Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases

Abstract

Human autoimmune diseases are thought to develop through a complex combination of genetic and environmental factors. Genome-wide linkage searches of autoimmune and inflammatory/immune disorders have identified a large number of non-major histocompatibility complex loci that collectively contribute to disease susceptibility. A comparison was made of the linkage results from 23 published autoimmune or immune-mediated disease genome-wide scans. Human diseases included multiple sclerosis, Crohn's disease, familial psoriasis, asthma, and type-I diabetes (IDDM). Experimental animal disease studies included murine experimental autoimmune encephalomyelitis, rat inflammatory arthritis, rat and murine IDDM, histamine sensitization, immunity to exogenous antigens, and murine lupus (systemic lupus erythematosus; SLE). A majority (approximately 65%) of the human positive linkages map nonrandomly into 18 distinct clusters. Overlapping of susceptibility loci occurs between different human immune diseases and by comparing conserved regions with experimental autoimmune/immune disease models. This nonrandom clustering supports a hypothesis that, in some cases, clinically distinct autoimmune diseases may be controlled by a common set of susceptibility genes.

Figure 1

Clustering of autoimmune candidate loci. Positions of PMs for autoimmune diseases that fall into clusters are to the right of each chromosome relative to their cytogenetic location found in Table 1. Solid bar, human autoimmune disease PMs; circle or circle/bar, animal disease models; Human nonautoimmune diseases are to the left of each chromosome and are denoted by triangles. MS, multiple sclerosis; CD, Crohn disease; EAE, experimental autoimmune encephalomyelitis; IA, rat inflammatory arthritis; PS, familial psoriasis; AS, asthma; IDDM, insulin-dependent diabetes (type I) (IDDM-H, human; IDDM-M, mouse; IDDM-R, rat); HR, B. pertussis-induced histamine sensitization; SLE, murine lupus; HI, humoral immunity; SZ, schizophrenia; NIDDM, non-insulin-dependent diabetes (type II); BP, bipolar disorder; LP, leptin-associated obesity; and HT, hypertension.