Abstract
In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using Sall statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.
Highlights
Type 2 diabetes (T2D) is a major public health problem of 21st century and the fifth leading cause of death worldwide
This study has identified linkage regions, primarily high-density lipoprotein (HDL) cholesterol (10q21.1–21.2) and total cholesterol (22q13.32) that were previously reported for lipid traits or cardiovascular disease (CVD)
Our genome-wide linkage scan could not identify any significant chromosomal region associated with T2D in this unique family cohort of Punjabi Sikhs with increased risk to developing T2D and cardiovascular illnesses
Summary
Type 2 diabetes (T2D) is a major public health problem of 21st century and the fifth leading cause of death worldwide. According to Global Burden of Disease Study predictions, India, China and USA will be the top three leading countries for the prevalence of diabetes [1]. The approximate estimate of 31.7 million people with diabetes in India in 2000 will increase to 79.4 million by year 2030 and the size of the USA population with diabetes, both diagnosed and undiagnosed, will rise from approximately 30 million to 44 million by the year 2030 [2]. Linkage and candidate-gene focused studies successfully identified some rare forms of T2D controlled by one or two genes such as the various forms of maturity onset diabetes of young (MODY), mitochondrial diabetes, and neonatal diabetes. No single locus was noted to have strong and consistent evidence of linkage with the most common form of T2D in multiple populations [3]
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