi:10.1371/journal.pgen.1004190
PMCID: PMC3945436  PMID: 24603370
Journal of hypertension  2013;31(1):201-207.
Research in industrialized countries has demonstrated that a key factor limiting the control of hypertension is poor patient adherence and that the most successful interventions for long-term adherence employ multiple strategies. Very little data exist on this question in low-income countries, where medication-taking behavior may be less well developed. We conducted a treatment adherence trial of 544 subjects (mean age ~63 years, mean BP ~168/92 mmHg) with previously untreated hypertension in urban and rural Nigeria. Eligible participants were randomized to one of two arms: clinic management only, or clinic management + home visits. Both interventions included three elements: a community based, nurse-led treatment program with physician backup; facilitation of clinic visits and health education; and the use of diuretics plus a beta blocker as needed. After initial diagnosis, the management protocol was implemented by a nurse with physician backup. Participants were evaluated monthly for 6 months. Medication adherence was assessed with pill count and urine testing. Dropout rates, by treatment group, ranged from 12% to 28%. Among participants who completed the 6 month trial, overall adherence was high (~77% of participants took > 98% of prescribed pills). Adherence did not differ by treatment arm, but was better at the rural than the urban site and among those with higher baseline BP. Hypertension control (BP < 140/90 mmHg) was achieved in ~66% of participants at 6 months. This community-based intervention confirms relatively modest default rates compared to industrialized societies, and suggests that medication adherence can be high in developing world settings in clinic attenders.
doi:10.1097/HJH.0b013e32835b0842
PMCID: PMC3530610  PMID: 23137954
anti-hypertensive; adherence; compliance trial
Journal of hypertension  2011;29(10):10.1097/HJH.0b013e32834b000d.
Objective
Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African–Americans.
Methods
We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African–Americans and performed a case–control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components).
Results
A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P = 9.3 × 10–3). For SBP, rs3917420 in the SELE gene (P = 9.0 × 10–4) and rs4657251 in the RGS5 gene (P = 9.7 × 10–3) were the top hits. Effect size for each of these variants was approximately 2–3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01).
Conclusion
These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.
doi:10.1097/HJH.0b013e32834b000d
PMCID: PMC3862027  PMID: 21881522
African–Americans; candidate gene; haplotype; hypertension; single nucleotide polymorphism
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
doi:10.1038/ng.2608
PMCID: PMC3694490  PMID: 23583978
Human Molecular Genetics  2012;21(20):4530-4536.
Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10−6 in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10−8 and 2.9 × 10−8 for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10−9 and 4.9 × 10−10 for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.
doi:10.1093/hmg/dds282
PMCID: PMC3459464  PMID: 22791750
Liu, Ching-Ti | Monda, Keri L. | Taylor, Kira C. | Lange, Leslie | Demerath, Ellen W. | Palmas, Walter | Wojczynski, Mary K. | Ellis, Jaclyn C. | Vitolins, Mara Z. | Liu, Simin | Papanicolaou, George J. | Irvin, Marguerite R. | Xue, Luting | Griffin, Paula J. | Nalls, Michael A. | Adeyemo, Adebowale | Liu, Jiankang | Li, Guo | Ruiz-Narvaez, Edward A. | Chen, Wei-Min | Chen, Fang | Henderson, Brian E. | Millikan, Robert C. | Ambrosone, Christine B. | Strom, Sara S. | Guo, Xiuqing | Andrews, Jeanette S. | Sun, Yan V. | Mosley, Thomas H. | Yanek, Lisa R. | Shriner, Daniel | Haritunians, Talin | Rotter, Jerome I. | Speliotes, Elizabeth K. | Smith, Megan | Rosenberg, Lynn | Mychaleckyj, Josyf | Nayak, Uma | Spruill, Ida | Garvey, W. Timothy | Pettaway, Curtis | Nyante, Sarah | Bandera, Elisa V. | Britton, Angela F. | Zonderman, Alan B. | Rasmussen-Torvik, Laura J. | Chen, Yii-Der Ida | Ding, Jingzhong | Lohman, Kurt | Kritchevsky, Stephen B. | Zhao, Wei | Peyser, Patricia A. | Kardia, Sharon L. R. | Kabagambe, Edmond | Broeckel, Ulrich | Chen, Guanjie | Zhou, Jie | Wassertheil-Smoller, Sylvia | Neuhouser, Marian L. | Rampersaud, Evadnie | Psaty, Bruce | Kooperberg, Charles | Manson, JoAnn E. | Kuller, Lewis H. | Ochs-Balcom, Heather M. | Johnson, Karen C. | Sucheston, Lara | Ordovas, Jose M. | Palmer, Julie R. | Haiman, Christopher A. | McKnight, Barbara | Howard, Barbara V. | Becker, Diane M. | Bielak, Lawrence F. | Liu, Yongmei | Allison, Matthew A. | Grant, Struan F. A. | Burke, Gregory L. | Patel, Sanjay R. | Schreiner, Pamela J. | Borecki, Ingrid B. | Evans, Michele K. | Taylor, Herman | Sale, Michele M. | Howard, Virginia | Carlson, Christopher S. | Rotimi, Charles N. | Cushman, Mary | Harris, Tamara B. | Reiner, Alexander P. | Cupples, L. Adrienne | North, Kari E. | Fox, Caroline S.
