Genome-Wide Association Meta-analysis Identifies Novel Variants Associated With Fasting Plasma Glucose in East Asians

Abstract

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Interactions Between Amino Acid–Defined Major Histocompatibility Complex Class II Variants and Smoking in Seropositive Rheumatoid Arthritis

“…We note three important observations about the association of smoking with RA susceptibility on our study, in order to address potential concerns. First, to investigate whether there was a selection bias resulting in low ever-smoking rate among the Korean controls compared to Korean cases, we obtained the smoking status in Health2 Study (39), a community-based cohort study where the 2,987 participants aged 40 – 69 were recruited by Korea National Institute of Health (KNIH). We found very similar ever-smoking rates (3.2% in females and 76.4% in males vs. (3.0% in females and 76.1% in males) in this independent cohort of general subjects in Korea (Supplementary Table 1).…”

Penetrance of Polygenic Obesity Susceptibility Loci across the Body Mass Index Distribution

“…Excluding seven SNPs that have also been associated with comorbidities of obesity from the gene score GS-BMI (stringent) did not alter the pattern of increasing effects across the sample BMI distribution ( Figure S5). [48][49][50][51][52][53][54][55] Moreover, MR analysis indicated that BMI percentile was significantly and positively associated with the CQR estimates for GS-BMI (stringent) (b MR [95% CI] ¼ 0.14 [0.11, 0.16], p ¼ 2.18 3 10 À23 ). In addition, CQR models were refitted with adjustment for diabetic status because this had been shown to mitigate the effects of possible stratification within the sample population (see Supplemental Note and Figure S2).…”

“…In addition to being associated with BMI, GIPR (MIM: 137241; rs10423928, LD R 2 ¼ 1 with rs11672660 in EA), TCF7L2 (MIM: 602228; rs7903146), TOMM40 (MIM: 608061) and APOE (MIM: 107741) (both rs2075650), HMGCR (MIM: 142910; rs4604177, LD R 2 ¼ 0.63 with rs6453133 in EA), PCSK1 (rs6235), CDKAL1 (MIM: 611259; rs9356744), and KCNQ1 (MIM: 607542; rs2283228) have also been associated with several co-morbidities of obesity, including glucose homeostasis, T2D, increased lipid levels, and heightened C-reactive protein (CRP) levels. [48][49][50][51][52][53][54][55] To mitigate potential biases stemming from these comorbidities at higher BMI percentiles, we also calculated a GS excluding these seven SNPs: GS-BMI (stringent). Finally, GSs for both BMI and height were calculated without imputation of missing genotypes: GS-BMI (no imputation) and GS-height (no imputation).…”

A Novel Type 2 Diabetes Locus in sub-Saharan Africans, ZRANB3, is Implicated in Beta Cell Proliferation

“…Of relevance to T2D is our finding two known-T2D associated genes associated with cis-eQTLs (MCM6, DARS) and four with trans-eQTLs (DGKB, GTF3AP5-AGMO, IL23R/IL12RB2, SLC44A4). The DGKB/GTF3AP5-AGMO region has the most annotation to GWAS hits with variants in the genes showing genome-wide significant associations with T2D 28,29 , fasting plasma glucose traits [30][31][32] and glycated hemoglobin 33 . IL23R/IL12RB2 is a known GWAS locus for age of onset of T2D 34 while variants in SLC44A4 have been implicated in the interaction between T2D and iron status biomarkers.…”