Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome

Abstract

The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1,427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86x10−8, OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63x10−8, OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37x10−9, OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52x10−8, Pmeta=7.82x10−9, OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations

“…[36, 37] Other variants may be identified in novel loci based on a higher frequency of risk alleles in this population. We used high density imputed genotypes from the 1000 Genomes Project (1000G) to expand the genome coverage of genetic variants so that we could examine the evidence for association with BP traits.…”

Interethnic Differences in Serum Lipids and Implications for Cardiometabolic Disease Risk in African Ancestry Populations

“…In contrast, associations in these genes in EA and AA have been observed to be broadly similar[78, 84, 87, 88]. Both LPL and CETP have been implicated in genome-wide studies of MetSyn in EA [89, 90], AA [91], and, recently, in Africans[92]. …”

Transcultural Diabetes Care in The United States – A Position Statement by the American Association of Clinical Endocrinologists

“…In fact, these factors, modifiers, and traits can be intertwined in such curious ways to account for subtle differences in disease expression among different ethno-cultural populations. For example, Tekoya-Ayele et al (100) found that certain SNPs associated with metabolic syndrome (MetS) risk implicated physiologic pathways involving brain function and insulin resistance, and Simons et al (101) found that financial pressures in patients with low-income levels were associated with epigenetic measures, or "weathering," of biological aging. A common-ality among cardio-metabolic risks is inflammation, and Kocarnik et al (102) found 16 SNP-C-reactive protein (CRP) associations spanning multiple ancestral groups (European American, African American, and Hispanic, but not Asian/Pacific Islander or Native American), with many exhibiting pleiotropic effects.…”