We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

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A variant in CDKAL1 influences insulin response and risk of type 2 diabetes.

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

The evidence for the existence of genetic susceptibility variants for the common form of hypertension (‘‘essential hypertension’’) remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D.C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p=5.8610 27 ) or with hypertension as a binary trait (top scoring SNP rs9791170, p=5.1610 27 ). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring topscoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments.

/pdf/a-genome-wide-association-study-of-hypertension-and-blood-3jorme9xpb.pdf

A genome-wide association study of hypertension and blood pressure in African Americans.

Africa is one of the most ethnically and genetically diverse regions of the world. It is thought to be the ancestral homeland of all modern humans, and is the homeland of millions of people of the recent African diaspora. Because of the central role of African populations in human history, characterizing their patterns of genetic diversity and linkage disequilibrium is crucial for reconstructing human evolution and for understanding the genetic basis of complex diseases.

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Genetic analysis of African populations: human evolution and complex disease

https://www.cell.com/trends/genetics/pdf/S0168-9525(09)00185-1.pdf

Next generation disparities in human genomics: concerns and remedies.

Objectives. We compared voluntary participation and comprehension of informed consent among individuals of African ancestry enrolled in similarly designed genetic studies of hypertension in the United States and Nigeria. Methods. Survey questionnaires were used to evaluate factors associated with voluntariness (the number of people volunteering) and understanding of the study’s genetic purpose. A total of 655 individuals (United States: 348; Nigeria: 307) were interviewed after participation in the genetic studies. Results. Most US respondents (99%), compared with 72% of Nigerian respondents, reported being told the study purpose. Fewer than half of the respondents at both sites reported that the study purpose was to learn about genetic inheritance of hypertension. Most respondents indicated that their participation was voluntary. In the United States, 97% reported that they could withdraw, compared with 67% in Nigeria. In Nigeria, nearly half the married women reported asking permission from husbands to enroll in the hypertension study; no respondents sought permission from local elders to participate in the study. Conclusions. Our findings highlight the need for more effective approaches and interventions to improve comprehension of consent for genetic research among ethnically and linguistically diverse populations in all settings. (Am J Public Health. 2006;96:1989‐1995. doi:10.2105/AJPH.2005.076232)

https://ajph.aphapublications.org/doi/pdfplus/10.2105/AJPH.2005.076232

Mirjana Vekich

Papers

Voluntary Participation and Informed Consent to International Genetic Research

In Search of Susceptibility Genes for Type 2 Diabetes in West Africa: The Design and Results of the First Phase of the AADM Study