Identification of Novel Candidate Markers of Type 2 Diabetes and Obesity in Russia by Exome Sequencing with a Limited Sample Size

Abstract

Type 2 diabetes (T2D) and obesity are common chronic disorders with multifactorial etiology. In our study, we performed an exome sequencing analysis of 110 patients of Russian ethnicity together with a multi-perspective approach based on biologically meaningful filtering criteria to detect novel candidate variants and loci for T2D and obesity. We have identified several known single nucleotide polymorphisms (SNPs) as markers for obesity (rs11960429), T2D (rs9379084, rs1126930), and body mass index (BMI) (rs11553746, rs1956549 and rs7195386) (p < 0.05). We show that a method based on scoring of case-specific variants together with selection of protein-altering variants can allow for the interrogation of novel and known candidate markers of T2D and obesity in small samples. Using this method, we identified rs328 in LPL (p = 0.023), rs11863726 in HBQ1 (p = 8 × 10−5), rs112984085 in VAV3 (p = 4.8 × 10−4) for T2D and obesity, rs6271 in DBH (p = 0.043), rs62618693 in QSER1 (p = 0.021), rs61758785 in RAD51B (p = 1.7 × 10−4), rs34042554 in PCDHA1 (p = 1 × 10−4), and rs144183813 in PLEKHA5 (p = 1.7 × 10−4) for obesity; and rs9379084 in RREB1 (p = 0.042), rs2233984 in C6orf15 (p = 0.030), rs61737764 in ITGB6 (p = 0.035), rs17801742 in COL2A1 (p = 8.5 × 10−5), and rs685523 in ADAMTS13 (p = 1 × 10−6) for T2D as important susceptibility loci in Russian population. Our results demonstrate the effectiveness of whole exome sequencing (WES) technologies for searching for novel markers of multifactorial diseases in cohorts of limited size in poorly studied populations.

PLEKHA5, PLEKHA6 and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis

“…Here we identify PLEKHA5, PLEKHA6 and PLEKHA7, and their ligand adaptor PDZD11, as proteins involved in the copper-dependent localization of ATP7A at the cell periphery and in the maintenance of copper homeostasis. PLEKHA5 and PLEKHA6 were first characterized as PH domain-containing proteins implicated in phosphoinositide signaling (Dowler et al, 2000), and genetic studies indicate that they participate in several developmental processes and diseases (Barbitoff et al, 2018;Cox et al, 2018;Daulagala et al, 2019;Fromer et al, 2014;Huang et al, 2020;Jamain et al, 2014;Jilaveanu et al, 2015;Liu et al, 2020;Shah et al, 2016;Spellmann et al, 2014;Tavano et al, 2018;Thapa et al, 2015;Wythe et al, 2011). However, little is known about the cellular localization and function of PLEKHA5 and PLEKHA6, and the molecular basis for the involvement of WW-PLEKHAs in physiological and pathological processes.…”

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

“…Recent reports from Barbitoff et al () found a strong association of the rs6271 Arg549Cys polymorphism with Type 2 diabetes and obesity in Russia populations (Barbitoff et al ). Noradrenergic signaling has been implicated in Type 2 diabetes and obesity dating back to 1970 (Giachetti ; Munoz et al ; Commins et al ; Bozek et al ; Barbitoff et al ). Most of the work was performed in rodent models that noted that NE and DβH were drastically reduced in heart, kidney, and salivary glands in spontaneously diabetic mice (Giachetti ).…”

Transcription Factor RREB1: from Target Genes towards Biological Functions

“…An intronic mutation rs3099797 in RREB1 has been identified as a candidate risk allele for T2D in Starr County Mexican-Americans [45]. In another Russian population based investigation, a coding region SNP rs9379084 (p. Asp1171Asn) in RREB1 shows strong association with T2D (p = 0.042) [46]. In 2014, a Genome-wide trans-ancestry meta-analyses containing populations from European, East Asian, South Asian, and Mexican and Mexican American ancestry discovered seven novel T2D susceptibility loci, and rs9505118 in RREB1 is one of them (p=1.4×10−9) [12].…”