Aims: Diabetic nephropathy (DN) has become a serious public health problem. Genetic factors are involved in the pathogenesis of DN, but the exact mode of inheritance is still unknown. Genome-wide linkage scans (GWLS) have produced inconclusive or inconsistent results. In an effort to test consistency and provide more conclusive results, we applied a heterogeneity-based genome search meta-analysis (HEGESMA) to GWLS regarding DN.
Materials and methods: We combined results from eight GWLS in the primary analysis and nine GWLS for a conditional analysis about DN for both diabetes types, as well as in each type of diabetes and ethnicity in subgroup analyses.
Results: HEGESMA identified cytogenetic locations that rank highly on average in terms of linkage statistics across multiple genome scans, taking into consideration the magnitude of heterogeneity of the results between scans. Main analyses: Our meta-analysis identified 13 cytogenetic locations (bins) with statistical significance (Prank ≤ 0.05), 11 of which were significant in both weighted and unweighted analyses located on chromosomes 1q, 3q, 4p, 5q, 7q, 15q, 16p, 17q, 19q, and 22p. In addition, four novel regions (5q11.2-5q14.3, 5q23.2-5q34, 17q24.3-17q25.3, and 22q12.3-22q13.3) were identified. Seven bins on chromosomes 4p, 5q, 7q, 15q, 22p, and 22q were common between both types of diabetes and in all subgroup analyses, in addition 5q14.3-5q23.2 was significant across all analyses. Conditional analyses: meta-analysis identified nine different cytogenetic locations, among which 7p22.3-7p15.3 was significant only in type 2 diabetes mellitus conditional analysis. Ethnicity subgroup analyses identified 11 different cytogenetic locations, 5 out of which are novel findings. However, none of the chromosomal regions reached genome-wide statistical significance (Prank < 0.00042).
Discussion: This meta-analysis provides evidence for linkage for nine novel cytogenetic regions that should be further investigated for genes that confer susceptibility to DN.
Keywords: GSMA; HEGESMA; diabetic nephropathy; genome scan; heterogeneity; meta-analysis.