Therefore, an in-depth study of the remotely controlled regulatory mechanisms selleck chemicals Sorafenib is needed to clarify which SNPs are functional and how these genes actually influence circulating TG concentrations. Although none of the six SNPs most associated with TG actually belong to the APOA5-A4-C3-A1 gene cluster the presence of two top signals (rs964184, p=1.06��10?39 and rs7350481, p=7.52��10?26) within this LD region (stretching up to ~65.9 Kb interval in block 1) (Figure 1 and Table 6) suggests the possible presence of rare or less frequent causal variants in this region. Confirmation of positive associations in some of the strongest GWAS signals, CETP (rs3726461) with HDL-C and BUD13-ZNF259 (rs964184) with TG, in these independently ascertained non-European populations of Indian origin validate the strength of GWAS studies and their usefulness and potential to find disease loci affecting complex chronic disorders.
However, the identified genes and inter-genic variants most likely represent just the tip of the iceberg for cardiovascular risk as the overall residual variance contributed by these SNPs is <5% and even the meta-analysis ORs do not exceed 1.22. These findings suggest that rarer or less common variants which are currently invisible in GWAS may exist within these regions. Further fine mapping and targeted resequencing in these gene regions in different ethnicities, as well as functional studies, would help detection of putative loci of therapeutic significance. Methods Human Subjects- Punjabi and US Cohorts DNA and serum samples from a total of 3,781 individuals (2,902 Punjabi Cohort [52% T2D]; 879 US Cohort [16%T2D]) were studied.
The healthy control participants from the Punjabi cohort were random unrelated individuals recruited from the same Asian Indian community as the T2D patients and matched for ethnicity and geographic location. The US subjects were recruited through public advertisement as part of a population-based study involving free health screening for cardiovascular risk factors. The individuals with mixed ancestry or non-Asian Indian ancestry were not enrolled. Two third of the participants from the US cohort were originally from the state of Punjab, and the remaining one third were from other western and southern states of India. Men and women aged 25�C79 years participated.
The diagnoses of T2D were confirmed by reviewing medical records for symptoms, use of medication, and measuring FBG levels following the guidelines of the American Diabetes Association (2004) [38], as described in detail previously [39]. A medical record indicating either (1) a FBG Dacomitinib ��126 mg/dL or ��7.0 mmol/L after a minimum 12 h fast or (2) a 2 h post-glucose level (2 h oral glucose tolerance test) ��200 mg/dL or ��11.1 mmol/L on more than one occasion, combined with symptoms of diabetes, confirmed the diagnosis.