Positive Association Between Type 2 Diabetes Risk Alleles Near CDKAL1 and Reduced Birthweight in Chinese Han Individuals

Abstract

Background:Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population.Methods:Twelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed.Results:Birthweight was inversely associated with CDKAL1-rs10946398 (β = −41 g [95% confidence interval [CI]: −80, −3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (β = −36 g [95% CI: −72, −0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085).Conclusions:This study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.

Common genetic variants in ADCY5 and gestational glycemic traits

“…A study, which was performed in a population consisting of 56.4% of European descent and 43.6% of non-European descent, also got positive results [25]. Three studies were conducted in Asians, two in Chinese Han [26,27] and one in South Asians of Punjabi ancestry [28]. Of note, most studies investigated only one or two ADCY5 variants (i.e.…”

“…Hu et al (2010) [26] investigated only two ADCY5 variants (SNP rs11708067 and rs2877716) and Sun et al (2015) [27] investigated SNP rs11708067 and rs9883204. SNP rs9883204 is in perfect LD with rs2877716 in many populations such as CHB, Utah residents of northern and western European ancestry from the CEPH collection (CEU) (r 2 = 1) (data derived from the 1000 Genomes Project, based on GRCh38).…”

“…In addition to SNP rs11708067 and rs9883204, Sun et al (2015) [27] also investigated SNP rs6777397 (SNP 2), rs9881942, rs4678017 and rs7641344 (SNP 27). In CHB and CHS populations, SNP rs9881942 and rs4678017 were in high LD with rs2332510 (SNP 19) and rs11923120 (SNP 20), respectively (both r 2 >0.976) (data derived from the 1000 Genomes Project, based on GRCh38).…”

tRNA modifications and islet function

“…The risk CDKAL1 SNPs appeared to associate with reduced first‐phase secretion but not second‐phase . In addition to insulin secretion, CDKAL1 has been negatively associated with body mass index (BMI) and birth weight . Although the precise molecular mechanism has been unknown, the negative effect on the BMI and birth weight might be attributed to the reduced insulin secretion, since insulin is also known as an important growth hormone .…”

“…19 In addition to insulin secretion, CDKAL1 has been negatively associated with body mass index (BMI) [20][21][22] and birth weight. [23][24][25][26] Although the precise molecular mechanism has been unknown, the negative effect on the BMI and birth weight might be attributed to the reduced insulin secretion, 27 since insulin is also known as an important growth hormone. 28 A decrease in insulin secretion during infancy might cause growth defects, leading to low birth weight and BMI in carriers of risk CDKAL1 SNPs.…”