PLoS Genetics  2013;9(8):e1003681.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Author Summary
Central obesity is a marker of body fat distribution and is known to have a genetic underpinning. Few studies have reported genome-wide association study (GWAS) results among individuals of predominantly African ancestry (AA). We performed a collaborative meta-analysis in order to identify genetic loci associated with body fat distribution in AA individuals using waist circumference (WC) and waist to hip ratio (WHR) as measures of fat distribution, with and without adjustment for body mass index (BMI). We uncovered 2 genetic loci potentially associated with fat distribution: LHX2 in association with WC-adjusted-for-BMI and at RREB1 for WHR-adjusted-for-BMI. Six of fourteen previously reported loci for waist in EA populations were significant in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). These findings reinforce the concept that there are loci for body fat distribution that are independent of generalized adiposity.
doi:10.1371/journal.pgen.1003681
PMCID: PMC3744443  PMID: 23966867
The American journal of cardiology  2008;102(7):835-841.
C-reactive protein (CRP) largely has been studied in white non-Hispanic cohorts. There is limited information on CRP’s range of values, heritability and relation to cardiovascular disease (CVD) risk factors in African Americans. We sought to evaluate the distribution, clinical correlates, heritability and genetic linkage of log-transformed CRP in participants of the middle-aged to elderly African American community-based Jackson Heart Study. The distribution and correlates of CRP were analyzed for the entire study cohort who underwent the first examination (2001–2004). Heritability was estimated for the family cohort nested within the larger Jackson Heart Study (246 families, n=1,317). The relation between CRP and CVD risk factors were tested with multivariable stepwise regression analyses. Heritability was estimated using a variance components method. Linkage analysis was performed using the multipoint variance components approach. The study sample consisted of 4,919 participants (mean age 55±13 years, 63% women); median CRP concentration was 2.7 mg/L. In stepwise models traditional risk factors explained 23.8% of CRP’s variability, with body mass index (BMI, partial R2=13.6%) explaining 57.1% of the variability of CRP due to traditional risk factors. The heritability of CRP (adjusted for age, sex and BMI) was 0.45. The strongest linkage evidence for CRP was observed on chromosome 11 (11p13–11p11.2) with a logarithm of odds score of 2.72. In conclusion, in this large population-based cohort of African Americans, circulating CRP concentration was heritable and associated with several traditional cardiovascular risk factors, particularly BMI.
doi:10.1016/j.amjcard.2008.05.049
PMCID: PMC3733442  PMID: 18805107
C-reactive protein; risk factors; genetics; heritability; blood pressure; cholesterol; body mass index; African Americans
Human Molecular Genetics  2012;21(13):3063-3072.
C-reactive protein (CRP) is an acute phase reactant protein produced primarily by the liver. Circulating CRP levels are influenced by genetic and non-genetic factors, including infection and obesity. Genome-wide association studies (GWAS) provide an unbiased approach towards identifying loci influencing CRP levels. None of the six GWAS for CRP levels has been conducted in an African ancestry population. The present study aims to: (i) identify genetic variants that influence serum CRP in African Americans (AA) using a genome-wide association approach and replicate these findings in West Africans (WA), (ii) assess transferability of major signals for CRP reported in European ancestry populations (EA) to AA and (iii) use the weak linkage disequilibrium (LD) structure characteristic of African ancestry populations to fine-map the previously reported CRP locus. The discovery cohort comprised 837 unrelated AA, with the replication of significant single-nucleotide polymorphisms (SNPs) assessed in 486 WA. The association analysis was conducted with 2 366 856 genotyped and imputed SNPs under an additive genetic model with adjustment for appropriate covariates. Genome-wide and replication significances were set at P < 5 × 10−8 and P < 0.05, respectively. Ten SNPs in (CRP pseudogene-1) CRPP1 and CRP genes were associated with serum CRP (P = 2.4 × 10−09 to 4.3 × 10−11). All but one of the top-scoring SNPs associated with CRP in AA were successfully replicated in WA. CRP signals previously identified in EA samples were transferable to AAs, and we were able to fine-map this signal, reducing the region of interest from the 25 kb of LD around the locus in the HapMap CEU sample to only 8 kb in our AA sample.
