Common and Ethnic-Specific Genetic Determinants of Hemoglobin Concentration between Taiwanese Han Chinese and European Whites: Findings from Comparative Two-Stage Genome-Wide Association Studies.

Human iron nutrition is a result of interplays between genetic and environmental factors. However, there has been scarcity of data on the genetic variants associated with altered iron homeostasis and ethnic-specific associations are further lacking. In this study, we compared between the Taiwanese Han Chinese (HC) and European Whites the genetic determinants of hemoglobin (Hb) concentration, a biochemical parameter that in part reflects the amount of functional iron in the body. Through sex-specific two-stage genome-wide association studies (2S-GWAS), we observed the consistent Hb-association of SNPs in TMPRSS6 (chr 22), ABO (chr 9), and PRKCE (chr 2) across sexes in both ethnic groups. Specific to the Taiwanese HC, the Hb-association of AXIN1, together with other loci near the chr 16 alpha-globin gene cluster, was found novel. On the other hand, majority of the Hb-associated SNPs among Europeans were identified along the chr 6 major histocompatibility complex (MHC) region, which has established roles in immune system control. We report here strong Hb-associations of HFE and members of gene families (SLC17; H2A, H2B, H3, H4, H1; TRIM; ZSCAN, ZKSCAN, ZNF; HLA; BTN, OR), numerous SNPs in/nearby CARMIL1, PRRC2A, PSORS1C1, NOTCH4, TSBP1, C6orf15, and distinct associations with non-coding RNA genes. Our findings provide evidence for both common and ethnic-specific genetic determinants of Hb between East Asians and Caucasians. These will help to further our understanding of the iron and/or erythropoiesis physiology in humans and to identify high risk subgroups for iron imbalances - a primary requirement to meet the goal of precision nutrition for optimal health.