Association of the HLA-DQA1 and HLA-DQB1 Alleles in Type 2 Diabetes Mellitus and Diabetic Nephropathy in the Han Ethnicity of China

Abstract

HLA gene system is one of the most polymorphic regions of the human genome. The association of HLA class II genes in T1DM pathogenesis has been reported for several ethnicities. Associations of HLA class II genes with T2DM have revealed inconsistent results. Moreover, correlations between DN and HLA alleles remain unclear. We carried out DNA typing chip by specific medium resolution typing probes in 310 T2DM subjects (including 210 patients with DN and 100 patients without DN) in addition to 100 healthy controls. Differences were found between patients with T2DM and the control group in the frequencies of the HLA-DQA1∗0301 (15.5% versus 8.0%, P < 0.01) and the HLA-DQA1∗0501 alleles (16.6% versus 8.5%, P < 0.01). Differences were found between patients with DN and without DN in the frequencies of the HLA-DQA1∗0302 (6.9% versus 13.5%, P < 0.01) and HLA-DQB1∗0501 alleles (5.8% versus 14.5%, P < 0.01). Diabetes duration and systolic blood pressure were independent risk factors associated with DN (OR = 2.277 and 1.366, resp., P < 0.05), whereas the HLA-DQB1∗0501 llele had a protective effect on DN (OR = 0.53, P < 0.05). These data suggest the HLA-DQA1∗0301 and HLA-DQA1∗0501 alleles are markers of susceptibility for T2DM, and the HLA-DQB1∗0501 allele is associated with a protective effect on DN in Han ethnicity of China.

Functional mechanisms for diabetic nephropathy-associated genetic variants

“…Great progress has been made in the field of genetic epidemiology for the identification of genes important for DN (Hamzeh et al 2015;Ma et al 2013;Mueller et al 2006;Palmer et al 2014;Pezzolesi et al 2010;Rizvi et al 2014); and a large list of SNPs were recently compiled based on the studies from population allele association (Hamzeh et al 2015;Ma et al 2013;Palmer et al 2014;Rizvi et al 2014). However, the etiology of DN cannot be explicitly revealed unless the mechanisms of gene action underlying variation of susceptibility to DN are established.…”

“…HLA region is the locus of genes which encodes for proteins on the surface of cells that are responsible for regulation of the immune system in humans. The genes in this region are associated with autoimmune, infectious, and inflammatory diseases, such as DN, diabetes, systemic lupus erythematosus, pulmonary tuberculosis and multiple sclerosis (Alves-Leon et al 2007;Amirzargar et al 2004;Hamzeh et al 2015;Ma et al 2013;Rezaieyazdi et al 2008;Thomson et al 2007). Our results also showed that this region is important for DN.…”

“…Various research efforts are being executed worldwide to identify the susceptibility gene for DN (Hamzeh et al 2015;Ma et al 2013;Mueller et al 2006;Palmer et al 2014;Pezzolesi et al 2010;Rizvi et al 2014). Number of genetic variations has been accumulated showing robust association with DN (Hamzeh et al 2015;Ma et al 2013;Palmer et al 2014;Rizvi et al 2014).…”

“…Number of genetic variations has been accumulated showing robust association with DN (Hamzeh et al 2015;Ma et al 2013;Palmer et al 2014;Rizvi et al 2014). A key consideration is how these large-scale genetic associations are expected to yield more insight into DN.…”

“…A key consideration is how these large-scale genetic associations are expected to yield more insight into DN. This is due to the fact that these large sets of genetic data are always generated from statistical associations at the DNA level, generally without direct functional evidence regarding their association mechanisms underlying DN (Hamzeh et al 2015;Ma et al 2013;Palmer et al 2014;Rizvi et al 2014). From a biological and clinical point of view, it is still a challenge to integrate those data from genetic association analyses into a comprehensive understanding of how genetic loci are related to DN.…”