doi:10.1093/hmg/dds133
PMCID: PMC3373247  PMID: 22492993
PLoS ONE  2013;8(6):e66930.
High risk HPV (hrHPV) infection is a necessary cause of cervical cancer but the host genetic determinants of infection are poorly understood. We enrolled 267 women who presented to our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. We collected information on demographic characteristics, risk factors of cervical cancer and obtained samples of blood and cervical exfoliated cells from all participants. We used Roche Linear Array HPV Genotyping Test® to characterize the prevalent HPV according to manufacturer's instruction; Sequenom Mass Array to test 21 SNPs in genes/regions previously associated with hrHPV and regression models to examine independent factors associated with HPV infection. We considered a p<0.05 as significant because this is a replication study. There were 65 women with and 202 women without hrHPV infection. Under the allelic model, we found significant association between two SNPs, rs2305809 on RPS19 and rs2342700 on TYMS, and prevalent hrHPV infection. Multivariate analysis of hrHPV risk adjusted for age, body mass index, smoking, age of menarche, age at sexual debut, lifetime total number of sexual partners and the total number of pregnancies as covariates, yielded a p-value of 0.071 and 0.010 for rs2305809 and rs2342700, respectively. Our findings in this unique population suggest that a number of genetic risk variants for hrHPV are shared with other population groups. Definitive studies with larger sample sizes and using genome wide approaches are needed to understand the genetic architecture of hrHPV risk in multiple populations.
doi:10.1371/journal.pone.0066930
PMCID: PMC3694982  PMID: 23826176
BMC Medical Ethics  2013;14:21.
Background
Rapid advances in high throughput genomic technologies and next generation sequencing are making medical genomic research more readily accessible and affordable, including the sequencing of patient and control whole genomes and exomes in order to elucidate genetic factors underlying disease. Over the next five years, the Human Heredity and Health in Africa (H3Africa) Initiative, funded by the Wellcome Trust (United Kingdom) and the National Institutes of Health (United States of America), will contribute greatly towards sequencing of numerous African samples for biomedical research.
Discussion
Funding agencies and journals often require submission of genomic data from research participants to databases that allow open or controlled data access for all investigators. Access to such genotype-phenotype and pedigree data, however, needs careful control in order to prevent identification of individuals or families. This is particularly the case in Africa, where many researchers and their patients are inexperienced in the ethical issues accompanying whole genome and exome research; and where an historical unidirectional flow of samples and data out of Africa has created a sense of exploitation and distrust. In the current study, we analysed the implications of the anticipated surge of next generation sequencing data in Africa and the subsequent data sharing concepts on the protection of privacy of research subjects. We performed a retrospective analysis of the informed consent process for the continent and the rest-of-the-world and examined relevant legislation, both current and proposed. We investigated the following issues: (i) informed consent, including guidelines for performing culturally-sensitive next generation sequencing research in Africa and availability of suitable informed consent documents; (ii) data security and subject privacy whilst practicing data sharing; (iii) conveying the implications of such concepts to research participants in resource limited settings.
Summary
We conclude that, in order to meet the unique requirements of performing next generation sequencing-related research in African populations, novel approaches to the informed consent process are required. This will help to avoid infringement of privacy of individual subjects as well as to ensure that informed consent adheres to acceptable data protection levels with regard to use and transfer of such information.
doi:10.1186/1472-6939-14-21
PMCID: PMC3668248  PMID: 23714101
African populations; Ethical; legal; and societal issues; Next generation sequencing; Whole genome and whole exome sequencing
Immunogenetics  2011;64(5):351-359.
Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p<5×10−8) with eight SNPs, the most significant of which was rs5743185 in thePMS1 gene (p=2.30×10−10). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated SNP rs17365948 in the YWHAZ gene (p=0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p=2.55×10−7), 10 SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p=1.04×10−6 to 1.75×10−6), and 23 SNPs near the IL1A gene (p=1.22×10−6 to 1.63×10−6). We also successfully replicated rs4251961 (p=0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p=8.63×10−9). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.
doi:10.1007/s00251-011-0596-7
PMCID: PMC3418332  PMID: 22205395
interleukin; interleukin-10; interleukin-1Ra; interleukin-6; genome-wide association study; African American
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with variable clinical presentation frequently affecting the skin, joints, haemopoietic system, kidneys, lungs and central nervous system. It can be life threatening when major organs are involved. The full pathological and genetic mechanisms of this complex disease are yet to be elucidated; although roles have been described for environmental triggers such as sunlight, drugs and chemicals, and infectious agents. Cellular processes such as inefficient clearing of apoptotic DNA fragments and generation of autoantibodies have been implicated in disease progression. A diverse array of disease-associated genes and microRNA regulatory molecules that are dysregulated through polymorphism and copy number variation have also been identified; and an effect of ethnicity on susceptibility has been described.
doi:10.1186/1750-1172-8-2
PMCID: PMC3551738  PMID: 23289717
Systemic lupus erythematosus; Autoimmunity; Genetic susceptibility; Apoptosis; dsDNA; Disease genes
Background
It has been suggested that adiponectin may offer protection against the adverse health effects of obesity. In this study, we determined the prevalence of paradoxically high adiponectin or paradoxical hyperadiponectinemia (PHA) among obese African Americans and investigated its relationship with the metabolically healthy obese (MHO) phenotype.
Methods
Total adiponectin and metabolic markers including fasting glucose, insulin, serum lipids and obesity measures were determined in 822 unrelated participants from the Howard University Family Study (HUFS). Logistic regression models were used to evaluate the association between MHO phenotype and PHA while adjusting for relevant covariates.
Results
Overall, men had significantly lower adiponectin levels than women. However, adiponectin level was associated with obesity measures, glucose, insulin and insulin resistance index in both men and women. Equal proportion of the obese male and female subjects (19.2%; 66/343) had PHA; these obese individuals with PHA had a healthier metabolic profile including higher HDL-cholesterol, lower insulin levels and smaller waist circumference and insulin levels compared to those without PHA. Also, 28% (96/343) of the study participants met the criteria of MHO phenotype. Interestingly, 42% (28/66) of the obese individuals with PHA also had the MHO phenotype. Finally, the MHO phenotype was associated with PHA in both men and women.
Conclusions
These findings confirm the presence of MHO in African Americans and demonstrate the association of PHA with the MHO phenotype. In all, our findings along with other published results provide evidence for a more systematic investigation of the mechanisms underlying the protective function of adiponectin and its potential therapeutic applications in human metabolic disorders.
doi:10.4021/jem95W
PMCID: PMC3534968  PMID: 23293696
Obesity; paradoxical hyperadiponectinemia (PHA); metabolically healthy obese phenotype (MHO)
Journal of Human Hypertension  2011;26(5):315-324.
Habitual levels of dietary sodium and potassium are correlated with age-related increases in blood pressure (BP) and likely play a role in this phenomenon. Although extensive published evidence exists from randomized trials, relatively few large-scale community surveys with multiple 24-hour urine collections have been reported. We obtained three 24-hour samples on 2,704 individuals from Nigeria, Jamaica and the US to evaluate patterns of intake and within-person relationships to blood pressure. The average (±s.d.) age and weight of participants across all three sites were 39.9±8.6 years and 76.1±21.2 kg, respectively, and 55% of the total participants were females. Sodium excretion increased across the East-West gradient (e.g., 123.9±54.6, 134.1±48.8, 176.6±71.0 (±s.d.) mmol, Nigeria, Jamaica and US, respectively), while potassium was essentially unchanged (e.g., 46.3±22.9, 40.7±16.1, 44.7±16.4 (±s.d.) mmol, respectively). In multivariate analyses both sodium (positively) and potassium (negatively) were strongly correlated with blood pressure (p < 0.001); quantitatively the association was stronger, and more consistent in each site individually, for potassium. Within-population day-to-day variation was also greater for sodium than for potassium. Among each population group a significant correlation was observed between sodium and urine volume, supporting the prior finding of sodium as a determinant of fluid intake in free-living individuals. These data confirm the consistency with the possible role of dietary electrolytes as hypertension risk factors, reinforcing the relevance of potassium in these populations.
doi:10.1038/jhh.2011.39
PMCID: PMC3158967  PMID: 21593783
blood pressure; sodium excretion; potassium excretion; African Diaspora

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